PL203687B1 - Compounds from the group of diphenylureas, pharmaceutical compositions containing them and their use - Google Patents

Compounds from the group of diphenylureas, pharmaceutical compositions containing them and their use

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Publication number
PL203687B1
PL203687B1 PL360085A PL36008500A PL203687B1 PL 203687 B1 PL203687 B1 PL 203687B1 PL 360085 A PL360085 A PL 360085A PL 36008500 A PL36008500 A PL 36008500A PL 203687 B1 PL203687 B1 PL 203687B1
Authority
PL
Poland
Prior art keywords
phenyl
trifluoromethyl
chloro
urea
pyridyloxy
Prior art date
Application number
PL360085A
Other languages
Polish (pl)
Other versions
PL360085A1 (en
Inventor
Riedl Bernd
Dumas Jacques
Khire Uday
B. Lowinger Timothy
J. Scott William
A. Smith Roger
E. Wood Jill
Monahan Mary-Katherine
Natero Reina
Renick Joel
N. Sibley Robert
Original Assignee
Bayer Corporation
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
Application filed by Bayer Corporation filed Critical Bayer Corporation
Priority claimed from PCT/US2000/000648 external-priority patent/WO2000042012A1/en
Publication of PL360085A1 publication Critical patent/PL360085A1/en
Publication of PL203687B1 publication Critical patent/PL203687B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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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    • A61K31/395—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
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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
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    • 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
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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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
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    • 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
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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
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    • 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
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    • C07C275/40—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 nitrogen atoms not being part of nitro or nitroso groups
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Description

Opis wynalazku Przedmiotem wynalazku s a nowe zwi azki z grupy difenylomoczników, kompozycje farmaceu- tyczne zawieraj ace te zwi azki oraz ich zastosowanie. Zwi azki znajduj a zastosowanie w przemy sle farmaceutycznym do wytwarzania kompozycji farma- ceutycznych i leków, zw laszcza do leczenia chorób nowotworowych w których po sredniczy kinaza raf. Onkogen p21 ras jest g lównym czynnikiem uczestnicz acym w rozwoju i post epie ludzkich raków litych i jest zmutowany w 30% wszystkich ludzkich raków (Bolton i in. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). W swojej normalnej, niezmutowanej formie, bia lko ras jest klu- czowym elementem kaskady sygna lu transdukcji ukierunkowanej przez receptory czynnika wzrostu w prawie wszystkich tkankach (Avruch i in. Trends Biochem. Sci. 1994, 19, 279-83). Biochemicznie, ras jest bia lkiem wiaz acym nukleotyd guanin e i obieg pomi edzy form a aktywn a zwi azan a z GTP i spo- czynkow a zwi azan a z GDP jest dok ladnie kontrolowany przez aktywno sc endogennej GTPazy, jak a posiada bia lko ras i inne bia lka regulatorowe. W mutantach ras w komórkach rakowych, aktywno sc endogennej GTPazy jest z lagodzona, a wi ec bia lko dostarcza konstytucyjnych sygna lów wzrostu pod- legaj acym mu efektorom takim jak enzym kinaza raf. To prowadzi do rakowatego wzrostu komórek, które zawieraj a te mutanty (Magnuson i in. Sernin. Cancer Biol. 1994, 5, 247-53). Wykazano, ze ha- mowanie wp lywu aktywnego bia lka ras przez hamowanie szlaku sygna lowego kinazy raf metod a po- dawania dezaktywuj acych przeciwcia l dla kinazy raf lub metod a koekspresji dominuj acej negatywnej kinazy raf lub dominuj acej negatywnej MEK, substratu kinazy raf, prowadzi do powrotu transformowa- nych komórek do normalnego fenotypu wzrostowego (patrz: Daum i in. Trends Biochem. Sci. 1994, 19, 474-80; Fridman i in. J. Biol. Chem. 1994, 269, 30105-8. Kolch i in. (Nature 1991, 349, 426-28) wskazali nast epnie, ze hamowanie ekspresji raf przez antysensowny RNA blokuje proliferacj e komór- kow a okogenów zwi azanych z b lon a. Podobnie, hamowanie kinazy raf (przez antysensowne oligode- oksynukleotydy) skorelowano in vitro i in vivo z hamowaniem wzrostu rozmaitych typów guzów ludz- kich (Monia i in., Nat. Med. 1996, 2, 668-75). Przedmiotem niniejszego wynalazku s a wi ec zwi azki, które s a inhibitorami enzymu kinazy raf. Poniewa z ten enzym jest efektorem podlegaj acym p21 ras , inhibitory s a przydatne w kompozycjach farma- ceutycznych stosowanych do wytwarzania leków do leczenia ludzi lub zwierz at tam, gdzie jest wska- zane hamowanie szlaku kinazy raf, np. w leczeniu guzów i/lub wzrostu komórek rakowatych, w którym po sredniczy kinaza raf. W szczególno sci, zwi azki s a przydatne do wytwarzania leków do leczenia ludzkich lub zwierz ecych raków litych, np. raka u myszy, poniewa z post ep tych schorzen zale zy od kaskady sygna lu transdukcji bia lka ras, a wi ec jest podatny na leczenie metod a przerwania kaskady, tj. metod a hamowania kinazy raf. Zgodnie z tym, zwi azki wed lug wynalazku s a przydatne w leczeniu raków obejmuj acych raki lite, takie jak np. raki (np. p luc, trzustki, tarczycy, p echerza lub okr eznicy), zaburzenia szpikowe (np. bia laczka szpikowa) lub gruczolaki (np. gruczolak kosmkowy okreznicy). Niniejszy wynalazek obejmuje wi ec zwi azki na ogó l opisane jako arylomoczniki, a dok ladniej jako di- fenylomoczniki, które hamuj a szlak kinazy raf. Wynalazek obejmuje tak ze zastosowanie tych zwi azków do wytwarzania leków do leczenia stanów chorobowych, w których po sredniczy kinaza raf u ludzi lub ssaków. Tak wi ec, przedmiotem wynalazku s a zwi azki, które hamuj a enzym kinaz e raf, oraz kompo- zycje farmaceutyczne zawieraj ace te zwi azki wraz z fizjologicznie dopuszczalnym no snikiem, a tak ze zastosowanie zwi azków do wytwarzania leków do leczenia rakowatego wzrostu komórek, w którym po sredniczy kinaza raf, gdy podaje si e dany zwi azek lub jego farmaceutycznie dopuszczaln a sól. Istot a wynalazku jest nowy zwi azek chemiczny wybrany z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N- (4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik,PL 203 687 B1 3 N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalna sól. Korzystne jest, gdy farmaceutycznie dopuszczaln a sol a jest sól wybrana z grupy obejmuj acej a) zasadowe sole kwasów organicznych i kwasów nieorganicznych wybranych z grupy obejmu- jacej kwas chlorowodorowy, kwas bromowodorowy, kwas siarkowy, kwas fosforowy, kwas meta- nosulfonowy, kwas trifluorosulfonowy, kwas benzenosulfonowy, kwas p-toluenosulfonowy (tosylan), kwas 1-naftalenosulfonowy, kwas 2-naftalenosulfonowy, kwas octowy, kwas trifluorooctowy, kwas jab lkowy, kwas winowy, kwas cytrynowy, kwas mlekowy, kwas szczawiowy, kwas bursztynowy, kwas fumarowy, kwas maleinowy, kwas benzoesowy, kwas salicylowy, kwas fenylooctowy i kwas migda lowy; i b) kwa sne sole organicznych i nieorganicznych zasad zawieraj ace kationy wybrane z grupy obejmuj acej kationy metali alkalicznych, kationy metali ziem alkalicznych, kation amonowy, alifatycz- nie podstawiony kation amoniowy i aromatycznie podstawiony kation amoniowy. Kompozycja farmaceutyczna zawieraj aca substancj e aktywn a oraz fizjologicznie dopuszczalny no snik, wedlug wynalazku charakteryzuje si e tym, ze zawiera zwi azek wybrany z wymieniony powy zej grupy lub jego farmaceutycznie dopuszczaln a sól. Dla zwi azku wed lug wynalazku korzystne jest, gdy jest on wybrany z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub gdy jest nim jego farmaceutycznie dopuszczalna sól, a zw laszcza gdy sól wybrana jest z grupy obejmuj acej a) zasadowe sole kwasów organicznych i kwasów nieorganicznych wybranych z grupy obejmu- jacej kwas chlorowodorowy, kwas bromowodorowy, kwas siarkowy, kwas fosforowy, kwas meta- nosulfonowy, kwas trifluorosulfonowy, kwas benzenosulfonowy, kwas p-toluenosulfonowy (tosylan), kwas 1-naftalenosulfonowy, kwas 2-naftalenosulfonowy, kwas octowy, kwas trifluorooctowy, kwas jab lkowy, kwas winowy, kwas cytrynowy, kwas mlekowy, kwas szczawiowy, kwas bursztynowy, kwas fumarowy, kwas maleinowy, kwas benzoesowy, kwas salicylowy, kwas fenylooctowy i kwas migda lowy; i b) kwa sne sole organicznych i nieorganicznych zasad zawieraj ace kationy wybrane z grupy obejmuj acej kationy metali alkalicznych, kationy metali ziem alkalicznych, kation amonowy, alifatycz- nie podstawiony kation amoniowy i aromatycznie podstawiony kation amoniowy. Korzystna kompozycja farmaceutyczna wed lug wynalazku, zawieraj aca substancj e aktywn a oraz fizjologicznie dopuszczalny no snik, charakteryzuje si e tym, ze substancj a aktywn a jest zwi azek wybrany z wymienionej korzystnej grupy zwi azków lub jego farmaceutycznie dopuszczalna sól. Wynalazek obejmuje tak ze zastosowanie zwi azków wed lug wynalazku. Zastosowanie wed lug wynalazku charakteryzuje si e tym, ze zwi azek wybrany z grupy obejmuj acej 4-chloro-3-(trifluorometylo)fenylomoczniki: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik,PL 203 687 B1 4 4-bromo-3-(trifluorometylo)fenylomoczniki: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczniki: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalna sól, stosuje si e do wytwarzania leku do leczenia rozwoju ra- kowatych komórek, w którym po sredniczy kinaza raf. Inne zastosowanie zwi azku wybranego z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-piydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalnej sli, charakteryzuje si e tym, ze stosuje si e go do wytwarzania leku do leczenia raka p luc, trzustki, tarczycy, p echerza, okreznicy, przewlek lej bia laczki szpikowej, lub kosmkowego gruczolaka okr eznicy. Jeszcze inne zastosowanie zwi azku wybranego z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników:PL 203 687 B1 5 N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, charakteryzuje si e tym, ze stosuje si e go do wytwarzania leku do leczenia nowotworów. Korzystne jest zastosowanie zwi azku wed lug wynalazku, wybranego z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fe- nylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydylo- ksy))fenylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia rozwoju rakowatych komórek, w którym po sredniczy kinaza raf. Inne korzystne zastosowanie zwi azku, wybranego z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, jest wtedy, gdy jest on stosowany do wytwarzania leku do leczenia raka p luc, trzustki, tarczycy, p echerza, okr eznicy, przewlek lej bia laczki szpikowej, lub kosmkowe- go raka okr eznicy. Jeszcze inne korzystne zastosowanie zwi azku wybranego z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, jest wtedy, gdy jest on stosowany do wytwarzania leku do leczenia nowotworów. Dla zwi azku wed lug wynalazku najkorzystniej jest, gdy jest nim N-(4-chloro-3-(trifluorometylo)- fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, albo gdy jest nim N-(4-chloro-3-(trifluorometylo)- fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik. Dla kompozycji farmaceutycznej wed lug wynalazku, zawieraj acej substancj e aktywn a oraz fizjo- logicznie dopuszczalny no snik, najkorzystniej jest, gdy kompozycja, jako substancj e aktywn a zawiera N- -(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik lub jego farmaceu- tycznie dopuszczaln a sól, albo gdy kompozycja, jako substancj e aktywn a zawiera N-(4-chloro-3-(trifluoro- metylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik lub jego farmaceutycznie dopuszczaln a sól. Dla zastosowania wed lug wynalazku najkorzystniej jest, gdy do wytwarzania leku do leczenia roz- woju rakowatych komórek, w którym po sredniczy kinaza raf, stosuje si e N-(4-chloro-3-(trifluorometylo)- fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, albo N-(4-chloro-3-(trifluorometylo)fenylo)- -N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik.PL 203 687 B1 6 Szereg zwi azków wed lug wynalazku mo ze posiada c asymetryczne atomy w egla i mo ze zatem wyst epowa c w racemicznych i optycznie czynnych postaciach. Metody rozdzielania enancjome- rycznych i diastereomerycznych mieszanin s a dobrze znane fachowcom w dziedzinie. Zwi azki wed lug wynalazku mo zna mo zna wytworzy c stosuj ac ogólne metody preparatywne oraz znane reakcje i metody chemiczne, przy czym niektóre z substancji wyj sciowych s a dost epne na ryn- ku. Niemniej jednak poni zej przedstawiono ogólne metody preparatywne aby pomóc fachowcom w dziedzinie w syntetyzowaniu tych zwi azków, a bardziej szczegó lowe przyk lady przedstawiono dalej w czes c do swiadczalnej. Podstawione aniliny mo zna wytwarza c stosuj ac standardowe metody (March. Advanced Orga- nie Chemistry, Wydanie 3.; John Wiley: New York (1985). Larock. Comprehensive Organic Trans- formations; VCH Publishers: New York (1989)). Jak pokazano w Schemacie I, aryloaminy powszech- nie syntetyzuje si e przez redukcj e nitryli z zastosowaniem katalizatora metalicznego, takiego jak Ni, Pd, lub Pt, i H 2 lub srodka przenosz acego wodór, takiego jak mrówczan, cykloheksadien lub borowo- dorek (Rylander, Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryle mo zna tak ze bezpo srednio redukowa c stosuj ac silne zród lo wodoru, takie jak LiAlH 4 (Seyden-Penne. Re- ductions by the Alumino- i Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), lub stosuj ac zerowarto sciowy metal, taki jak Fe, Sn lub Ca, cz esto w kwasowym srodowisku. Znanych jest wiele metod syntezy nitryli (March. Advanced Organic Chemistry, Wydanie 3.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). (np. Fe, Sn, Ca) Schemat I. Redukcja nitroaryli do aryloaminy Nitroaryle powszechnie wytwarza si e przez elektrofilowe aromatyczne nitrowanie z zastosowa- niem HNO 3 lub alternatywnego zród la NO 2 - . Nitroaryle mo zna nast epnie podda c obróbce przed reduk- cja. Tak wi ec, nitroaryle podstawione przez potencjalne grupy opuszczajace (np. F, Cl, Br, itp.) mo zna podda c reakcjom podstawienia dzia laj ac nukleofilem, takim jak tiolan (co przedstawia przyk ladowo Schemat II) lub fenolanem. Nitroaryle mog a tak ze podlega c reakcjom sprz egania typu Ullmana (Schemat II). Schemat II. Wybrane nukleofilowe podstawienie aromatyczne z zastosowaniem nitroaryli Nitroaryle mo zna tak ze poddawa c reakcjom wzajemnego sprz egania za po srednictwem metalu przej sciowego. Np. nitroarylowe elektrofile, takie jak nitrobromki arylu, jodki lub triflaty, podlegaj a reak- cjom wzajemnego sprz egania za po srednictwem palladu z zastosowaniem arylowych nukleofili, takichPL 203 687 B1 7 jak kwasy aryloboronowe (reakcje Suzuki przedstawione przyk ladowo poni zej), arylocyny (reakcje Stille'a) lub arylocynki (Negishi reakcja) z wytworzeniem biarylu (5). Nitroaryle lub aniliny mo zna przekszta lcic w odpowiedni zwi azek arenosulfonylu (7) dzia laj ac kwasem chlorosulfonowym. Reakcja chlorku sulfonylu ze zród lem fluorku, takim jak KF prowadzi do fluorku sulfonylu (8). Reakcja fluorku sulfonylu 8 z trimetylosililotrifluorometanem w obecno sci zród la fluorku, takiego jak tris(dimetyloamino) difluorotrimetylosilikonian sulfoniowy (TASF) prowadzi do odpowiedniego trifluorometylosulfonu (9). Alternatywnie, chlorek sulfonylu 7 mo zna zredukowa c do arenotiolu (10), np. stosuj ac amalgamat cynku. Reakcja tiolu 10 z CHCIF 2 w obecno sci zasady daje merkaptan difluorometylowy (11), który mo zna utleni c do sulfonu (12) stosuj ac dowolny z rozmaitych utleniaczy, w tym bezwodnik CrO 3 -octowy (Sedova i in. Zh. Org. Khim. 1970, 6, (568). Schemat III. Wybrane metody syntezy fluorowanego arylosulfonu Jak pokazano na Schemacie IV, wytworzenie niesymetrycznego mocznika mo ze wymaga c re- akcji izocyjanianu arylu (14) z aryloamin a (13). Heteroaryloizocyjanian mo zna zsyntetyzowa c z hete- roaryloaminy dzia laj ac fosgenem lub jego odpowiednikiem, takim jak chloromrówczan trichlorometylu (difosgen), w eglan bis(trichlorometylu) (trifosgen), lub N,N'-karbonylodiimidazol (CDI). Izocyjanian mo zna tak ze wytwarza c metod a przegrupowania typu Curtiusa z pochodnej heterocyklicznego kwasu karboksylowego, takiej jak ester, kwas fluorowcowodorowy lub bezwodnik. Tak wi ec, reakcja pochod- nej kwasu 16 ze zród lem azydku, a nast epnie przegrupowanie daje izocyjanian. Odpowiedni kwas karboksylowy (17) mo zna tak ze podda c przegrupowaniu typu Curtiusa stosuj ac azydek difenylofosfo- rylu (DPPA) lub podobny reagent.PL 203 687 B1 8 Schemat IV. Wybrane metody wytwarzania niesymetrycznego mocznika Na koniec, moczniki mo zna nast epnie przetwarza c stosuj ac metody znane fachowcom w dzie- dzinie. Kompozycje farmaceutyczne zawieraj ace zwi azki wed lug wynalzku i fizjologicznie dopuszczalny no snik, mo zna podawa c doustnie, miejscowo, pozajelitowo, inhalacyjnie lub w spraju albo doodbytni- czo w preparatach jednostkowej postaci dawkowania. Termin „podawanie przez iniekcj e” obejmuje iniekcje do zylne, domi esniowe, podskórne i pozajelitowe, jak równie z zastosowanie techniki wlewu. Jeden lub kilka zwi azków mo ze wyst epowa c wspólnie z jednym lub wi ecej nietoksycznym farmaceu- tycznie dopuszczalnym no snikiem i, je sli to po zadane, innymi aktywnymi sk ladnikami. Kompozycje przeznaczone do doustnego zastosowania mo zna wytworzy c dowoln a odpowied- ni a metod a znan a w dziedzinie dla wytwarzania kompozycji farmaceutycznych. Takie kompozycje mog a zawiera c jeden lub wi ecej srodków wybranych z grupy obejmuj acej rozcie nczalniki, srodki s lo- dz ace, srodki smakowe, srodki barwi ace i srodki konserwuj ace stosowane do otrzymywania apetycz- nych preparatów. Tabletki zawieraj a aktywny sk ladnik w mieszance z nietoksycznymi farmaceutycznie dopuszczalnymi rozczynnikami, odpowiednimi do wytwarzania tabletek. Takimi rozczynnikami mog a by c np. oboj etne rozcie nczalniki, takie jak w eglan wapnia, w eglan sodu, laktoza, fosforan wapnia lub fosforan sodu; srodki granuluj ace i rozdrabniaj ace, jak np. skrobia kukurydziana lub kwas alginowy; i srodki wiaz ace, np. stearynian magnezu, kwas stearynowy lub talk. tabletki mog a by c niepowlekane lub mog a by c powleczone znanymi technikami w celu opó znienia rozdrobnienia i adsorpcji w przewo- dzie zo ladkowo-jelitowym i tym samym zapewniaj a one przed lu zone dzia lanie w d lu zszym okresie czasu. Np. mo zna stosowa c substancj e opó zniaj ac a tak a jak monostearynian glicerylu lub distearynian glicerylu. Te zwi azki mo zna tak ze wytwarza c w sta lej, szybko uwalnianej postaci. Preparaty do doustnego zastosowania mog a tak ze wyst epowa c w postaci twardych zelatyno- wych kapsu lek, w których aktywny sk ladnik jest zmieszany z oboj etnym sta lym rozcie nczalnikiem, jak np. w eglan wapnia, fosforan wapnia lub kaolin, lub w postaci mi ekkich zelatynowych kapsu lek, w któ- rych aktywny sk ladnik jest zmieszany z wod a lub oleistym medium, jak np. olej arachidowy, ciek la parafina lub oliwa z oliwek. Wodne zawiesiny zawieraj a aktywne substancje w mieszance z rozczynnikami odpowiednimi do wytwarzania wodnych zawiesin. Takimi rozczynnikami s a srodki zawieszaj ace, np. sól sodowa karboksy- metylocelulozy, metyloceluloza, hydroksypropylometyloceluloza, alginian sodu, poliwinylopirolidon, guma tragakantowa i guma arabska; srodki dysperguj ace lub zwil zaj ace mog a by c naturalnie wyst e- puj acym fosfatydem, jak np. lecytyna, lub produktami kondensacji tlenku alkilenu z kwasem t luszczo- wym, jak np. stearynian polioksyetylenu, lub produktami kondensacji tlenku etylenu z d lugo la ncucho- wymi alifatycznymi alkoholami, jak np. heptadekaetyleno-oksycetanol, lub produktami kondensacji tlenku etylenu z cz esciowymi estrami pochodz acymi z kwasu t luszczowego i heksytolu takimi jak po- lioksyetylen - monooleinian sorbitolu, lub produktami kondensacji tlenku etylenu z cz esciowymi estra- mi pochodz acymi z kwasu t luszczowego i bezwodników heksytolu, jak np. polietylen - monooleinian sorbitolu. Wodne zawiesiny mog a tak ze zawiera c jeden lub wi ecej srodków konserwuj acych, jak np.PL 203 687 B1 9 p-hydroksybenzoesan etylu lub n-propylu, jeden lub wi ecej srodków barwi acych, jeden lub wi ecej srodków smakowych, i jeden lub wi ecej srodków s lodz acych, takich jak sacharoza lub sacharyna. Dyspergowalne proszki i granulki odpowiednie do otrzymywania wodnej zawiesiny przez doda- nie wody, zawieraj a aktywny sk ladnik w mieszance ze srodkiem dysperguj acym lub zwil zaj acym, srodkiem zawieszaj acym i jednym lub wiecej srodkami konserwuj acymi. Odpowiednie srodki dysper- guj ace lub zwil zaj ace i srodki zawieszaj ace przedstawiaj a przyk ladowo srodki ju z wymienione powy- zej. Mog a tak ze wyst epowa c dodatkowe rozczynniki, np. srodki s lodz ace, smakowe i barwi ace. Zwi azki mog a tak ze wyst epowa c w postaci niewodnych ciek lych preparatów, np. oleistych za- wiesin, które mo zna komponowa c przez zawieszenie aktywnych sk ladników w oleju ro slinnym, jak np. olej z orzeszków ziemnych, oliwa z oliwek, olej sezamowy lub olej arachidowy, lub w oleju mineralnym takim jak ciek la parafina. Oleiste zawiesiny mog a zawiera c srodek zag eszczaj acy, jak np. wosk pszczeli, twarda parafina lub alkohol cetylowy. W celu uzyskania apetycznych preparatów doustnych mo zna dodawa c srodki s lodz ace i smakowe takie jak przedstawiono powy zej. Kompozycje te mo zna zabezpieczy c przez dodanie przeciwutleniacza takiego jak kwas askorbinowy. Kompozycje farmaceutyczne wed lug wynalazku mog a tak ze wyst epowa c w postaci emulsji typu olej w wodzie. Oleist a faz e mo ze stanowi c olej ro slinny, np. oliwa z oliwek lub olej z orzeszków ziem- nych, lub olej mineralny, jak np. ciek la parafina lub ich mieszaniny. Odpowiednimi srodkami zawiesza- jacymi mog a by c naturalnie wyst epuj ac gumy, jak np. guma arabska lub guma tragakantowa, natural- nie wyst epuj ac fosfatydy, np. fasola sojowa, lecytyna, i estry lub cz esciowe estry pochodz ace z kwasu t luszczowego i bezwodników hehsytol, jak np. monooleinian sorbitolu, i produkty kondensacji tych cz esciowych estrów z tlenkiem etylenu, jak np. polioksyetylen - monooleinian sorbitolu. Emulsje mog a tak ze zawiera c srodki s lodz ace i smakowe. Syropy i eliksiry mo zna komponowa c z zastosowaniem srodków s lodz acych, jak np. glicerol, glikol propylenowy, sorbitol lub sacharoza. Takie preparaty mog a tak ze zawiera c srodek lagodz acy, srodek konserwuj acy i smakowy i srodki barwi ace. Zwi azki mo zna te z podawa c w postaci czopków do doodbytniczego podawania leku. Te kom- pozycje mo zna wytworzy c przez zmieszanie leku z odpowiednim niedra zni acym rozczynnikiem, który jest w stanie sta lym w zwyk lych temperaturach, lecz ciek lym w temperaturze odbytu, a wi ec takim, który topi si e w odbycie z uwolnieniem leku. Takie substancje obejmuj a mas lo kakaowe i glikole poli- etylenowe. We wszystkich re zimach podawania ujawnionych tu zwi azków, dzienna doustna dawka b edzie korzystnie wynosi c od 0,01 do 200 mg/kg ca lkowitej masy cia la. Dzienne dawkowanie do podawania metod a iniekcji, obejmuj acej iniekcje do zylne, domi esniowe, podskórne i pozajelitowe, oraz zastoso- wanie techniki wlewu, b edzie korzystnie wynosi lo od 0,01 do 200 mg/kg ca lkowitej masy cia la. Dzien- ny re zim dawkowania doodbytniczego b edzie korzystnie wynosi l od 0,01 do 200 mg/kg ca lkowitej masy cia la. Dzienna re zim miejscowego dawkowania b edzie korzystnie wynosi l od 0,1 do 200 mg przy podawaniu pomi edzy jeden do sze sciu razy dziennie. Dzienna re zim dawkowania inhalacyjnego b e- dzie korzystnie wynosi l od 0,01 do 10 mg/kg ca lkowitej masy cia la. Fachowcy w dziedzinie doceni a, ze poszczególna metoda podawania b edzie zale za la od roz- maitych czynników, przy czym wszystkie s a rozwa zane rutynowo przy podawaniu srodków terapeu- tycznych. Fachowcy w dziedzinie doceni a te z, ze specyficzny poziom dawkowania dla danego pacjen- ta zale zy od rozmaitych czynników, obejmujacych aktywno sc specyficznego, podawanego zwi azku, wiek, mas e cia la, stan zdrowia, p le c, diet e, czas i sposób podawania, .szybko sc wydalania, itp. Nale zy ponadto zwróci c uwag e, ze optymalny przebieg leczenia, tj. sposób leczenia i dzienna liczba dawek zwi azku o wzorze I lub jego farmaceutycznie dopuszczalnej soli, podana dla okre slonej liczby dni, mo ze by c potwierdzona przez fachowców w dziedzinie z zastosowaniem typowych testów medycznych. Zrozumia le b edzie jednak, ze specyficzny poziom dawkowania dla dowolnego, poszczególnego pacjenta, b edzie zale za l od rozmaitych czynników, obejmuj acych takie jak aktywno sc specyficznego, stosowanego zwi azku, wiek, mas e cia la, ogólny stan zdrowia, p le c, dieta, czas podawanie, sposób podawania i szybko sc wydalania, kombinacja leków i zaawansowanie stanu chorobowego leczonego. Zwi azki wed lug wynalazku mo zna wytworzy c stosuj ac znane reakcje i metody chemiczne, przy czym niektóre z substancji wyj sciowych s a dost epne na rynku. Zwi azki mo zna wytwarza c ze znanych zwi azków (lub z substancji wyj sciowych, które z kolei mo zna wytwarza c ze znanych zwi azków), np. stosuj ac ogólne metody preparatywne przedstawione poni zej. Aktywno sc danego zwi azku co do ha- mowania kinazy raf mo zna potwierdzi c rutynowo, np. metodami ujawnionymi w dalszej cz esci opisu.PL 203 687 B1 10 Szczegó lowe przyk lady otrzymywania zwi azków przedstawiono poni zej w cz es c do swiadczal- nej. Przyk lady podano jedynie dla ilustracji i nie s a one przeznaczone, ani nie powinny by c skonstru- owane w celu ograniczenia wynalazku w jakikolwiek sposób. Wszystkie reakcje przeprowadzono w osuszonej p lomieniem lub w piecu aparaturze szklanej pod dodatnim ci snieniem suchego argonu lub suchego azotu, i z zastosowaniem mieszania magne- tycznego, je sli nie wskazano tego inaczej. Wra zliwe ciecze i roztwory przenoszono strzykawk a lub rurk a i wprowadzano do naczynia reakcyjnego poprzez gumow a przegrod e. Je sli nie wskazano ina- czej, termin „zatezenie pod zmniejszonym ci snieniem” odnosi si e do zastosowania wyparki obrotowej Buchi'ego przy ci snieniu w przybli zeniu 15 mmHg. Je sli nie wskazano inaczej, termin pod silnie zmniejszonym ci snieniem' odnosi si e do pró zni 0,4 - 1,0 mmHg. Wszystkie temperatury przedstawiono jako niekorygowane i w stopniach Celsjusza (°C). Je sli nie wskazano tego inaczej, wszystkie czesci i procenty podano wagowo. Reagenty i rozpuszczalniki o czysto sci technicznej stosowano bez dalszego oczyszczania. N-cykloheksylo-N'-(metylopolistyreno)karbodiimid zakupiono w Calbiochem-Novabiochem Corp. 3-tert- -butyloanilin e, 5-tert-butylo-2-metoksyanilin e, 4-bromo-3-(trifluorometylo)anilin e, 4-chloro-3-(trifluorome- tylo)anilin e 2-metoksy-5-(trifluorometylo)-anilin e, 4-tert-butylo-2-nitroanilin e, 3-amino-2-naftol, 4-izocyjana- tobenzoesan etylu, N-acetylo-4-chloro-2-metoksy-5-(trifluorometylo)anilin e i izocyjanian 4-chloro-3- -(trifluorometylo)fenylu zakupiono i u zyto bez dalszego oczyszczania. Syntezy 3-amino-2-metoksychino- liny (E. Cho i in. WO 98/00402; A. Cordi i in. EP 542,609; IBID Bioorg. Med. Chem., 3, 7995, 129), 4-(3-karbamoilfenoksy)-1-nitrobenzenu (K. Ikawa Yakugaku Zasshi 79, 7959, 760; Chem. Abstr. 53, 7959, 12761b), izocyjanianu 3-tert-butylofenylu (O. Rohr i in. DE 2,436,108) i izocyjanianu 2-metoksy- -5-(trifluorometylo)fenylu (K. Inukai i in. JP 42025067; IBID Kogyo Kagaku Zasshi 70, 7967, 491) zo- staly uprzednio opisane. Chromatografi e cienkowarstwow a (TLC) przeprowadzono na p lytkach szklanych Whatman® pokrytych fabrycznie zelem krzemionkowym 60A F-254, grubo sc ziarna 250 µm. Wizualizacj e p lytek przeprowadzono jedn a lub wi ecej z nast epuj acych technik: (a) na swietlanie ultrafioletem, (b) poddanie dzia laniu par jodu, (c) zanurzenie p lytki w 10%-owym roztworze kwasu fosforomolibdenowego w eta- nolu i nast epnie ogrzewanie, (d) zanurzenie p lytki w roztworze siarczanu ceru, a nast epnie ogrzewa- nie, i/lub (e) zanurzenie p lytki w kwa snym etanolowym roztworze 2,4-dinitrofenylohydrazyny, a na- st epnie ogrzewanie. Szybk a (flash) chromatografi e kolumnow a przeprowadzono stosuj ac zel krze- mionkowy 230-400 mesh EM Science®. Temperatury topnienia (t.t.) okre slono stosuj ac aparat Thomasa-Hoovera do pomiaru tempera- tury topnienia lub aparat Mettler FP66 do automatycznego pomiaru temperatury topnienia i temperatur nie korygowano. Widma w podczerwieni z transformacj a Fouriera zarejestrowano na spektrofotome- trze Mattson 402 0 Galaxy Series. Widma protonowego ( 1 H) magnetycznego rezonansu j adrowego (NMR) zarejestrowano na spektrometrze General Electric GN-Omega 300 (300 MHz) z zastosowa- niem jako wzorca albo Me 4 Si ( d 0,00) lub sygna lów od resztowych protonów rozpuszczalnika (CHCI 3 d 7,26; MeOH d 3,30; DMSO d 2,49). Widmo w eglowego ( 13 C) magnetycznego rezonansu j adrowego (NMR) zarejestrowano na spektrometrze General Electric GN-Omega 300 (75 MHz) z zastosowaniem jako wzorca sygna lów od rozpuszczalnika (CDCI 3 d 77,0; MeOD-d 6 d 49,0; DMSO-d 6 8 39,5). Widma masowe niskorozdzielcze (MS) i wysokorozdzielcze (HRMS) wykonywano technik a jonizacji elektro- nami (El) i technik a bombardowania szybkimi atomami (FAB). Widma masowe (EI-MS) z jonizacj a elektronami otrzymano na spektrometrze masowym Hewlett Packard 5989A zaopatrzonym w sond e do wprowadzania próbek i przeprowadzania jonizacji chemicznej przez desorpcj e (Vacumetrics De- sorption Chemical Ionization Probe). Zród lo jonów utrzymywano w temperaturze 250°C. Jonizacj e w wi azce elektronów przeprowadzano przy energii elektronów 70 eV i pr adzie wychwytywania 300 µA. Spektrometri e masow a jonów wtórnych w ciek lej matrycy cezowej (Liquid-cesium Secondary Ion Mass Spectrometry) (FAB-MS), wed lug unowocze snionej wersji bombardowania szybkimi atomami wykona- no na spektrometrze Kratos Concept 1-H. Widmo masowe jonizacji chemicznej (CI-MS) zarejestrowa- no na przyrz adzie Hewlett Packard MS-Engine (5989A) z zastosowaniem metanu lub amoniaku jako gazów reaguj acych (1 x 10 -4 torr do 2,5 x 10 -4 torr). Sond e do bezpo sredniego przeprowadzania jonizacji chemicznej przez desorpcj e chemiczn a (DCI) (Vaccumetrics, Inc.) doprowadzono od 0-1,5 do 10 amps przez 10 sek i trzymano w 10 amps a z do zaniku sladowych ilo sci próbki (~1-2 min). Widma skanowa- no od 50-800 razy przy czasie jednej rejestracji wynosz acym 2 sekundy. Chromatografi e HPLC sprz e- zon a ze spektrometria masow a wykonywan a technik a elektrospreju (HPLC ES-MS) wykonywano na przyrz adzie Hewlett-Packard 1100 HPLC zaopatrzonym w poczwórn a pomp e, detektor o zmiennejPL 203 687 B1 11 d lugo sci fal, kolumn e C-18 i wychwytuj acy jony spektrometr masowy Finnigan LCQ do techniki elekto- spre-ju. Widma skanowano od 120-800 razy stosuj ac zmienny czas jonizacji zgodnie z liczb a jonów w zródle. Chromatografie gazow a sprz ezon a z selektywn a spektrometi a masow a (GC-MS) wykony- wano na chromatografie gazowym Hewlett Packard 5890 zaopatrzonym w kolumn e metylosilikonow a HP-1 (pow loka 0,33 µM; 25 mx 0,2 mm) i selektywny detektor masowy model Hewlett Packard 5971 (energia jonizacji 70 eV). Analizy elementarne wykonano w Robertson Mikrolit Labs, Madison NJ. Wszystkie zwi azki dawa ly widmo NMR, LRMS i wyniki analizy elementarnej lub HRMS zgodne z przypisanymi strukturami. Lista skrótów i akronimów: AcOH kwas octowy anh bezwodny atm atmosfera (atmosfery) BOC tert-butoksykarbonyl CDI 1,1'-karbonylodiimidazol conc zat ezono d dzie n (dni) dec rozk lad DMAC N,N-dimetyloacetamid DMPU 1,3-dimetylo-3,4,5,6-tetrahydro-2(1H)pirymidynon DMF N,N-dimetyloformamid DMSO dimetylosulfotlenek DPPA azydek difenylofosforylu EDCI 1-(3-dimetyloaminopropylo)-3-etylokarbodiimid EtOAc octan etylu EtOH etanol (100%) Et 2 O eter dietylowy EtaN trietyloamina h godzina (godziny) HOBT 1-hydroksybenzotriazol m-CPBA kwas 3-chloronadoksybenzoesowy MeOH metanol pet. eter eter naftowy (zakres wrzenia 30-60°C) temp. temperatura THF tetrahydrofuran TFA trifluoro-AcOH Tf trifluorometanosulfonyl A. Ogólne metody syntezy podstawionych anilin A1. Metoda ogólna powstawania aryloaminy poprzez powstawanie eteru, a nast epnie zmydla- nie estru, przegrupowanie Curtius'a, i odbezpieczenie karbaminianu. Synteza 2-amino-3-metoksy-naftalenu Etap 1. 3-metoksy-2-naftoesan metylu. Zawiesin e 3-hydroksy-2-naftoesanu metylu (10,1 g, 50,1 mmola) i K 2 CO 3 (7,96 g, 57,6 mmola) w DMF (200 ml) mieszano w temperaturze pokojowej przez 15 minut, a nast epnie potraktowano jo- dometanem (3,43 ml, 55,1 mmola). Mieszanin e mieszano w temperaturze pokojowej przez noc, na- st epnie potraktowano wod a (200 ml). Uzyskan a mieszanin e ekstrahowano EtOAc (2 x 200 ml). Pola- czone warstwy organiczne przemyto nasyconym roztworem NaCl (100 ml), osuszono (MgSO 4 ), zat e- zono pod zmniejszonym ci snieniem (w przybli zeniu 0,4 mmHg przez noc), uzyskuj ac 3-metoksy-2- -naftoesan metylu w postaci bursztynowego oleju (10,30 g).PL 203 687 B1 12 1 H-NMR (DMSO-d 6 ) d 2,70 (s, 3H), 2,85 (s, 3H), 7,38 (ok. t, J = 8,09 Hz, 1H), 7,44 (s, 1H), 7,53 (ok. t, J = = 8,09 Hz, 1H), 7,84 (d, J = 8,09 Hz, 1H), 7,90 (s, 1H), 8,21 (s, 1H). Etap 2. Kwas 3-metoksy-2-naftoesowy. Roztwór 3-metoksy-2-naftoesanu metylu (6,28 g, 29,10 mmola) i wody (10 ml) w MeOH (100 ml) w temperaturze pokojowej potraktowano 1N roztworem NaOH (33,4 ml, 33,4 mmola). Mieszanin e ogrzewano w temperaturze wrzenia przez 3 godziny, och lodzono do temperatury pokojowej i zakwa- szono 10% roztworem kwasu cytrynowego. Uzyskany roztwór ekstrahowano EtOAc (2 x 100 ml). Po- laczone warstwy organiczne przemyto nasyconym roztworem NaCl, osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem. Pozosta losc roztarto z heksanem, nast epnie przemyto kilka razy hek- sanem uzyskuj ac kwas 3-metoksy-2-naftoesowy w postaci bia lego cia la sta lego (5,40 g, 92%). 1 H-NMR (DMSO-d 6 ) d 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 (szeroki s, 1H). Etap 3. 2-(N-(karbobenzylooksy)amino-3-metoksynaftalen. Roztwór kwasu 3-metoksy-2-naftoesowego (3,36 g, 16,6 mmola) i Et 3 N (2,59 ml, 18,6 mmola) w bezwodnym toluenie (70 ml) mieszano w temperaturze pokojowej przez 15 minut, nast epnie potrak- towano roztworem DPPA (5,12 g, 18,6 mmola) w toluenie (10 ml) poprzez pipet e. Uzyskan a miesza- nin e ogrzewano w temperaturze 80°C przez 2 godziny. Po ozi ebieniu mieszaniny do temperatury po- kojowej dodano strzykawk a alkohol benzylowy (2,06 ml, 20 mmoli). Nast epnie mieszanin e ogrzewano w temperaturze 80°C przez noc. Uzyskan a mieszanin e och lodzono do temperatury pokojowej, reakcj e zatrzymano stosuj ac 10% roztwór kwasu cytrynowego i ekstrahowano EtOAc (2 x 100 ml). Po laczone warstwy organiczne przemyto nasyconym roztworem NaCl, osuszono (MgSO 4 ) i zat ezono pod zmniejszo- nym ci snieniem. Pozosta lo sc oczyszczono metod a kolumnowej chromatografii (14% EtOAc/86% heksan) uzyskuj ac 1-(N-(karbobenzylooksy)amino-3-metoksynaftalen w postaci jasno zó ltego oleju (5,1 g, 100%). 1 H-NMR (DMSO-d 6 ) d 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). Etap 4. 2-amino-3-metoksynaftalen. Zawiesin e 2-(N-(karbobenzylooksy)amino-3-metoksynaftalenu (5,0 g, 16,3 mmola) i 10% Pd/C (0,5 g) w EtOAc (70 ml) utrzymywano w atmosferze H 2 (balon), w temperaturze pokojowej, przez noc. Uzyskan a mieszanin e przes aczono przez Celite® i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 2-amino-3-metoksynaftalen w postaci jasnoró zowego proszku (2,40 g, 85%). 1 H-NMR (DMSO-d 6 ) d 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 Hz, 1H); EI-MS m/z 173 (M + ).PL 203 687 B1 13 A2. Synteza ?-karbamyloaniliny poprzez powstawanie karbamylopirydyny, a nast epnie sprz e- ganie nukleofilowe z aryloamin a. Synteza 4-(2-N-metylokarbamylo-4-pirydylooksy)aniliny Etap 1a. Synteza 4-chloro-N-metylo-2-pirydynakarboksyamidu poprzez reakcj e Menisci. Uwaga: jest to reakcja bardzo niebezpieczna, potencjalnie wybuchowa. Do mieszanego roztwo- ru 4-chloropirydyny (10,0 g) w N-metyloformamidzie (250 ml) w temperaturze pokojowej dodano st e- zony H 2 SO 4 (3,55 ml), w celu zwi ekszenia ciep la reakcji. Do tej mieszaniny dodano H 2 O 2 (30% wago- wych w H 2 O, 17 ml) a nast epnie FeSO 4 •7H 2 O (0,56 g) w celu dodatkowego zwi ekszenia ciep la reakcji. Uzyskan a mieszanin e mieszano w ciemno sci w temperaturze pokojowej przez 1 godzin e, nast epnie ogrzano powoli, w czasie 4 godzin do 45°C. Po zaprzestaniu wydzielania si e p echerzyków, mieszani- n e reakcyjn a ogrzewano w temperaturze 60°C przez 16 godzin. Uzyskany nieprzezroczysty brunatny roztwór rozcie nczono H 2 O (700 ml), a nast epnie 10% roztworem NaOH (250 ml). Uzyskan a mieszani- n e ekstrahowano EtOAc (3 x 500 ml). Fazy organiczne przemyto oddzielnie nasyconym roztworem NaCl (3 x 150 ml), nast epnie polaczono je, osuszono (MgSO 4 ) i przes aczono poprzez warstw e zelu krzemionkowego, z pomoc a EtOAc. Uzyskany brunatny olej oczyszczono metod a kolumnowej chro- matografii (gradient od 50% EtOAc/50% heksan do 80% EtOAc/20% heksan). Uzyskany zó lty olej krystalizowano w temperaturze 0°C w czasie 72 godzin, uzyskuj ac 4-chloro-N-metylo-2-pirydynokarboksy- amid (0,61 g, 5,3%). TLC (50% EtOAc/50% heksan) R f 0,50; 1 H NMR (CDCI 3 ) d 3,04 (d, J = 5,1 Hz, 3H), 7,43 (dd, J = 5,4, 2,4 Hz, 1H), 7,96 (szeroki s, 1H), 8,21 (s, 1H), 8,44 (d, J = 5, 1 Hz, 1H); CI-MS m/z 171 ((M+H) + ). Etap 1b. Synteza chlorowodorku chlorku 4-chloropirydyno-2-karbonylu poprzez kwas pikolinowy Bezwodny DMF (6,0 ml) powoli dodano do SOCI 2 (180 ml) o temperaturze pomi edzy 40°C i 50°C. Roztwór mieszano w tym zakresie temperatur przez 10 minut. Nast epnie dodano porcjami kwas pikolinowy (60,0 g, 487 mmoli) w czasie 30 minut. Uzyskany roztwór ogrzewano w temperaturze 72°C (silne wydzielanie si e SO 2 ) przez 16 godzin w celu wytworzenia zó ltego sta lego osadu. Uzyska- n a mieszanin e och lodzono do temperatury pokojowej, rozcie nczono toluenem (500 ml) i zat ezono do obj eto sci 200 ml. Proces dodanie toluenu/zat ezanie powtórzono dwukrotnie. Uzyskan a prawie such a pozosta losc przes aczono i cia lo sta le przemyto toluenem (2 x 200 ml) i suszono pod silnie zmniejszo- nym ci snieniem przez 4 godziny, uzyskuj ac chlorowodorek chlorku 4-chloropirydyno-2-karbonylu w postaci zó lto-pomara nczowego cia la sta lego (92,0 g, 89%). Etap 2. Synteza chlorowodorku 4-chloropirydyno-2-karboksylanu metylu. Bezwodny DMF (10,0 ml) powoli dodano do SOCI 2 (300 ml) w temperaturze 40-48°C. Roztwór mieszano w tym zakresie temperatur przez 10 minut, nast epnie dodano kwas pikolinowy (100 g, 812 mmoli) w czasie 30 minut. Uzyskany roztwór ogrzewano w temperaturze 72°C (silne wydzielanie si e SO 2 ) przez 16 godzin, w celu wytworzenia zó ltego cia la sta lego. Uzyskan a mieszanin e och lodzono do temperatury pokojowej, rozcie nczono toluenem (500 ml) i zatezono do 200 ml. Proces dodanie tolu- enu/zat ezanie powtórzono dwukrotnie. Uzyskan a prawie such a pozosta lo sc przes aczono i cia lo sta le przemyto toluenem (50 ml) i suszono pod silnie zmniejszonym ci snieniem przez 4 godziny, uzyskuj ac chlorowodorek chlorku 4-chloropirydyno-2-karbonylu w postaci bia lawego cia la sta lego (27,2 g, 16%). Te substancj e odstawiono.PL 203 687 B1 14 Czerwony przesacz dodano do MeOH (200 ml) z szybko scia, przy której utrzymywa la si e tem- peratura wewn etrzna poni zej 55°C. Zawartosc mieszano w temperaturze pokojowej przez 45 minut, och lodzono do temperatury 5°C i potraktowano kroplami Et 2 O (200 ml). Uzyskane cia lo sta le przes aczono, przemyto Et 2 O (200 ml) i osuszono pod zmniejszonym ci snieniem w temperaturze 35°C, uzyskuj ac chlorowodorek 4-chloropirydyno-2-karboksylanu metylu w postaci bia lego cia la sta lego (110 g, 65%). Temperatura topnienia 108-112°C. 1 H-NMR (DMSO-d 6 ) d 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, 68 (szeroki s, 1H); HPLC ES-MS m/z 172 ((M+H) + ). Etap 3a. Synteza 4-chloro-N-metylo-2-pirydynokarboksyamidu z 4-chloropirydyno-2-karboksylanu metylu. Zawiesin e chlorowodorku 4-chloropirydyno-2-karboksylanu metylu (89,0 g, 428 mmoli) w MeOH (75 ml), w temperaturze 0°C potraktowano 2,0M roztworem metyloaminy w THF (1 l) z szybko scia przy której utrzymywa la si e temperatura wewn etrzna poni zej 5°C. Uzyskan a mieszanin e przechowy- wano w temperaturze 3°C przez 5 godzin, nast epnie zatezono pod zmniejszonym ci snieniem. Uzy- skane cia lo sta le zawieszono w EtOAc (1 l) i przes aczono. Przes acz przemyto nasyconym roztworem NaCl (500 ml), osuszono (Na 2 SO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 4-chloro-N- -metylo-2-pirydynokarboksyamid w postaci jasno zó ltych kryszta lów (71,2 g, 97%). Temperatura topnienia 41-43°C; 1 H-NMR (DMSO-d 6 ) d 2,81 (s, 3H), 7,74 (dd, J-5A, 2,2 Hz, 1H), 8,00 (d, J = 2,2, 1H), 8,61 (d, J = 5,1 Hz, 1H), 8,85 (szeroki d, 1H); CI-MS m/z 171 ((M+H)+). Etap 3b. Synteza 4-chloro-N-metylo-2-pirydynokarboksyamidu z chlorku 4-chloropirydyno-2-karbonylu Chlorowodorek chlorku 4-chloropirydyno-2-karbonylu (7,0 g, 32,95 mmola) dodano porcjami do mieszaniny 2,0M roztworu metyloaminy w THF (100 ml) i MeOH (20 ml) w temperaturze 0°C. Uzyska- n a mieszanin e przechowywano w temperaturze 3°C przez 4 godziny, nast epnie zatezono pod zmniej- szonym ci snieniem. Uzyskane prawie suche cz esci sta le zawieszono w EtOAc (100 ml) i przes aczono. Przes acz przemyto nasyconym Roztwór NaCl (2 x 100 ml), osuszono (Na 2 SO 4 ) i zatezono pod zmniejszonym ci snieniem, uzyskuj ac 4-chloro-N-metylo-2-pirydynokarboksyamid w postaci zó ltego, krystalicznego cia la sta lego (4,95 g, 88%). Temperatura topnienia 37-40°C. Etap 4. Synteza 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)aniliny Roztwór 4-aminofenolu (9,60 g, 88,0 mmola) w bezwodnym DMF (150 ml) potraktowano tert- -butanolanem potasu (10,29 g, 91,7 mmola) i czerwonawo-brunatn a mieszanin e mieszano w tempera- turze pokojowej przez 2 godziny. Zawarto sc potraktowano 4-chloro-N-metylo-2-pirydynokarboksyamidem (15,0 g, 87,9 mmola) i K 2 CO 3 (6,50 g, 47,0 mmola) i nast epnie ogrzewano w temperaturze 80°C przez 8 godzin. Mieszanin e och lodzono do temperatury pokojowej i podzielono pomi edzy EtOAc (500 ml) i nasycony roztwór NaCl (500 ml). Faze wodn a ekstrahowano ponownie EtOAc (300 ml). Po laczone warstwy organiczne przemyto nasyconym roztworem NaCl (4 x 1000 ml), osuszono (Na 2 SO 4 ) i zat e- zono pod zmniejszonym ci snieniem. Uzyskane cia lo sta le suszono pod zmniejszonym ci snieniem w temperaturze 35°C przez 3 godziny, uzyskuj ac 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)anilin e w postaci jasno-brunatnego cia la sta lego (17,9 g, 84%).PL 203 687 B1 15 1 H-NMR (DMSO-d 6 ) d 2,77 (d, J = 4,8 Hz, 3H), 5,17 (szeroki s, 2H), 6,64, 6,86 (AA'BB' kwartet, 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 (szeroki d, 1H); HPLC ES-MS m/z 244 ((M+H)+). A3. Metoda ogólna syntezy aniliny metod a nukleofilowej addycji aromatycznej, a nast epnie redukcji nitroarenu. Synteza 5-(4-aminofenoksy)izoindolino-1,3-dionu Etap 1. Synteza 5-hydroksyizoindolino-1,3-dionu. Do mieszaniny w eglanu amonu (5,28 g, 54,9 mmola) w st ezonym AcOH (25 ml) powoli dodano kwas 4-hydroksyftalowy (5,0 g, 27,45 mmola). Uzyskan a mieszanin e ogrzewano w temperaturze 120°C przez 45 minut, nast epnie klarown a, jasno zó lt a mieszanin e ogrzewano w temperaturze 160°C przez 2 godziny. Uzyskan a mieszanin e utrzymywano w temperaturze 160°C i zat ezono do w przybli- zeniu 15 ml, nast epnie och lodzono do temperatury pokojowej i warto sc pH uregulowano do 10 stosu- jac 1N roztwór NaOH. T e mieszanin e och lodzono do temperatury 0°C i powoli zakwaszono do uzy- skania warto sci pH 5 stosuj ac 1N Roztwór HCI. Uzyskany osad zebrano przez przes aczenie i osuszo- no pod zmniejszonym ci snieniem, uzyskuj ac 5-hydroksyizoindolino-1,3-dion w postaci jasno zó ltego proszku jako produktu (3,24 g, 72%), 1 H NMR (DMSO-d 6 ) d 7,00-7,03 (m, 2H), 7,56 (d, J = 9,3Hz, 1H). Etap 2. Synteza 5-(4-nitrofenoksy)izoindolino-1,3-dionu Do mieszanej zawiesiny NaH (1,1 g, 44,9 mmola) w DMF (40 ml), w temperaturze 0°C, dodano kroplami roztwór 5-hydroksyizoindolino-1,3-dionu (3,2 g, 19,6 mmola) w DMF (40 ml). Jasn a zó lto- -zielon a mieszanin e pozostawiono do powrotu do temperatury pokojowej i mieszano przez 1 godzin e, nast epnie dodano strzykawk a 1-fluoro-4-nitrobenzen (2,67 g, 18,7 mmola) w 3-4 porcjach. Uzyskan a mieszanin e ogrzewano w temperaturze 70°C przez noc, nast epnie och lodzono do temperatury poko- jowej, powoli rozcie nczono wod a (150 ml) i ekstrahowano EtOAc (2 x 100 ml). Po laczone warstwy organiczne osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 5-(4-nitrofenoksy)izo- indolino-1,3-dion w postaci zó ltego cia la sta lego (3,3 g, 62%). TLC (30% EtOAc/70% heksan) R f 0,28; 1 H NMR (DMSO-d 6 ) d 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 (szeroki s, 1H); CI-MS m/z 285 ((M+H) + 100%). Etap 3. Synteza 5-(4-aminofenoksy)izoindolino-1,3-dionu Roztwór 5-(4-nitrofenoksy)izoindolino-1,3-dionu (0,6 g, 2,11 mmola) w st ezonym AcOH (12 ml) i wodzie (0,1 ml) mieszano w strumieniu argonu, podczas powolnego dodawania proszku zelaza (0,59 g, 55,9 mmola). T e mieszanin e mieszano w temperaturze pokojowej przez 72 godziny, nast epnie roz- cie nczono wod a (25 ml) i ekstrahowano EtOAc (3 x 50 ml). Po laczone warstwy organiczne osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 5-(4-aminofenoksy)izoindolino-1,3-dion w postaci brunatnawego cia la sta lego (0,4 g, 75%). TLC (50% EtOAc/50% heksan) R f 0,27;PL 203 687 B1 16 1 H NMR (DMSO-d 6 ) d 5,14 (szeroki 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%). A4. Metoda ogólna w syntezie piroliloanilin. Synteza 5-tert-butylo-2-(2,5dimetylopirolilo)aniliny Etap 1. Synteza 1-(4-tert-butylo-2-nitrofenylo)-2,5-dimetylopirolu. Do mieszanego roztworu 2-nitro-4-tert-butyloaniliny (0,5 g, 2,57 mmola) w cykloheksanie (10 ml) dodano strzykawk a AcOH (0,1 ml) i acetonyloaceton (0,299 g, 2,63 mmola). Mieszanin e reakcyjn a ogrzewano w temperaturze 120°C przez 72 godziny, usuwaj ac azeotropowo cz esci lotne. Mieszanin e reakcyjn a och lodzono do temperatury pokojowej, rozcie nczono CH 2 CI 2 (10 ml) i kolejno przemyto 1N roztworem HCI (15 ml), 1N roztworem NaOH (15 ml) i nasycony roztworem NaCl (15 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem. Uzyskane pomara nczowo-brunatne cia lo sta le oczyszczono metod a chromatografii kolumnowej (60 g SiO 2 ; gradient od 6% EtOAc/94% heksan do 25% EtOAc/75% heksan), uzyskuj ac 1-(4-tert-butylo-2-nitrofenylo)-2,5-dimetylopirol w postaci pomara nczowo- - zó ltego cia la sta lego (0,34 g, 49%). TLC (15% EtOAc/85% heksan) R f 0,67; 1 H NMR (CDCI 3 ) d 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 = = 2A Hz, 1H); CI-MS m/z 273 ((M+H) + , 50%). Etap 2. Synteza 5-tert-butylo-2-(2,5-dimetylopirolilo)aniliny Zawiesin e 1-(4-tert-butylo-2-nitrofenylo)-2,5-dimetylopirolu (0,341 g, 1,25 mmola), 10%Pd/C (0,056 g) i EtOAc (50 ml) w atmosferze H 2 (balon) mieszano przez 72 godziny, nast epnie przes aczono poprzez warstw e Celite®. Przes acz zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 5-tert-butylo- -2-(2,5-dimetylopirolilo)anilin e w postaci zó ltawego cia la sta lego (0,30 g, 99%). TLC (10% EtOAc/90% heksan) R f 0,43; 1 H NMR (CDCI 3 ) d 1,28 (s, 9h), 1,87-1,91 (m, 8H), 5,85 (szeroki s, 2h), 6,73-6,96 (m, 3h), 7,28 (szero- ki s, 1H). A5 Metoda ogólna syntezy anilin z anilin metod a nukleofilowego podstawienia aromatycznego. Synteza chlorowodorku 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-metyloaniliny Roztwór 4-amino-3-metylofenolu (5,45 g, 44,25 mmola) w suchym dimetyloacetamidzie (75 ml) potraktowano tert-butanolanem potasu (10,86 g, 96,77 mmola) i czarn a mieszanin e mieszano w tem- peraturze pokojowej a z kolba osi agn ela temperatur e pokojow a. Nast epnie zawarto sc potraktowano 4-chloro-N-metylo-2-pirydynokarboksyamidem (Metoda A2, Etap 3b; 7,52 g, 44,2 mmola) i ogrzewanoPL 203 687 B1 17 w temperaturze 110°C przez 8 godzin. Mieszanin e och lodzono do temperatury pokojowej i rozcie n- czono wod a (75 ml). Warstw e organiczn a ekstrahowano EtOAc (5 x 100 ml). Po laczone warstwy orga- niczne przemyto nasyconym roztworem NaCl (200 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszo- nym ci snieniem. Pozosta ly czarny olej potraktowano Et 2 O (50 ml) i sonikowano. Nast epnie roztwór potraktowano HCI (1M w Et 2 O; 100 ml) i mieszano w temperaturze pokojowej przez 5 minut. Uzyska- ne ciemnoró zowe cia lo sta le (7,04 g, 24,1 mmola) usuni eto przez przes aczenie z roztworu i przecho- wywano w warunkach beztlenowych, w temperaturze 0°C przed u zyciem. 1 H NMR (DMSO-d 6 ) d 2,41 (s, 3H), 2,78 (d, J = 4,4 Hz, 3H), 4,93 (szeroki 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. Metoda ogólna syntezy anilin z hydroksyanilin przez N-zabezpieczenie, nukleofilowe podstawienie aromatyczne i odbezpieczenie. Synteza 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloroaniliny Etap 1: Synteza 3-chloro-4-(2,2,2-trifluoroacetyloamino)fenolu Zelazo (3,24 g, 58,00 mmola) dodano do mieszanego TFA (200 ml). Do tej zawiesiny dodano 2- -chloro-4-nitrofenol (10,0 g, 58,0 mmola) i bezwodnik trifluorooctowy (20 ml). T e szar a zawiesin e mie- szano w temperaturze pokojowej przez 6 dni. Zelazo ods aczono od roztworu i pozosta la substancj e zat ezono pod zmniejszonym ci snieniem. Uzyskany szary osad rozpuszczono w wodzie (20 ml). Do uzyskanego zó ltego roztworu dodano nasycony roztwór NaHCO 3 (50 ml). Wytr acone cia lo sta le usu- ni eto z roztworu. Reakcj e w przes aczu powoli zatrzymywano roztworem wodorow eglanu sodu a z do widzialnego oddzielenia produktu od roztworu (okre slanego z zastosowaniem ma lej probówki robo- czej). S labo m etny zó lty roztwór ekstrahowano EtOAc (3 x 125 ml). Polaczone warstwy organiczne przemyto nasyconym roztworem NaCl (125 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym cisnieniem. Analiza 1 H NMR (DMSO-d 6 ) wykaza la nitrofenolow a substancj e wyj sciow a i zamierzony produkt 3-chloro-4-(2,2,2-trifluoroacetyloamino)fenol w stosunku 1:1. Surow a substancj e zastosowano w nast epnym etapie bez dalszego oczyszczania. Etap 2: Synteza (2,2,2-trifluoro)acetamidu 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloro- fenylu Roztwór surowego 3-chloro-4-(2,2,2-trifluoroacetyloamino)fenolu (5,62 g, 23,46 mmola) w su- chym dimetyloacetamidzie (50 ml) potraktowano tert-butanolanem potasu (5,16 g, 45,98 mmola) i brunatnawo-czarn a mieszanin e mieszano w temperaturze pokojowej a z do och lodzenia kolby do tempe- ratury pokojowej. Uzyskan a mieszanin e potraktowano 4-chloro-N-metylo-2-pirydynokarboksyamidem (Metoda A2, Etap 3b; 1,99 g, 11,7 mmola) i ogrzewano w temperaturze 100°C w atmosferze argonu przez 4 dni. Czarn a mieszanin e reakcyjn a och lodzono do temperatury pokojowej i wylano nast epnie do zimnej wody (100 ml). Mieszanin e ekstrahowano EtOAc (3 x 75 ml) i po laczone warstwy organicz- ne zat ezono pod zmniejszonym ci snieniem. Pozosta ly brunatny olej oczyszczono metod a kolumnowej chromatografii (gradient od 20% EtOAc/eter naftowy do 40% EtOAc/eter naftowy), uzyskuj ac (2,2,2- -trifluoro)acetamid 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chlorofenylu w postaci zó ltego cia la stalego (8,59 g, 23,0 mmole).PL 203 687 B1 18 Etap 3. Synteza 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloroaniliny. Roztwór surowego (2,2,2-trifluoro)acetamidu 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chlorofe- nylu (8,59 g, 23,0 mmole) w suchym 4-dioksanie (20 ml) potraktowano 1N roztworem NaOH (20 ml). Ten brunatny roztwór mieszano przez 8 godzin. Do tego roztworu dodano EtOAc (40 ml). Zielon a warstw e organiczn a ekstrahowano EtOAc (3 x 40 ml) i rozpuszczalnik zat ezono uzyskuj ac 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloroanilin e w postaci zielonego oleju, który zestali l si e po odstaniu (2,86 g, 10,30 mmola). 1 H NMR (DMSO-d 6 ) d 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, 1H). A7. Metoda ogólna odbezpieczania acylowanej aniliny. Synteza 4-chloro-2-metoksy-5-(trifluorometylo)aniliny Zawiesin e 3-chloro-6-(N-acetylo)-4-(trifluorometylo)-anizolu (4,00 g, 14,95 mmola) w 6M roztworze HCI (24 ml) ogrzewano w temperaturze wrzenia przez 1 godzin e. Uzyskany roztwór pozostawiono do och lodzenia do temperatury pokojowej, a po tym czasie zestali l si e on s labo. Uzyskan a mieszanin e rozcie nczono wod a (20 ml) nast epnie potraktowano kombinacj a sta lego NaOH i nasyconego roz- tworu NaHCO 3 a z do uzyskania zasadowego odczynu roztworu. Warstw e organiczn a ekstrahowano CH 2 CI 2 (3 x 50 ml). Po laczone cz esci organiczne osuszono (MgSO 4 ) i zatezono pod zmniejszonym cisnieniem, uzyskuj ac 4-chloro-2-metoksy-5-(trifluorometylo)anilin e w postaci brunatnego oleju (3,20 g, 14,2 mmola). 1 H NMR (DMSO-d 6 ) d 3,84 (s, 3H), 5,30 (s, 2H), 7,01 (s, 2H). A8. Metoda ogólna syntezy ?-alkoksy- ?-karboksyfenyloanilin. Synteza 4-(3-(N-metylokarbamoilo)-4-metoksyfenoksy)aniliny Etap 1. 4-(3-metoksykarbonylo-4-metoksyfenoksy)-1-nitrobenzen. Do roztworu 4-(3-karboksy-4-hydroksyfenoksy)-1-nitrobenzenu (wytworzonegoo z kwasu 2,5- -dihydroksybenzoesowego sposobem analogicznym do opisanego w Metodzie A13, Etap 1, 12 mmoli) w acetonie (50 ml) dodano K 2 CO 3 (5 g) i siarczanu dimetylu (3,5 ml). Uzyskan a mieszanin e ogrzewa- no w temperaturze wrzenia przez noc, nast epnie och lodzono do temperatury pokojowej i przes aczono poprzez warstw e Celitu®. Uzyskany roztwór zatezono pod zmniejszonym ci snieniem, poddano ab- sorbcji na SiO 2 i oczyszczono metod a chromatografii kolumnowej (50% EtOAc/50% heksan), uzysku- jac 4-(3-metoksykarbonylo-4-metoksyfenoksy)-1-nitrobenzen w postaci zó ltego proszku (3 g). Temperatura topnienia 115-118°C. Etap 2. 4-(3-karboksy-4-metoksyfenoksy)-1-nitrobenzen. Mieszanin e 4-(3-metoksykarbonylo-4-metoksyfenoksy)-1-nitrobenzenu (1,2 g), KOH (0,33 g) i wody (5 ml) w MeOH (45 ml) mieszano w temperaturze pokojowej przez noc i nast epnie ogrzewano w temperaturze wrzenia przez 4 godziny. Uzyskan a mieszanin e och lodzono do temperatury pokojowej i zatezono pod zmniejszonym ci snieniem. Pozosta lo sc rozpuszczono w wodzie (50 ml) i wodn a mie- szanin e zakwaszono 1N roztworem HCl. Uzyskan a mieszanin e ekstrahowano EtOAc (50 ml). Warstw ePL 203 687 B1 19 organiczn a osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem, uzyskuj ac 4-(3-karboksy-4- -metoksyfenoksy)-1-nitrobenzen (1,04 g). Etap 3. 4-(3-(N-metylokarbamoilo)-4-metoksyfenoksy)-1-nitrobenzen. Do roztworu 4-(3-karboksy-4-metoksyfenoksy)-1-nitrobenzenu (0,50 g, 1,75 mmola) w CH 2 CI 2 (12 ml) dodano porcjami SOCI 2 (0,64 ml, 8,77 mmola). Uzyskany roztwór ogrzewano w temperaturze wrzenia przez 18 godzin, och lodzono do temperatury pokojowej i zatezono pod zmniejszonym ci snie- niem. Uzyskane zó lte cz esci sta le rozpuszczono w CH 2 CI 2 (3 ml), nast epnie uzyskany roztwór potrak- towano porcjami roztworem metyloaminy (2,0M w THF, 3,5 ml, 7,02 mmola) (UWAGA: wydzielanie si e gazu) i mieszano w temperaturze pokojowej przez 4 godziny. Uzyskan a mieszanin e potraktowano 1N roztworem NaOH, nast epnie ekstrahowano CH 2 CI 2 (25 ml). Warstw e organiczn a osuszono (Na 2 SO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 4-(3-(N-metylokarbamoilo)-4-metoksyfenoksy)-1- -nitrobenzen w postaci zó ltego cia la sta lego (0,50 g, 95%). Etap 4. 4-(3-(n-metylokarbamoilo)-4-metoksyfenoksy)anilina. Zawiesin e 4-(3-(N-metylokarbamoilo)-4-metoksyfenoksy)-1-nitrobenzenu (0,78 g, 2,60 mmola) i 10% Pd/C (0,20 g) w EtOH (55 ml) mieszano pod ci snieniem 1 atmosfery H 2 (balon) przez 2,5 dnia, nast epnie przes aczono poprzez warstw e Celitu®. Uzyskany roztwór zat ezono pod zmniejszonym cisnieniem uzyskuj ac 4-(3-(N-metylokarbamoilo)-4-metoksyfenoksy)anilin e w postaci bia lawego cia la stalego (0,68 g, 96%). TLC (0,1% Et 3 N/99,9% EtOAc) R f 0,36. A9. Metoda ogólna otrzymywania anilin zawieraj acych ?-alkiloftalimid. Synteza 5-(4-aminofenoksy)-2-metyloizoindolino-1,3-dionu Etap 1. Synteza 5-(4-nitrofenoksy)-2-metyloizoindolino-1,3-dionu. Zawiesin e 5-(4-nitrofenoksy)izoindolino-1,3-dionu (A3, Etap 2; 1,0 g, 3,52 mmola) i NaH (0,13 g, 5,27 mmola) w DMF (15 ml) mieszano w temperaturze pokojowej przez 1 godzin e, nast epnie potrak- towano jodkiem metylu (0,3 ml, 4,57 mmola). Uzyskan a mieszanin e mieszano w temperaturze poko- jowej przez noc, nast epnie och lodzono do temperatury °C i potraktowano wod a (10 ml). Uzyskane cia lo sta le zebrano i osuszono pod zmniejszonym ci snieniem uzyskuj ac 5-(4-nitrofenoksy)-2-metyloizo- indolino-1,3-dion w postaci jasno zó ltego cia la sta lego (0,87 g, 83%). TLC (35% EtOAc/65% heksan) R f 0,61. Etap 2. Synteza 5-(4-aminofenoksy)-2-metyloizoindolino-1,3-dionu. Zawiesin e nitrofenoksy-2-metyloizoindolino-1,3-dionu (0,87 g, 2,78 mmola) i 10% Pd/C (0,10 g) w MeOH mieszano pod ci snieniem 1 atmosfery H 2 (balon) przez noc. Uzyskan a mieszanin e przes a- czono poprzez warstw e Celitu® i zat ezono pod zmniejszonym ci snieniem. Uzyskane zó lte cz esci sta lePL 203 687 B1 20 rozpuszczono w EtOAc (3 ml) i przes aczono poprzez warstw e SiO 2 (60% EtOAc/40% heksan), uzy- skuj ac 5-(4-aminofenoksy)-2-metyloizoindolino-1,3-dion w postaci zó ltego cia la sta lego (0,67 g, 86%). TLC (40% EtOAc/60% heksan) R f 0,27. A10. Metoda ogólna syntezy ?-karbamoiloaryloaniliny poprzez reakcj e prekursorów ?-alkoksykarbonylo- arylu z aminami. Synteza 4-(2-(N-(2-morfolin-4-yloetylo)karbamoilo)pirydylooksy)aniliny Etap 1. Synteza 4-chloro-2-(N-(2-morfolin-4-yloetylo)karbamoilo)pirydyny. Do roztworu chlorowodorku 4-chloropirydyno-2-karboksylanu metylu (Metoda A2, Etap 2; 1,01 g, 4,86 mmola) w THF (20 ml) dodano kroplami 4-(2-aminoetylo)morfolin e (2,55 ml, 19,4 mmola) i uzy- skany roztwór ogrzewano w temperaturze wrzenia przez 20 godzin, och lodzono do temperatury poko- jowej i potraktowano wod a (50 ml). Uzyskan a mieszanin e ekstrahowano EtOAc (50 ml). Warstw e or- ganiczn a osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem uzyskuj ac 4-chloro-2-(N-(2- -morfolin-4-yloetylo)karbamoilo)pirydyn e w postaci zó ltego oleju (1,25 g, 95%). TLC (10% MeOH/90% EtOAc) R f 0,50. Etap 2. Synteza 4-(2-(N-(2-morfolin-4-yloetylo)karbamoilo)pirydylooksy)aniliny. Roztwór 4-aminofenolu (0,49 g, 4,52 mmola) i tert-butanolanu potasu (0,53 g, 4,75 mol) w DMF (8 ml) mieszano w temperaturze pokojowej przez 2 godziny, nast epnie traktowano kolejno 4-chloro-2- -(N-(2-morfolin-4-yloetylo)karbamoilo)pirydyn a (1,22 g, 4,52 mmola) i K 2 CO 3 , (0,31 g, 2,26 mmola). Uzyskan a mieszanin e ogrzewano w temperaturze 75°C przez noc, och lodzono do temperatury poko- jowej i podzielono pomi edzy EtOAc (25 ml) i nasycony roztwór NaCl (25 ml). Warstw e wodn a ekstra- howano ponownie EtOAc (25 ml). Polaczone warstwy organiczne przemyto nasyconym roztworem NaCl (3 x 25 ml) i zat ezono pod zmniejszonym ci snieniem. Uzyskane brunatne cia lo sta le oczyszczo- no metod a kolumnowej chromatografii (58 g; gradient od 100% EtOAc do 25% MeOH/75% EtOAc) uzyskuj ac 4-(2-(N-(2-morfolin-4-yloetylo)karbamoilo)pirydylooksy)anilin e (1,0 g, 65%). TLC (10% MeOH/90% EtOAc) R f 0,32. A11. Metoda ogólna redukcji nitroarenów do aryloamin. Synteza 4-(3-karboksyfenoksy)aniliny. Zawiesin e 4-(3-karboksyfenoksy)-1-nitrobenzenu (5,38 g, 20,7 mmola) i 10% Pd/C (0,50 g) w MeOH (120 ml) mieszano w atmosferze H 2 (balon) przez 2 dni. Uzyskan a mieszanin e przes aczono po- przez warstw e Celitu®, nast epnie zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 4-(3-karboksyfeno- ksy)anilin e w postaci brunatnego cia la sta lego (2,26 g, 48%). TLC (10% MeOH/90% CH 2 Cl 2 ) R f 0,44 (smu zenie). A12. Metoda ogólna syntezy anilin zawieraj acych izoindolinon. Synteza 4-(1-oksoizoindolin-5-yloksy)aniliny. Etap 1. Synteza 5-hydroksyizoindolin-1-onu Do roztworu 5-hydroksyftalimidu (19,8 g, 121 mmola) w AcOH (500 ml) powoli dodano porcjami py l cynkowy (47,6 g, 729 mmola), nast epnie mieszanin e ogrzewano w temperaturze wrzenia przez 40 minut, przes aczono na gor aco i zatezono pod zmniejszonym ci snieniem. Reakcj e powtórzono w tejPL 203 687 B1 21 samej skali i po laczone oleiste pozosta losci oczyszczono metod a kolumnowej chromatografii (1,1 kg SiO 2 ; gradient od 60% EtOAc/40% heksan do 25% MeOH/75% EtOAc), uzyskuj ac 5-hydroksyizoindolin-1- -on (3,77 g). TLC (100% EtOAc) R f 0,17; HPLC ES-MS m/z 150 ((M+H) + ). Etap 2. Synteza 4-(1-izoindolinon-5-yloksy)-1-nitrobenzenu. Do zawiesiny NaH (0,39 g, 16,1 mmola) w DMF, w temperaturze 0°C dodano porcjami 5-hydroksy- izoindolin-1-on (2,0 g, 13,4 mmola). Uzyskan a zawiesin e pozostawiono do ogrzania do temperatury pokojowej i mieszano przez 45 minut, nast epnie dodano 4-fluoro-1-nitrobenzen i nast epnie mieszani- n e ogrzewano w temperaturze 70°C przez 3 godziny. Mieszanin e och lodzono do temperatury 0°C i potraktowano kroplami wod a a z do utworzenia osadu. Wytr acone cia lo sta le zebrano, uzyskuj ac 4-(1-izoindolinon-5-yloksy)-1-nitrobenzen w postaci ciemno zó ltego cia la sta lego (3,23 g, 89%). TLC (100% EtOAc) R f 0,35. Etap 3. Synteza 4-(1-oksoizoindolin-5-yloksy)aniliny. Zawiesin e 4-(1-izoindolinon-5-yloksy)-1-nitrobenzenu (2,12 g, 7,8 mmola) i 10% Pd/C (0,20 g) w EtOH (50 ml) mieszano w atmosferze H 2 (balon) przez 4 godziny, nast epnie przes aczono poprzez warstw e Celitu®. Przes acz zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 4-(1-oksoizoindolin-5- -yloksy)anilin e w postaci ciemno zó ltego cia la sta lego. TLC (100% EtOAc) R f 0,15. A13. Metoda ogólna syntezy ?-karbamoilo-aniliny poprzez wytwarzanie amidu za po srednictwem EDCI, a nast epnie redukcj e nitroarenu. Synteza 4-(3-N-metylokarbamoilofenoksy)aniliny. Etap 1. Synteza 4-(3-etoksykarbonylofenoksy)-1-nitrobenzenu Mieszanin e 4-fluoro-1-nitrobenzenu (16 ml, 150 mmoli), 3-hydroksybenzoesanu etylu (25 g, 150 mmoli) i K 2 CO 3 (41 g, 300 mmoli) w DMF (125 ml) ogrzewano w temperaturze wrzenia przez noc, och lodzono do temperatury pokojowej i potraktowano wod a (250 ml). Uzyskan a mieszanin e ekstra- howano EtOAc (3 x 150 ml). Po laczone fazy organiczne przemyto kolejno wod a (3 x 100 ml) i nasyco- nym roztworem NaCl (2 x 100 ml), osuszono (Na 2 SO 4 ) i zatezono pod zmniejszonym ci snieniem. Po- zostalo sc oczyszczono metod a kolumnowej chromatografii (10% EtOAc/90% heksan), uzyskuj ac 4-(3- -etoksykarbonylofenoksy)-1-nitrobenzen w postaci oleju (38 g). Etap 2. Synteza 4-(3-karboksyfenoksy)-1-nitrobenzenu Do energicznie mieszanej mieszaniny 4-(3-etoksykarbonylofenoksy)-1-nitrobenzenu (5,14 g, 17,9 mmola) w roztworze THF/woda 3:1 (75 ml) dodano roztwór LiOH•H 2 O (1,50 g, 35,8 mmola) w wodzie (36 ml). Uzyskan a mieszanin e ogrzewano w temperaturze 50°C przez noc, nast epnie och lo- dzono do temperatury pokojowej, zat ezono pod zmniejszonym ci snieniem i warto sc pH uregulowano do 2 stosuj ac 1M roztwór HCI. Uzyskane jasno zó lte cz esci sta le usuni eto przez przes aczenie i prze- myto heksanem, uzyskuj ac 4-(3-karboksyfenoksy)-1-nitrobenzen (4,40 g, 95%).PL 203 687 B1 22 Etap 3. Synteza 4-(3-(N-metylokarbamoilo)fenoksy)-1-nitrobenzenu. Mieszanin e 4-(3-karboksyfenoksy)-1-nitrobenzenu (3,72 g, 14,4 mmola), EDCI•HCl (3,63 g, 18,6 mmola), N-metylomorfoliny (1,6 ml, 14,5 mmola) i metyloaminy (2,0M w THF; 8 ml, 16 mmoli) w CH 2 CI 2 (45 ml) mieszano w temperaturze pokojowej przez 3 dni, a nast epnie zatezono pod zmniej- szonym ci snieniem. Pozosta losc rozpuszczono w EtOAc (50 ml) i uzyskan a mieszanin e ekstrahowano 1M roztworem HCI (50 ml). Warstw e wodn a ekstrahowano ponownie EtOAc (2 x 50 ml). Polaczone fazy organiczne przemyto nasyconym roztworem NaCl (50 ml), osuszono (Na 2 SO 4 ) i zat ezono pod zmniej- szonym ci snieniem, uzyskuj ac 4-(3-(N-metylokarbamoilo)fenoksy)-1-nitrobenzen w postaci oleju (1,89 g). Etap 4. Synteza 4-(3-(N-metylokarbamoilo)fenoksy)aniliny Zawiesin e 4-(3-(N-metylokarbamoilo)fenoksy)-1-nitrobenzenu (1,89 g, 6,95 mmola) i 5% Pd/C (0,24 g) w EtOAc (20 ml) mieszano w atmosferze H 2 (balon) przez noc. Uzyskan a mieszanin e przes a- czono poprzez warstw e Celitu® i zatezono pod zmniejszonym ci snieniem. Pozosta lo sc oczyszczono metod a kolumnowej chromatografii (5% MeOH/95% CH 2 CI 2 ). Uzyskany olej zestali l si e pod zmniej- szonym ci snieniem przez noc, daj ac 4-(3-(N-metylokarbamoilo)fenoksy)anilin e w postaci zó ltego cia la stalego (0,95 g, 56%). A14. Metoda ogólna syntezy ?-karbamoiloaniliny poprzez wytwarzanie amidu za po srednictwem EDCI, a nast epnie redukcj e nitroarenu. Synteza 4-3-(5-metylokarbamoilo)pirydylooksy)aniliny Etap 1. Synteza 4-(3-(5-metoksykarbonylo)pirydylooksy)-1-nitrobenzenu. Do zawiesiny NaH (0,63 g, 26,1 mmola) w DMF (20 ml) dodano roztwór 5-hydroksynikotynianu metylu (2,0 g, 13,1 mmola) w DMF (10 ml). Uzyskan a mieszanin e dodano do roztworu 4-fluoronitro- benzenu (1,4 ml, 13,1 mmola) w DMF (10 ml) i uzyskan a mieszanin e ogrzewano w temperaturze 70°C przez noc, och lodzono do temperatury pokojowej i potraktowano MeOH (5 ml), a nast epnie wod a (50 ml). Uzyskan a mieszanin e ekstrahowano EtOAc (100 ml). Faz e organiczn a zatezono pod zmniej- szonym ci snieniem. Pozosta lo sc oczyszczono metod a kolumnowej chromatografii (30% EtOAc/70% heksan), uzyskuj ac 4-(3-(5-metoksykarbonylo)pirydylooksy)-1-nitrobenzen (0,60 g). Etap 2. Synteza 4-(3-(5-metoksykarbonylo)pirydylooksy)aniliny Zawiesin e 4-(3-(5-metoksykarbonylo)pirydylooksy)-1-nitrobenzenu (0,60 g, 2,20 mmola) i 10% Pd/C w MeOH/EtOAc mieszano w atmosferze H 2 (balon) przez 72 godziny. Uzyskan a mieszanin e przes aczono i przes acz zat ezono pod zmniejszonym ci snieniem. Pozosta losc oczyszczono metod a kolumnowej chromatografii (gradient od 10% EtOAc/90% heksan do 30% EtOAc/-70% heksan do 50% EtOAc/50% heksan), uzyskuj ac 4-(3-(5-metoksykarbonylo) pirydylooksy)anilin e (0,28 g, 60%). 1 H NMR (CDCI 3 ) d 3,92 (s, 3H), 6,71 (d, 2H), 6,89 (d, 2H), 7,73 (1H), 8,51 (d, 1H), 8,87 (d, 1H).PL 203 687 B1 23 A15. Synteza aniliny poprzez elektrofilowe nitrowanie, a nast epnie redukcj e. Synteza 4-(3-metylosulfamoilofenoksy)aniliny Etap 1. Synteza N-metylo-S-bromobenzenosulfonoamidu. Do roztworu chlorku 3-bromobenzenosulfonylu (2,5 g, 11,2 mola) w THF (15 ml) w temperatu- rze 0 °C dodano metyloamin e (2,0M w THF; 28 ml, 56 mmoli). Uzyskany roztwór pozostawiono do ogrzania do temperatury pokojowej i mieszano w temperaturze pokojowej prze noc. Uzyskan a mie- szanin e podzielono pomi edzy EtOAc (25 ml) i 1M roztwór HCl (25 ml). Faz e wodn a was ekstrahowano ponownie EtOAc (2 x 25 ml). Po laczone fazy organiczne przemyto kolejno wod a (2 x 25 ml) i nasyco- nym roztworem NaCl (25 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskujac N-metylo-3-bromobenzenosulfonamid w postaci bia lego cia la sta lego (2,8 g, 99%). Etap 2. Synteza 4-(3-(N-metylosulfamoilo)fenylooksy)benzenu Do zawiesiny fenolu (1,9 g, 20 moli), K 2 CO 3 (6,0 g, 40 mmoli) i CuI (4 g, 20 mmoli) w DMF (25 ml) dodano N-metylo-3-bromobenzenosulfonamid (2,5 g, 10 mmoli) i uzyskan a mieszanin e mieszano w temperaturze wrzenia przez noc, och lodzono do temperatury pokojowej i podzielono pomi edzy EtOAc (50 ml) i 1N roztwór HCl (50 ml). Warstw e wodn a ekstrahowano ponownie EtOAc (2 x 50 ml). Po laczone fazy organiczne przemyto kolejno wod a (2 x 50 ml) i nasyconym roztworem NaCl (50 ml), osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem. Pozostaj acy olej oczyszczono metod a kolumnowej chromatografii (30% EtOAc/70% heksan) uzyskuj ac 4-(3-(N-metylosulfamoilo)fenylooksy)- benzenu (0,30 g). Etap 3. Synteza 4-(3-(N-metylosulfamoilo)fenylooksy)-1-nitrobenzenu. Do roztworu 4-(3-(N-metylosulfamoilo)fenylooksy)benzenu (0,30 g, 1,14 mmola) w TFA (6 ml) w temperaturze -10°C dodano porcjami NaNO 2 (0,097 g, 1,14 mmola) w czasie 5 minut. Uzyskany roztwór mieszano w temperaturze -10 °C przez 1 godzin e, nastepnie pozostawiono do ogrzania do temperatury pokojowej, i zat ezono pos zmniejszonym ci snieniem. Pozosta lo sc podzielono pomi edzy EtOAc (10 ml) i wod e (10 ml). Faz e organiczn a przemyto kolejno wod a (10 ml) i nasyconym roztwo- rem NaCl (10 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 4-(3-(N- -metylosulfamoilo)fenylooksy)-1-nitrobenzen (0,20 g). Te substancj e zastosowano w nast epnym eta- pie bez dalszego oczyszczania. Etap 4. Synteza 4-(3-(N-metylosulfamoilo)fenylooksy)aniliny. Zawiesin e 4-(3-(N-metylosulfamoilo)fenylooksy)-1-nitrobenzenu (0,30 g) i 10% Pd/C (0,030 g) w EtOAc (20 ml) mieszano w atmosferze H 2 (balon) przez noc. Uzyskan a mieszanin e przes aczono poprze warstw e Celitu ®. Przes acz zat ezono pod zmniejszonym ci snieniem. Pozosta lo sc oczyszczono metod a kolumnowej chromatografii (30% EtOAc/70% heksan), uzyskuj ac 4-(3-(N-metylosulfamoilo)- fenylooksy)anilin e (0,070 g).PL 203 687 B1 24 A16. Modyfikacja ?-ketonów. Synteza chlorowodorku 4-(4-(1-(N-metoksy)iminoetylo)fenoksyaniliny Do zawiesiny chloroworku 4-(4-acetylofenoksy)aniliny (wytworzonego w sposób analogiczny do Metody A13, etap 4; 1,0 g, 3,89 mmola) w mieszaninie EtOH (10 ml) i pirydyny (1,0 ml) dodano chlo- rowodorek O-metylohydroksyloaminy (0,65 g, 7,78 mmola, 2,0 równowa zniki). Uzyskany roztwór ogrzewano w temperaturze wrzenia przez 30 minut, och lodzono do temperatury pokojowej i zat ezono pod zmniejszonym ci snieniem. Uzyskane cia lo sta le rozcierano z wod a (10 ml) i przemyto wod a, uzyskuj ac chlorowodorek 4-(4-(1-(N-metoksy)iminoetylo)fenoksyaniliny w postaci zó ltego cia la sta lego (0,85 g). TLC (50% EtOAc/50% eter naftowy) R f 0,78; 1 H NMR (DMSO-d 6 ) d 3,90 (s, 3H), 5,70 (s, 3H); HPLC-MS m/z 257 ((M+H) + ). A17. Synteza N-((o-sililooksyalkilo)amidów. Synteza 4-(4-(2-(N-(2-triizopropylosililooksy)etylokarbamoilo)pirydylooksyaniliny Etap 1. 4-chloro-N-(2-triizopropylosililooksy)etylopirydyno-2-karboksyamid. Do roztworu 4-chloro-N-(2-hydroksyetylo)pirydyno-2-karboksyamidu (wytworzonego w sposób analogiczny do Metody A2, Etap 3b; 1,5 g, 7,4 mmola) w bezwodnym DMF (7 ml) dodano chlorek triizopropylosililu (1,59 g, 8,2 mmola, 1,1 równowa znika) i imidazol (1,12 g, 16,4 mmola, 2,2 równo- wa znika). Uzyskany zó lty roztwór mieszano przez 3 godziny w temperaturze pokojowej, nast epnie zat ezono pod zmniejszonym ci snieniem. Pozosta lo sc podzielono pomi edzy wod e (10 ml) i EtOAc (10 ml). Warstw e wodn a ekstrahowano EtOAc (3 x 10 ml). Po laczone fazy organiczne osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem, uzyskuj ac 4-chloro-2-(N-(2-triizopropylosililooksy)etylo) pirydynokarboksyamid w postaci pomara nczowego oleju (2,32 g, 88%). T e substancj e u zyto w na- st epnym etapie bez dalszego oczyszczania. Etap 2. 4-(4-(2-(N-(2-triizopropylosililooksy)etylokarbamoilo)pirydylooksyanilina. Do roztworu 4-hydroksyaniliny (0,70 g, 6,0 mmola) w bezwodnym DMF (8 ml) dodano jednora- zowo tert-butanolan potasu (0,67 g, 6,0 mmola, 1,0 równowa znik) wywo luj ac ogrzanie mieszaniny reakcyjnej. Gdy t e mieszanin e och lodzono do temperatury pokojowej, roztwór dodano 4-chloro-2-(N- -(2-triizopropylosililooksy)etylo)pirydynokarboksyamid (2,32 g, 6 mmoli, 1 równowa znik) w DMF (4 ml), a nast epnie K 2 CO 3 (0,42 g, 3,0 mmole, 0,50 równowa znika). Uzyskan a mieszanin e ogrzewano w tem- peraturze 80°C przez noc. Nast epnie dodano dodatkow a cz esc tert-butanolanu potasu (0,34 g, 3 mmole, 0,5 równowa znika) i mieszanin e mieszano w temperaturze 80°C przez dodatkowe 4 godziny. Miesza- nin e och lodzono do temperatury 0°C w la zni lód/woda, nast epnie powoli dodano kroplami wod e (oko lo 1 ml). Warstw e organiczn a ekstrahowano EtOAc (3 x 10 ml). Po laczone warstwy organiczne przemyto nasyconym roztworem NaCl (20 ml), osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci sniniem. Brunatn a oleist a pozosta lo sc oczyszczono metod a kolumnowej chromatografii (SiO 2 ; 30% EtOAc/70% eteru naftowego), uzyskuj ac 4-(4-(2-(N-(2-triizopropylosililooksy)etylokarbamoilo)pirydyno-oksyanilin e w postaci klarownego, jasnobrunatnego oleju (0,99 g, 38%).PL 203 687 B1 25 A18. Synteza estrów 2-pirydynokarboksylanu poprzez utlenianie 2-metylopirydyn. Synteza 4-(5-(2-metoksykarbonylo)pirydylooksy)aniliny Etap 1. 4-(5-(2-metylo)pirydylooksy)-1-nitrobenzen. Mieszanin e 5-hydroksy-2-metylopirydyny (10,0 g, 91,6 mmola), 1-fluoro-4-nitrobenzenu (9,8 ml, 91,6 mmola, 1,0 równowa znik), K 2 CO 3 (25 g, 183 mmole, 2,0 równowa zniki) w DMF (100 ml) ogrze- wano w temperaturze wrzenia przez noc. Uzyskan a mieszanin e och lodzono do temperatury pokojowej, potraktowano wod a (200 ml) i ekstrahowano EtOAc (3 x 100 ml). Po laczone warstwy organiczne przemyto kolejno wod a (2 x 100 ml) i nasyconym roztworem NaCl ((100 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac 4-(5-(2-metylo)-pirydylooksy)-1-nitrobenzen w postaci brunatne- go cia la sta lego (12,3 g). Etap 2. Synteza 4-(5-(2-metoksykarbonylo)pirydylooksy)-1-nitrobenzenu. Mieszanin e 4-(5-(2-metylo)pirydylooksy)-1-nitrobenzenu (1,70 g, 7,39 mmola) i ditlenku selenu (2,50 g, 22,2 mmola, 3,0 równowa zniki) w pirydynie (20 ml) ogrzewano w temperaturze wrzenia przez 5 godzin, a nast epnie och lodzono do temperatury pokojowej. Uzyskan a zawiesin e przes aczono, na- st epnie zatezono pod zmniejszonym ci snieniem. Pozosta lo sc rozpuszczono w MeOH (100 ml). Roz- twór potraktowano stezonym roztworem HCI (7 ml), nast epnie ogrzewano w temperaturze wrzenia przez 3 godziny, och lodzono do temperatury pokojowej i zat ezono pod zmniejszonym ci snieniem. Pozostalo sc podzielono pomi edzy EtOAc (50 ml) i 1N roztwór NaOH (50 ml). Warstw e wodn a ekstra- howano EtOAc (2 x 50 ml). Po laczone warstwy organiczne przemyto kolejno wod a (2 x 50 ml) i nasy- conym roztworem NaCl (50 ml), osuszono (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem. Pozo- stalo sc oczyszczono metod a kolumnowej chromatografii (SiO 2 ; 50% EtOAc/50% heksan), uzyskuj ac 4-(5-(2-metoksykarbonylo)pirydylooksy)-1-nitrobenzen (0,70 g). Etap 3. Synteza 4-(5-(2-metoksykarbonylo)pirydylooksy)aniliny. Zawiesin e 4-(5-(2-metoksykarbonylo)pirydylooksy)-1-nitrobenzenu (0,50 g) i 10% Pd/C (0,050 g) w mieszaninie EtOAc (20 ml) i MeOH (5 ml) umieszczono w atmosferze H 2 (balon) przez noc. Uzy- skan a mieszanin e przes aczono poprzez warstw e Celitu® i przes acz zat ezono pod zmniejszonym cisnieniem. Pozosta lo sc oczyszczono metod a kolumnowej chromatografii (SiO 2 ; 70% EtOAc/30% heksan), uzyskuj ac 4-(5-(2-metoksykarbonylo)pirydylooksy)anilin e (0,40 g). A19. Synteza ?-sulfonylofenyloanilin. Synteza 4-(4-metylosulfonylofenyoksy)aniliny Etap 1. 4-(4-metylosulfonylofenoksy)-1-nitrobenzenu. Do roztworu 4-(4-metylotiofenoksy)-1-nitrobenzenu (2,0 g, 7,7 mmola) w CH 2 CI 2 (75 ml), w temperaturze 0°C powoli dodano m-CPBA (57-86%, 4,0 g) i mieszanin e reakcyjn a mieszano w temperaturze pokojowej przez 5 godzin. Mieszanin e reakcyjn a potraktowano 1N roztworem NaOH (25 ml). Warstw e organiczn a przemyto kolejno 1N roztworem NaOH (25 ml), wod a (25 ml) i nasyco- nym roztworem NaCl (25 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskujac 4-(4-metylosulfonylofenoksy)-1-nitrobenzen w postaci cia la sta lego (2,1 g).PL 203 687 B1 26 Etap 2. 4-(4-metylosulfonylofenoksy)-1-anilina. 4-(4-metylosulfonylofenoksy)-1-nitrobenzen zredukowano do aniliny w sposób analogiczny do opisanego w Metodzie A18, etap 3. B. Synteza prekursorów mocznika B1. Metoda ogólna syntezy izocyjanianów z aniliny, z zastosowaniem CDI. Synteza izocyjanianu 4-bromo-3-(trifluorometylo)fenylu Etap 1. Synteza chlorowodorku 4-bromo-3-(trifluorometylo)aniliny. Do roztworu 4-bromo-3-(trifluorometylo)aniliny (64 g, 267 mmoli) w Et 2 O (500 ml) dodano kro- plami roztwór HCl (1M w Et 2 O; 300 ml) i uzyskan a mieszanin e mieszano w temperaturze pokojowej przez 16 godzin. Uzyskany ró zowo-bia ly osad usuni eto przez przes aczenie i przemyto Et 2 O (50 ml) i uzyskano chlorowodorek 4-bromo-3-(trifluorometylo)aniliny (73 g, 98%). Etap 2. Synteza izocyjanianu 4-bromo-3-(trifluorometylo)fenylu Zawiesin e chlorowodorku 4-bromo-3-(trifluorometylo)aniliny (36,8 g, 133 mmola) w toluenie (278 ml) potraktowano kroplami chloromrówczanu trichlorometylu i uzyskan a mieszanin e ogrzewano w tempe- raturze wrzenia przez 18 godzin. Uzyskan a mieszanin e zat ezono pod zmniejszonym ci snieniem. Po- zostalo sc potraktowano toluenem (500 ml), nast epnie zatezono pod zmniejszonym ci snieniem. Pozo- stalo sc potraktowano CH 2 CI 2 (500 ml), nast epnie zat ezono pod zmniejszonym ci snieniem. Cykl trak- towanie CH 2 Cl 2 /zat ezanie powtórzono i uzyskany bursztynowy olej przechowywano w temperaturze -20°C przez 16 godzin, uzyskuj ac izocyjanian 4-bromo-3-(trifluorometylo)fenylu w postaci brazowego cia la stalego (35,1 g, 86%). GC-MS m/z 265 (M + ). C. Metody otrzymywania mocznika C1a. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(4- -chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)mocznika Roztwór izocyjanianu 4-chloro-3-(trifluorometylo)fenylu (14,60 g, 65,90 mmola) w CH 2 CI 2 (35 ml) dodano kroplami do zawiesiny 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)aniliny (Metoda A 2 , Etap 4; 16,0 g, 65,77 mmola) w CH 2 Cl 2 (35 ml), w temperaturze 0°C. Uzyskan a mieszanin e mieszano w temperaturze pokojowej przez 22 godziny. Uzyskane zó lte cz esci sta le usuni eto przez przes acze- nie, nast epnie przemyto CH 2 CI 2 (2 x 30 ml) i osuszono pod zmniejszonym ci snieniem (w przybli zeniu 1 mmHg), uzyskuj ac N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydylo- oksy)-fenylo)mocznik w postaci bia lawego cia la sta lego (28,5 g, 93%). Temperatura topnienia 207-209°C; 1 H-NMR (DMSO-d 6 ) d 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 (szeroki d, 1H), 8,99 (s, 1H), 9,21 (s, 1H); HPLC ES-MS m/z 465 ((M+H) + ).PL 203 687 B1 27 C1b. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4- -pirydylooksy)fenylo)mocznika Roztwór izocyjanianu 4-bromo-3-(trifluorometylo)fenylu (Metoda B1, Etap 2; 8,0 g, 3 0,1 mmola) w CH 2 Cl 2 (80 ml) dodano kroplami do roztworu 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)aniliny (Metoda A2, Etap 4; 7,0 g, 28,8 mmola) w CH 2 CI 2 (40 ml), w temperaturze 0°C. Uzyskan a mieszanin e miesza- no w temperaturze pokojowej przez 16 godzin. Uzyskane zó lte cz esci sta le usuni eto przez przes acze- nie, nast epnie przemyto CH 2 CI 2 (2 x 50 ml) i osuszono pod zmniejszonym ci snieniem (w przybli zeniu 1 mmHg) w temperaturze 40°C, uzyskuj ac N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarba- moilo)-4-pirydylooksy)fenylo)mocznik w postaci jasno zó ltego cia la sta lego (13,2 g, 90%). Temperatura topnienia 203-205°C; 1 H-NMR (DMSO-d 6 ) d 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 (szeroki d, 1H), 8,99 (s, 1H), 9,21 (s, 1H); HPLC ES-MS m/z 509 ((M+H) + ). C1c. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-metylo-4-(2-(N-metylokarbamoilo)(4- -pirydylooksy))fenylo)mocznika. Roztwór 2-metylo-4-(2-(N-metylokarbamoilo)(4-pirydylooksy))aniliny (Metoda A5; 0,11 g, 0,45 mmo- la) w CH 2 CI 2 (1 ml) potraktowano Et 3 N (0,16 ml) i izocyjanianem 4-chloro-3-(trifluorometylo)fenylu (0,10 g, 0,45 mmola). Uzyskany brunatny roztwór mieszano w temperaturze pokojowej przez 6 dni, nast epnie potraktowano wod a (5 ml). Warstw e wodn a ekstrahowano ponownie EtOAc (3 x 5 ml). Po- laczone warstwy organiczne osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzyskuj ac N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-metylo-4-(2-(N-metylokarbamoilo)(4pirydylooksy))fenylo)- mocznik w postaci brunatnego oleju (0,11 g, 0,22 mmola). 1 H NMR (DMSO-d 6 ) d 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 (ok. d, 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. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(4-chloro-3-(trifluorometylo)-fenylo)-N'-(4-aminofenylo)mocznika Do roztworu izocyjanianu 4-chloro-3-(trifluorometylo)fenylu (2,27 g, 10,3 mmola) w CH 2 CI 2 (308 ml) dodano jednorazowo N-fenylenodiamin e (3,32 g, 30,7 mmola). Uzyskan a mieszanin e mieszano w tempe- raturze pokojowej przez 1 godzin e, potraktowano CH 2 Cl 2 (100 ml) i zatezono pod zmniejszonym ci- snieniem. Uzyskane ró zowe cz esci sta le rozpuszczono w mieszaninie EtOAc (110 ml) i MeOH (15 ml) i klarowny roztwór przemyto 0,05N roztworem HCl. Warstw e organiczn a zatezono pod zmniejszonymPL 203 687 B1 28 ci snieniem, uzyskuj ac zanieczyszczony N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-aminofenylo)mocznik (3,3 g). TLC (100% EtOAc) R f 0,72. C1e. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-etoksykarbonylofenylo)mocznika Do roztworu 4-izocyjanianobenzoesanu etylu (3,14 g, 16,4 mmola) w CH 2 CI 2 (30 ml) dodano 4-chloro-3-(trifluorometylo)anilin e (3,21 g, 16,4 mmola) i roztwór mieszano w temperaturze pokojowej przez noc. Uzyskan a zawiesin e rozcie nczono CH 2 CI 2 (50 ml) i przes aczono uzyskuj ac N-(4-chloro-3- -(trifluorometylo)fenylo)-N'-(4-etoksykarbonylofenylo)mocznik w postaci bia lego cia la sta lego (5,93 g, 97%). TLC (40% EtOAc/60% heksan) R f 0,44. C1f. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-karboksyfenylo)mocznika Do roztworu izocyjanianu 4-chloro-3-(trifluorometylo)fenylu (1,21 g, 5,46 mmola) w CH 2 Cl 2 (8 ml) dodano 4-(3-karboksyfenoksy)anilin e (Metoda A11; 0,81 g, 5,76 mmola) i uzyskan a mieszanin e mie- szano w temperaturze pokojowej przez noc, nast epnie potraktowano MeOH (8 ml) i mieszano jeszcze przez 2 godziny. Uzyskan a mieszanin e zat ezono pod zmniejszonym ci snieniem. Uzyskane brunatne cia lo sta le roztarto z roztworem EtOAc/heksan 1:1, uzyskuj ac N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-karbo- ksyfenylo)mocznik w postaci bia lawego cia la sta lego (1,21 g, 76%). C2a. Metoda ogólna syntezy mocznika na drodze reakcji aniliny z N,N'-karbonylodiimidazolem, a nast ep- nie addycji drugiej aniliny. Synteza N-(2-metoksy-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)- -4-pirydylooksy)fenylo)mocznika Do roztworu 2-metoksy-5-(trifluorometylo)aniliny (0,15 g) w bezwodnym CH 2 C I2 (15 ml), w tem- peraturze 0°C dodano CDI (0,13 g). Uzyskany roztwór pozostawiono do ogrzania do temperatury poko- jowej w czasie 1 godziny, mieszano w temperaturze pokojowej przez 16 godzin, nast epnie potraktowano 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)anilin a (0,18 g). Uzyskany zó lty roztwór mieszano w tempe- raturze pokojowej przez 72 godziny, nast epnie potraktowano H 2 O (125 ml). Uzyskan a wodn a miesza- nin e ekstrahowano EtOAc (2 x 150 ml). Po laczone cz esci organiczne przemyto nasyconym roztworem NaCl (100 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem. Pozosta lo sc roztarto (90% EtOAc/10% heksan). Uzyskane bia le cia lo sta le zebrano przez przes aczenie i przemyto EtOAc. Przes acz zat ezono pod zmniejszonym ci snieniem i pozostaj acy olej oczyszczono metod a kolumnowej chromatografii (gradient od 33% EtOAc/67% heksan do 50% EtOAc/50% heksan do 100% EtOAc), uzyskuj ac N-(2-metoksy-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)- mocznik w postaci jasnobr azowego cia la sta lego (0,098 g, 30%). TLC (100% EtOAc) R f 0,62; 1 H NMR (DMSO-d 6 ) d 2,76 (d, J = 4,8 Hz, 3H), 3,96 (s, 3H), 7,1-7,6 i 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) + ).PL 203 687 B1 29 C2b. Metoda ogólna syntezy mocznika na drodze reakcji aniliny z N,N'-karbonylodiimidazolem, a nast ep- nie addycji drugiej aniliny. Symetryczne moczniki jako produkty uboczne reakcji N,N'-karbonylodiimi- dazolu. Synteza bis(4-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)mocznika Do mieszanego roztworu 3-amino-2-metoksychinoliny (0,14 g) w bezwodnym CH 2 CI 2 (15 ml) w temperaturze 0°C dodano CDI (0,13 g). Uzyskany roztwór pozostawiono do ogrzania do temperatu- ry pokojowej w czasie 1 godziny, nast epnie mieszano w temperaturze pokojowej przez 16 godzin. Uzyskan a mieszanin e potraktowano 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)anilin a (0,18 g). Uzy- skany zó lty roztwór mieszano w temperaturze pokojowej przez 72 godziny, nast epnie potraktowano wod a (125 ml). Uzyskan a wodn a mieszanin a ekstrahowano EtOAc (2 x 150 ml). Po laczone fazy orga- niczne przemyto nasyconym roztworem NaCl (100 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszo- nym ci snieniem. Pozosta lo sc roztarto (90% EtOAc/10% heksan). Uzyskane bia le cia lo sta le zebrano przez przes aczenie i przemyto EtOAc, uzyskuj ac bis(4-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)mocznik (0,081 g, 44%). TLC (100% EtOAc) R f 0,50; 1 H NMR (DMSO-d 6 ) d 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. Metoda ogólna syntezy moczników na drodze reakcji izocyjanianu z anilin a. Synteza N-(2-metoksy-5- -(trifluorometylo)-fenylo-N'-(4-(1,3-dioksoizoindolin-5-yloksy)fenylo)mocznika Do mieszanego roztworu izocyjanianu 2-metoksy-5-(trifluorometylo)fenylu (0,10 g, 0,47 mmola) w CH 2 Cl 2 (1,5 ml) dodano jednorazowo 5-(4-aminofenoksy)izoindolino-1,3-dion (Metoda A3, Etap 3; 0,12 g, 0,47 mmola). Uzyskan a mieszanin e mieszano przez 12 godzin, nast epnie potraktowano CH 2 CI 2 (10 ml) i MeOH (5 ml). Uzyskan a mieszanin e przemyto kolejno 1N roztworem HCl (15 ml) i nasyconym roztworem NaCl (15 ml), osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem, uzy- skuj ac N-(2-metoksy-5-(trifluorometylo)fenylo-N'-(4-(1,3-dioksoizoindolin-5-yloksy)fenylo)mocznik w po- staci bia lego cia la sta lego (0,2 g, 96%). TLC (70% EtOAc/30% heksan) R f 0,50; 1 H NMR (DMSO-d 6 ) d 3,9 (s, 3H), 7,31-7,10 (m, 6H), 7,57 (d, J = 9,3Hz, 2H), 7,80 (d, J = 8,7 Hz, 1H), 8,53 (szeroki s, 2H), 9,57 (s, 1H), 11,27 (szeroki s, 1H); HPLC ES-MS 472,0 ((M+H) + , 100%). C2d. Metoda ogólna syntezy mocznika na drodze reakcji aniliny z N,N'-karbonylodiimidazolem a nast epnie addycji drugiej aniliny. Synteza N-(5-(tert-butyl)-2-(2,5-dimetylopirolilo)fenylo)- -N'-(4-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)mocznikaPL 203 687 B1 30 Do mieszanego roztworu CDI (0,21 g, 1,30 mmola) w CH 2 CI 2 (2 ml) dodano jednorazowo 5- -(tert-butylo)-2-(2,5-dimetylopirolilo)anilin e (Metoda A4, Etap 2; 0,30 g, 1,24 mmola). Uzyskan a mie- szanin e mieszano w temperaturze pokojowej przez 4 godziny, nast epnie dodano jednorazowo 4-(2- -(N-metylokarbamoilo)-4-pirydylooksy)anilin e (0,065 g, 0,267 mmola). Uzyskan a mieszanin e ogrzewa- no w temperaturze 36°C przez noc, nast epnie och lodzono do temperatury pokojowej i rozcie nczono EtOAc (5 ml). Uzyskan a mieszanin e przemyto kolejno wod a (15 ml) i 1N roztworem HCI (15 ml), osu- szono (MgSO 4 ) i przes aczono poprzez warstw e zelu krzemionkowego (50 g), uzyskuj ac N-(5-(tert- -butylo)-2-(2,5-dimetylopirolilo)fenylo)-N-(4-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)mocznik w po- staci zó ltawego cia la sta lego (0,033 g, 24%). TLC (40% EtOAc/60% heksan) R f 0,24; 1 H NMR (aceton-d 6 ) d 1,37 (s, 9H), 1,89 (s, 6H), 2,89 (d, J = 4,8Hz, 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 = 5AHz, 1H), 8,57 d, J = 2,1 Hz, 1H), 8,80 (szeroki s, 1H); HPLC ES-MS 512 ((M+H) + , 100%). C3. Metoda kombinatoryczna w syntezie difenylomoczników, z zastosowaniem trifosgenu Jedn a spo sród sprz eganych anilin rozpuszczono w dichloroetanie (0,10M). Ten roztwór do- dano do 8 ml probówki (0,5 ml) zawieraj acej dichloroetan (1 ml). Do tego dodano roztwór w eglanu bis(trichlorome-tylu) (0,12M w dichloroetanie, 0,2 ml, 0,4 równowa znika), a nast epnie diizopropy- loetyloamin e (0,35M w dichloroetanie, 0,2 ml, 1,2 równowa znika). Probówk e uszczelniono i ogrzewano w temperaturze 80°C przez 5 godzin, nast epnie pozostawiono do och lodzenia do temperatury pokojowej, przez w przybli zeniu 10 godzin. Dodano drug a anilin e (0,10M w dichloro- etanie, 0,5 ml, 1,0 równowa znik), a nast epnie diizopropyloetyloamin e (0,35M w dichloroetanie, 0,2 ml, 1,2 równowa znika). Uzyskan a mieszanin e ogrzewano w temperaturze 80°C przez 4 godziny, och lodzono do temperatury pokojowej i potraktowano MeOH (0,5 ml). Uzyskan a mieszanin e zat ezono pod zmniejszonym ci snieniem i produkty oczyszczono metod a HPLC w odwróconym uk ladzie faz. C4. Metoda ogólna syntezy mocznika na drodze reakcji aniliny z fosgenem, a nast epnie addycji drugiej aniliny. Synteza N-(2-metoksy-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)- -4-pirydylooksy)fenylo)mocznika Do mieszanego roztworu fosgenu (1,9M w toluenie; 2,07 ml, 0,11 g, 1,30 mmola) w CH 2 CI 2 (20 ml) w temperaturze 0°C dodano bezwodn a pirydyn e (0,32 ml), a nast epnie 2-metoksy-5-(trifluorome- tylo)anilin e (0,75 g). Zó lty roztwór pozostawiono do ogrzania do temperatury pokojowej, uzyskuj ac utworzenie osadu. Zó lt a mieszanin e mieszano przez 1 godzin e, nast epnie zat ezono pod zmniejszo- nym ci snieniem. Uzyskane cia lo sta le potraktowano bezwodnym toluenem (20 ml), a nast epnie 4-(2- -(N-metylokarbamoilo)-4-pirydylooksy)anilin a (wytworzon a jak opisano w Metodzie A2; 0,30 g) i uzy- skan a zawiesin e ogrzewano w temperaturze 80°C przez 20 godzin, nast epnie pozostawiono do och lo- dzenia do temperatury pokojowej. Uzyskan a mieszanin e rozcie nczono wod a (100 ml), nast epnie zalkali- zowano nasyconym roztworem NaHCO 3 (2-3 ml). Zasadowy roztwór ekstrahowano EtOAc (2 x 250 ml). Warstwy organiczne oddzielono, przemyto nasyconym roztworem NaCl, po laczono, osuszo- no (MgSO 4 ) i zatezono pod zmniejszonym ci snieniem. Uzyskan a ró zowo-brunatn a pozosta losc roz- puszczono w MeOH i poddano absorbcji na SiO 2 (100 g). Chromatografia kolumnowa (300 g SiO 2 ; gradient od 1% Et 3 N/33% EtOAc/66% heksan do 1% Et 3 N/99% EtOAc do 1% Et 3 N/20% MeOH/79% EtOAc), a nast epnie zat ezanie pod zmniejszonym ci snieniem w temperaturze 45°C da lo ciep ly, st ezo- ny roztwór EtOAc, który potraktowano heksanem (10 ml), uzyskuj ac powolne tworzenie kryszta lów N-(2-metoksy-5-trifluorometylo)fenylo)-N'-(2-(N-metylokarbamoilo)-4-pirydylooksy)fenylo)mocznika (0,44 g). TLC (1% Et 3 N/99% EtOAc) R f 0,40.PL 203 687 B1 31 D. Przekszta lcenia moczników D1a. Przekszta lcenie ?-aminofenylomoczników do ?-(aroiloamino)fenylomoczników. Synteza N-(4-chloro-3-((trifluorometylo)fenylo)-N-(4-(3- -metoksykarbonylofenylo)karboksyaminofenylo)mocznika Do roztworu N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-aminofenylo)mocznika (Metoda C1d; 0,050 g, 1,52 mmola), mono-metyloizoftalanu (0,25 g, 1,38 mmola), HOBT•H 2 O (0,41 g, 3,03 mmola) i N-metylomorfoliny (0,33 ml, 3,03 mmola) w DMF (8 ml) dodano EDCI•HCl (0,29 g, 1,52 mmola). Uzy- skan a mieszanin e mieszano w temperaturze pokojowej przez noc, rozcie nczono EtOAc (25 ml) i przemyto kolejno wod a (25 ml) i nasyconym roztworem NaHCO 3 (25 ml). Warstw e organiczn a osu- szono (Na 2 SO 4 ) i zat ezono pod zmniejszonym ci snieniem. Uzyskane cia lo sta le roztarto z roztworem EtOAc (80% EtOAc/20% heksan), uzyskuj ac N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(3-metoksykarbo- nylofenylo)karboksyaminofenylo)mocznik (0,27 g, 43%). Temperatura topnienia 121-122°C; TLC (80% EtOAc/20% heksan) R f 0,75. D1b. Konwersja ?-karboksyfenylomoczników do ?-(arylokarbamoilo)fenylomoczników. Synteza N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(3-metylokarbamoilofenylo)- karbamoilofenylo)mocznika Do roztworu N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(3-metylokarbamoilofenylo)karboksyami- nofenylo)mocznika (0,14 g, 0,48 mmola), 3-metylokarbamoiloaniliny (0,080 g, 0,53 mmola), HOBT•H 2 O (0,14 g, 1,07 mmola), i N-metylomorfoliny (0,5 ml, 1,07 mmola) w DMF (3 ml), w temperaturze 0°C dodano EDCI•HCl (0,10 g, 0,53 mmola). Uzyskan a mieszanin e pozostawiono do ogrzania do tempe- ratury pokojowej i mieszano przez noc. Uzyskan a mieszanin e potraktowano wod a (10 ml) i ekstraho- wano EtOAc (25 ml). Faz e organiczn a zat ezono pod zmniejszonym ci snieniem. Uzyskane zó lte cz esci stale rozpuszczono w EtOAc (3 ml) nast epnie przes aczono poprzez warstw e zelu krzemionkowego (17 g, gradient od 70% EtOAc/30% heksan do 10% MeOH/90% EtOAc), uzyskuj ac N-(4-chloro-3- -((trifluorometylo)fenylo)-N'-(4-(3-metylokarbamoilofenylo)karbamoilofenylo)mocznik w postaci bia lego cia la sta lego (0,097 g, 41%). Temperatura topnienia 225-229; TLC (100% EtOAc) R f 0,23. D1c. Kombinatoryczne podej scie do konwersji ?-karboksyfenylomoczników do ?-(arylokarbamoilo)fenylo- moczników. Synteza N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(N-(3-(N-(3-pirydylo)- karbamoilo)fenylo)karbamoilo)fenylo)mocznika Mieszanin e N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(3-karboksyfenylo)mocznika (Metoda C1f; 0,030 g, 0,067 mmola) i N-cykloheksylo-N'-(metylopolistyreno)karbodiimidu (55 mg) w 1,2-dichloroetanie (1 ml) potraktowano roztworem 3-aminopirydyny w CH 2 CI 2 (1M; 0,074 ml, 0,074 mmola) (w przypad- kach braku rozpuszczenia lub przy zm etnieniu dodawano tak ze ma la ilo sc DMSO). Uzyskan a mieszanin ePL 203 687 B1 32 ogrzewano w temperaturze 36°C przez noc. Nast epnie m etn a mieszanin e reakcyjn a potraktowano THF (1 ml) i ogrzewanie kontynuowano przez 18 godzin. Uzyskane mieszaniny potraktowano poli(4- -(izocyjanianometylo)styrenem) (0,040 g) i uzyskan a mieszanin e mieszano w temperaturze 36°C przez 72 godziny, nast epnie och lodzono do temperatury pokojowej i przes aczono. Uzyskany roztwór przes aczono poprzez warstw e zelu krzemionkowego (1 g). Zatezenie pod zmniejszonym ci snieniem da lo N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(N-(3-(N-(3-pirydylo)karbamoilo)fenylo)karbamoilo)- fenylo)mocznik (0,024 g, 59%). TLC (70% EtOAc/30% heksan) R f 0,12. D2. Konwersja ?-karboalkoksyarylomoczników do ?-karbamoiloarylomoczników. Synteza N-(4-chloro- -3-((trifluorometylo)-fenylo)-N'-(4-(3-metylokarbamoilofenylo)karboksyaminofenylo)mocznika Do próbki N-(4-chloro-3-((trifluorometylo)fenylo)-N-(4-(3-karbometoksyfenylo)karboksyaminofeny- lo)mocznika (0,17 g, 0,34 mmola) dodano metyloamin e (2M w THF; 1 ml, 1,7 mmola) i uzyskan a mie- szanin e mieszano w temperaturze pokojowej przez noc, nast epnie zat ezono pod zmniejszonym ci snieniem uzyskuj ac N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(3-metylokarbamoilofenylo)karboksyaminofenylo)- mocznik w postaci bia lego cia la sta lego. Temperatura topnienia 247°C; TLC (100% EtOAc) R f 0,35. D3. Konwersja ?-karboalkoksyarylomoczników do ?-karboksyarylomoczników. Synteza N-(4-chloro-3- -((trifluorometylo)-fenylo)-N'-(4-karboksyfenylo)mocznika Do zawiesiny N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-etoksykarbonylofenylo)mocznika (Me- toda C1e; 5,93 g, 15,3 mmola) w MeOH (75 ml) dodano wodny roztwór KOH (2,5N, 10 ml, 23 mmole). Uzyskan a mieszanin e ogrzewano w temperaturze wrzenia przez 12 godzin, och lodzono do temperatu- ry pokojowej i zat ezono pod zmniejszonym ci snieniem. Pozosta losc rozcie nczono wod a (50 ml), na- st epnie potraktowano 1N roztworem HCl w celu uregulowania warto sci pH do 2 do 3. Uzyskane cia lo sta le zebrano i osuszono pod zmniejszonym ci snieniem otrzymuj ac N-(4-chloro-3-((trifluorometylo)fenylo)- -N'-(4-karboksyfenylo)mocznik w postaci bia lego cia la sta lego (5,05 g, 92%). D4. Metoda ogólna konwersji ?-alkoksyestrów do ?-alkiloamidów. Synteza N-(4-chloro-3-((trifluorome- tylo)fenylo)-N'-((4-(3-(5-(2-dimetyloaminoetylo)karbamoilo)pirydylo)oksyfenylo)mocznika Etap 1. Synteza N-(4-chloro-3-(trifluorometylo)fenylo)-N'-((4-(3-(5-karboksypirydylo)oksyfenylo)mocznika N-(4-chloro-3-(trifluorometylo)fenylo)-N'((4-(3-(5-metoksykarbonylopirydylo)oksyfenylo)mocznik zsyntetyzowano z izocyjanianu 4-chloro-3-(trifluorometylo)fenylu i 4-(3-(5-metoksykarbonylopirydylo)- oksyaniliny (Metoda A14, Etap 2) w sposób analogiczny do Metody C1a. Zawiesin e N-(4-chloro-3-(tri- fluorometylo)fenylo)-N'-((4-(3-(5-metoksykarbonylopirydylo)oksyfenylo)mocznika (0,26 g, 0,56 mmola) w MeOH (10 ml) potraktowano roztworem KOH (0,14 g, 2,5 mmola) w wodzie (1 ml) i mieszano w temperaturze pokojowej przez 1 godzin e. Warto sc pH uzyskanej mieszaniny uregulowano do 5 stosuj ac 1N roztwór HCI. Uzyskany osad usuni eto przez przes aczenie i przemyto wod a. Uzyskane cia lo sta le rozpuszczono w EtOH (10 ml) i uzyskany roztwór zat ezono pod zmniejszonym ci snieniem. Procedur ePL 203 687 B1 33 EtOH/zat ezanie powtórzono dwukrotnie, uzyskujac N-(4-chloro-3-(trifluorometylo)fenylo)-N'-((4-(3-(5- -karboksypirydylo)oksyfenylo)mocznik (0,18 g, 71%). Etap 2. Synteza N-(4-chloro-3-trifluorometylo)fenylo)-N'-((4-(3-(5-(2-dimetyloaminoetylo)karbamo- ilo)pirydylo)oksyfenylo)mocznika. Mieszanin e N-(4-chloro-3-(trifluorometylo)fenylo)-N'-((4-(3-(5-karboksypirydylo)oksyfenylo)moczni- ka (0,050 g, 0,011 mmola), N,N-dimetyloetylenodiaminy (0,22 mg, 0,17 mmola), HOBT (0,028 g, 0,17 mmola), N-metylomorfoliny (0,035 g, 0,28 mmola) i EDCI•HCl (0,032 g, 0,17 mmola) w DMF (2,5 ml) mieszano w temperaturze pokojowej przez noc. Uzyskany roztwór podzielono pomi edzy EtOAc (50 ml) i wod e (50 ml). Faz e organiczn a przemyto wod a (35 ml), osuszono (MgSO 4 ) i zatezono pod zmniej- szonym ci snieniem. Pozosta losc rozpuszczono w minimalnej ilo sci CH 2 CI 2 (w przybli zeniu 2 ml). Uzy- skany roztwór potraktowano kroplami Et 2 O, uzyskuj ac N-(4-chloro-3-(trifluorometylo)fenylo)-N'-((4-(3-(5-(2- -dimetyloaminoetylo)karbamoilo)pirydylo)oksyfenylo)mocznik w postaci bia lego osadu (0,48 g, 84%). 1 H NMR (DMSO-d 6 ) d 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. Metoda ogólna odbezpieczenia N-( ?-sililooksyalkilo)amidów. Synteza N-(4-chloro-3-((trifluorome- tylo)fenylo)-N'-(4-(4-(2-(N-(2-hydroksy)etylokarbamoilo)pirydylooksyfenylo)mocznika. Do roztworu N-(4-chloro-3-((trifluorometylo)fenylo)-N'-(4-(2-(N-(2-triizopropylosililooksy)etylokarba- moilo)pirydylooksyfenylo)mocznika (wytworzonego sposobem analogicznym do Metoda C1a; 0,25 g, 0,37 mmola) w bezwodnym THF (2 ml) dodano fluorek tetrabutyloamoniowy (1,0M w THF; 2 ml). Mie- szanin e mieszano w temperaturze pokojowej przez 5 minut, nast epnie potraktowano wod a (10 ml). Wodn a mieszanin e ekstrahowano EtOAc (3 x 10 ml). Po laczone warstwy organiczne osuszono (MgSO 4 ) i zat ezono pod zmniejszonym ci snieniem. Pozosta lo sc oczyszczono metod a kolumnowej chromatografii (SiO 2 ; gradient od 100% heksan do 40% EtOAc/60% heksan), uzyskuj ac N-(4-chloro-3-((trifluorome- tylo)fenylo)-N'-(4-(4-(2-(N-(2-hydroksy)etylokarbamoilo)pirydylooksyfenylo)mocznik w postaci bia lego cia la sta lego (0,019 g, 10%). Poni zej przedstawiono zwi azki zsyntetyzowane wed lug opisanych poprzednio szczegó lowych metod do swiadczalnych. Pozycja 1: 4-(2-N-metylokarbamylo-4-pirydylooksy)anilin e zsyntetyzowano wed lug Metody A2. Izocy- janian 4-chloro-3-(trifluorometylo)fenylu poddano reakcji z 4-(2-N-metylokarbamylo-4-pirydylooksy)anilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 2: Chlorowodorek chlorku 4-chloropirydyno-2-karbonylu poddano reakcji z amoniakiem we- d lug Metody A2, Etap 3b, uzyskuj ac 4-chloro-2-pirydynokarboksyamid. 4-chloro-2-pirydynokarboksyamid poddano reakcji z 4-aminofenolem wed lug Metody A2, Etap 4, uzyskuj ac 4-(2-karbamoilo-4-pirydylooksy)- anilin e. Izocyjanian 4-chloro-3-(trifluorometylo)fenylu poddano reakcji z 4-(2-karbamoilo-4-pirydylooksy)- anilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 3: Chlorowodorek chlorku 4-chloropirydyno-2-karbonylu poddano reakcji z amoniakiem we- d lug Metody A2, Etap 3b, uzyskuj ac 4-chloro-2-pirydynokarboksyamid. 4-chloro-2-pirydynokarboksyamid poddano reakcji z 3-aminofenolem wed lug Metody A2, Etap 4, uzyskuj ac 3-(2-karbamoilo-4-pirydylooksy)- anilin e. Izocyjanian 4-chloro-3-(trifluorometylo)fenylu poddano reakcji z 3-(2-karbamoilo-4-pirydylooksy)- anilina wed lug Metody C1a, uzyskuj ac mocznik.PL 203 687 B1 34 Pozycja 4: 4-chloro-N-metylo-2-pirydynokarboksyamid, który zsyntetyzowano wed lug Metody A2, Etap 3a, poddano reakcji z 3-aminofenolem wed lug Metody A2, Etap 4, uzyskuj ac 3-(2-(N-metylokarbamoilo)-4- -pirydylooksy)anilin e. Izocyjanian 4-chloro-3-(trifluorometylo)fenylu poddano reakcji z 3-(2-(N-metylokarba- moilo)-4-pirydylooksy)anilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 5: 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloroanilin e zsyntetyzowano wed lug Metody A6. Izocyjanian 4-chloro-3-(trifluorometylo)fenylu poddano reakcji z 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)- -2-chloroanilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 6: 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)anilin e zsyntetyzowano wed lug Metody A2. 4-bromo- -3-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-bromo-3-(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-bromo-3-(trifluorometylo)fenylu poddano reakcji z 4-(2-(N-metylokarbamoilo)-4- -pirydylooksy)anilin a, uzyskuj ac mocznik. Pozycja 7: 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloroanilin e zsyntetyzowano wed lug Metody A6. 4-bromo-3-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-bromo-3-(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-bromo-3-(trifluorometylo)fenylu poddano reakcji z 4-(2-(N-metylokarba- moilo)-4-pirydylooksy)-2-chloroanilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 8: 4-amino-2-chlorofenol poddano reakcji, wed lug Metody A2, Etap 4, z 4-chloro-N-metylo-2- -pirydynokarboksyamidem, który zsyntetyzowano wed lug Metody A2, Etap 3b, uzyskuj ac 4-(2-(N- -metylokarbamoilo)-4-pirydylooksy)-3-chloroanilin e. 4-bromo-3-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-bromo-3-(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-bromo-3-(trifluorometylo)- fenylu poddano reakcji z 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-3-chloroanilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 9: 4-chloro-N-metylo-2-pirydynokarboksyamid, który zsyntetyzowano wed lug Metody A2, Etap 3a, poddano reakcji z 3-aminofenolem wed lug Metody A2, Etap 4, uzyskuj ac 3-(2-(N-metylokarbamoilo)-4- -pirydylooksy)anilin e. 4-bromo-3-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-bromo-3- -(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-bromo-3-(trifluorometylo)fenylu poddano reakcji z 3-(2-(N-metylokarbamoilo)-4-pirydylooksy)anilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 10: 4-chloro-N-metylopirydynokarboksyamid zsyntetyzowano wed lug Metody A2, Etap 3b. Chloropirydyn e poddano reakcji z 3-aminotiofenolem wed lug Metody A2, Etap 4, uzyskuj ac 3-(4-(2-(N- -metylokarbamoilo)fenylotio)anilin e. 4-bromo-3-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-bromo-3-(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-bromo-3-(trifluorometylo)fenylu podda- no reakcji z 3-(4-(2-(N-metylokarbamoilo)fenylotio)anilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 11: 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)anilin e zsyntetyzowano wed lug Metody A2. 4-chloro-2-metoksy-5-(trifluorometylo)anilin e zsyntetyzowano wed lug Metody A7. 4-chloro-2-nietoksy- -5-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-chloro-2-metoksy-5-(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-chloro-2-metoksy-5-(trifluorometylo)fenylu poddano reakcji z 4-(2- -(N-metylokarbamoilo)-4-pirydylooksy)anilin a wed lug Metody C1a, uzyskuj ac mocznik. Pozycja 12: 4-(2-(N-metylokarbamoilo)-4-pirydylooksy)-2-chloroanilin e zsyntetyzowano wed lug Metody A6. 4-chloro-2-metoksy-5-(trifluorometylo)anilin e zsyntetyzowano wed lug Metody A7. 4-chloro-2-metoksy- -5-(trifluorometylo)anilin e przekszta lcono do izocyjanianu 4-chloro-2-metoksy-5-(trifluorometylo)fenylu wed lug Metody B1. Izocyjanian 4-chloro-2-metoksy-5-(trifluorometylo)fenylu poddano reakcji z 4-(2-(N- -metylokarbamoilo)-4-pirydylooksy)-2-chloroanilin a wed lug Metody C1a, uzyskuj ac mocznik. W Tablicach 1-3 poni zej wyszczególniono zwi azki, które zsyntetyzowano wed lug szczegó lo- wych metod do swiadczalnychoraz podano ich cechy charakterystyczne:PL 203 687 B1 35 T a b l i c a 4. 3-(trifluorometylo)-4-chlorofenylomocznikiPL 203 687 B1 36 T a b l i c a 2. 3-(trifluorometylo)-4-bromofenylomocznikiPL 203 687 B1 37 T a b l i c a 3. 5-(trifluorometylo)-4-chloro-2-metoksyfenylomoczniki PL PL PLDescription of the invention The present invention relates to novel compounds from the group of diphenylureas, pharmaceutical compositions containing these compounds and their use. The compounds are used in the pharmaceutical industry for the production of pharmaceutical compositions and drugs, especially for the treatment of neoplastic diseases in which raf kinase is mediated. The ras p21 oncogene is a major 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, unmutated form, ras protein is a key element in 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 circulation between the active form bound to GTP and the rest and bound to GDP is closely controlled by the activity of endogenous GTPase, as does the protein ras and other proteins. regulatory drugs. In ras mutants in cancer cells, endogenous GTPase activity is moderated, so the protein provides constitutional growth signals to subordinate effectors such as the enzyme raf kinase. This leads to cancerous growth of cells that contain these mutants (Magnuson et al. Sernin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibition of the effect of active ras protein by inhibition of the raf kinase signaling pathway by the administration of inactivating raf kinase I antibodies or by the co-expression method of dominant negative raf kinase or dominant negative MEK, a raf kinase substrate, leads to the return of transformed cells to a 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) further showed that inhibition of raf expression by antisense RNA blocks cellular proliferation in membrane-associated organogens. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with growth inhibition of various types of human tumors (Monia et al. , Nat. Med. 1996, 2, 668-75). The present invention therefore relates to compounds that are inhibitors of the raf kinase enzyme. Since this enzyme is an effector undergoing p21 ras, the inhibitors are useful in pharmaceutical compositions used in the preparation of medicaments for the treatment of humans or animals where inhibition of the raf kinase pathway is indicated, e.g. in the treatment of tumors and / or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the preparation of medicaments for the treatment of human or animal solid cancers, e.g. cancer in mice, as the progression of these diseases depends on the ras protein transduction cascade and is therefore amenable to treatment by disrupting the cascade, i.e. methods for inhibiting raf kinase. Accordingly, the compounds of the invention are useful in the treatment of cancers including solid cancers such as e.g. crayfish (e.g. lung, pancreas, thyroid gland, bladder or colon), bone marrow disorders (e.g. myeloid leukemia) or adenomas (e.g. Chorionic adenoma of the colon). The present invention therefore includes compounds generally described as arylureas, and more particularly as diphenylureas, which inhibit the raf kinase pathway. The invention also includes the use of these compounds in the manufacture of medicaments for the treatment of disease states mediated by raf kinase in humans or mammals. Thus, the invention relates to compounds that inhibit the enzyme raf kinase, and to pharmaceutical compositions containing these compounds together with a physiologically acceptable carrier, as well as the use of the compounds for the manufacture of drugs for the treatment of cancerous cell growth. wherein the raf kinase mediates when the compound or pharmaceutically acceptable salt thereof is administered. The essence of the invention is a new chemical compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- ( N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, PL 203 687 B1 3 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-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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. It is preferred that the pharmaceutically acceptable salt is a salt selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid. , benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, jaalic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium, aliphatic substituted ammonium and aromatically substituted ammonium. A pharmaceutical composition containing the active substance and a physiologically acceptable carrier, according to the invention, is characterized in that it comprises a compound selected from the group mentioned above or a pharmaceutically acceptable salt thereof. It is preferred for the compound of the invention that it is selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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 '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 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 when it is a pharmaceutically acceptable salt thereof, in particular when the salt is selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid , hydrobromic acid, sulfuric acid, phosphoric acid, m ethanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, apple lactic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium, aliphatic substituted ammonium and aromatically substituted ammonium. A preferred pharmaceutical composition according to the invention, comprising the active substance and a physiologically acceptable carrier, is characterized in that the active substance is a compound selected from the said preferred group of compounds or a pharmaceutically acceptable salt thereof. The invention also includes the use of the compounds according to the invention. The use according to the invention is characterized in that a compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4 -bromo-3- (trifl uoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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, is used in the manufacture of a medicament for the treatment of cancerous cell development mediated by raf kinase. Another use of a compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methyl octarbamoyl) (4-pyridyloxy)) phenyl) - urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) )) phenyl) - urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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 its pharmaceutically acceptable form, is characterized by its use in the manufacture of a medicament for the treatment of lung, pancreatic, thyroid, bladder, colon, chronic myeloid or villous cancer colonic adenoma. Yet another use of a compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4 - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) ) (4-pyridyloxy)) phenyl) - urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -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-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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, is characterized in that it is used in the manufacture of a medicament for the treatment of tumors. It is preferred to use a compound according to the invention selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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 '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - (4 - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 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, in the manufacture of a medicament for the treatment of cancerous cell growth mediated by raf kinase. Another preferred use of a compound selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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' - (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 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, is when it is used in the manufacture of a medicament for the treatment of cancer of the lung, pancreas, thyroid, bladder, colon, chronic myeloid leukemia, or villous carcinoma. colon. Yet another preferred use of a compound selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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' - (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 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, is when it is used in the manufacture of a medicament for the treatment of tumors. The compound of the invention is most preferably N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, or when it is and nim N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. For a pharmaceutical composition according to the invention which comprises an active ingredient and a physiologically acceptable carrier, it is most preferred that the composition comprises N- (4-chloro-3- (trifluoromethyl) phenyl) -N as the active ingredient. '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof, or when the composition comprises N- (4-chloro-3- (trifluoromethyl) as the active ingredient phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof. For the use according to the invention, it is most preferred that N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ( 4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, or N- (4-chloro-3- (trifluoromethyl) phenyl) - -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy ) phenyl) urea. Several of the compounds according to the invention may have asymmetric carbon atoms and may therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The compounds of the invention can be prepared using general preparation methods and known chemical reactions and methods, some of the starting materials being commercially available. Nevertheless, general preparative methods are provided below to assist those skilled in the art in synthesizing these compounds, and more detailed examples are provided below in the experimental section. Substituted anilines can be prepared using standard methods (March. Advanced Organization Chemistry, 3rd Edition. ; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, arylamines are commonly synthesized by reducing nitriles with a metal catalyst such as Ni, Pd, or Pt, and H 2 or a hydrogen transfer agent such as formate, cyclohexadiene, or borohydride ( Rylander, Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls can also be reduced directly by using a strong source of hydrogen, such as LiAlH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero-ternary metal such as Fe, Sn or Ca, often in an acidic environment. Many methods are known for the synthesis of nitriles (March. Advanced Organic Chemistry, 3rd Edition. ; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). (e.g. Fe, Sn, Ca) Scheme I. Reduction of Nitroaryls to arylamines Nitroaryls are commonly prepared by electrophilic aromatic nitration using HNO 3 or an alternative source of Ia NO 2 -. The nitroaryls can then be treated prior to reduction. Thus, nitroaryls substituted with potential leaving groups (e.g. F, Cl, Br, etc. ) can be subjected to displacement reactions by treatment with a nucleophile such as a thiolate (as exemplified by Scheme II) or a phenate. Nitroaryls can also undergo Ullman-type coupling reactions (Scheme II). Scheme II. Selected Nucleophilic Aromatic Substitution with Nitroaryls Nitroaryls can also be subjected to interconnection reactions mediated by a transition metal. E.g. Nitroaryl electrophiles, such as aryl nitrobromides, iodides or triflates, are subject to palladium-mediated interconnection reactions with the use of aryl nucleophiles such as arylboronic acids (Suzuki reactions shown for example below), aryltins (reactions Stille) or arylzines (Negishi reaction) to form biaryl (5). Nitroaryls or anilines can be converted into the corresponding arenesulfonyl compound (7) by treatment with chlorosulfonic acid. Reaction of sulfonyl chloride with a fluoride source such as KF leads to sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a la fluoride source such as tris (dimethylamino) difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethyl sulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to an arenotiol (10), e.g. by using zinc amalgam. Reaction of thiol 10 with CHClF 2 in the presence of a base gives difluoromethyl mercaptan (11) which can be oxidized to the sulfone (12) using any of a variety of oxidants including CrO 3-acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568). Scheme III. Selected Methods for the Synthesis of Fluorinated arylsulfone As shown in Scheme IV, the preparation of unsymmetrical urea may require the reaction of an aryl isocyanate (14) with arylamines (13). Heteroaryl isocyanate can be synthesized from heteroarylamine by treatment with phosgene or its equivalent such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or N, N'-carbonyldiimidazole (CDI). The isocyanate can also be known by the preparation of a Curtius-type rearrangement from a heterocyclic carboxylic acid derivative such as an ester, hydrohalic acid or anhydride. Thus, reaction of acid derivative 16 with an azide source followed by rearrangement gives the isocyanate. The corresponding carboxylic acid (17) can also be subjected to a Curtius-type rearrangement using diphenylphosphorylazide (DPPA) or a similar reagent. Scheme IV. Selected methods for the preparation of unsymmetrical urea Finally, the ureas can be further processed using methods known to those skilled in the art. Pharmaceutical compositions containing the compounds according to the invention and a physiologically acceptable carrier can be administered orally, topically, parenterally, by inhalation or by spray, or rectally in dosage unit formulations. The term "injection administration" includes intravenous, intramammary, subcutaneous and parenteral injection as well as the use of infusion technique. One or more compounds may be co-present with one or more non-toxic pharmaceutically acceptable carriers and, if desired, other active ingredients. Compositions intended for oral use may be prepared by any suitable method known in the art for the preparation of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents and preservatives used in the preparation of an appetizing preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such factors can be e.g. neutral diluents such as calcium egate, sodium egate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, e.g. corn starch or alginic acid; and binders, e.g. magnesium stearate, stearic acid, or talc. tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thus provide prolonged slow action over an extended period of time. E.g. It may be known by using a retarder such as glyceryl monostearate or glyceryl distearate. These compounds can also be known to be produced in a solid, rapidly released form. Preparations for oral use may also take the form of hard gelatine capsules, in which the active ingredient is mixed with an neutral solid diluent, such as e.g. in calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatine capsules, in which the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; dispersants or wetting agents may be a naturally occurring phosphatide, such as lecithin, or the condensation products of an alkylene oxide with a fatty acid, such as e.g. polyoxyethylene stearate, or the condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadekaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acid and hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acid and hexitol anhydrides , like for example. polyethylene - sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as 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. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. There may be additional excipients, e.g. Agents are icing, flavoring and coloring. Compounds may also take the form of non-aqueous liquid preparations, e.g. oily suspensions, which can be formulated by suspending the active ingredients in vegetable oil, such as peanut oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid la paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as set out above may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. The pharmaceutical compositions according to the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, e.g. olive oil or peanut oil or mineral oil such as liquid la paraffin or mixtures thereof. Suitable suspending agents may be naturally occurring rubbers such as e.g. gum arabic or gum tragacanth, naturally occurring phosphatides, e.g. soybeans, lecithin, and esters or partial esters derived from fatty acid and hehsytol anhydrides, such as e.g. sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as e.g. polyoxyethylene - sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents. Syrups and elixirs can be composed with the use of sweetening agents, e.g. glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also include a soothing agent, preservative and flavoring agent, and coloring agents. 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 which is solid at ordinary temperatures but liquid at the rectal temperature and therefore which will melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. In all regimens of administration of the compounds disclosed herein, the 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, intramuscular, subcutaneous and parenteral injections, and the use of infusion technique, will preferably be from 0.01 to 200 mg / kg of total body weight Ia. The daily winter of rectal dosing will preferably be 0.01 to 200 mg / kg of total body weight Ia. The daily winter of topical dosing will preferably be between 0.1 and 200 mg when administered between one to six times daily. The daily regimen of inhalation dosing will preferably be between 0.01 and 10 mg / kg of total body weight. Those skilled in the art will appreciate that the particular method of administration will depend on a variety of factors, all of which are considered routinely in the administration of therapeutic agents. Those skilled in the art will appreciate that the specific dosage level for a given patient depends on a variety of factors, including the activity of the specific compound administered, age, weight, health, flight, diet, time and time. and method of administration,. fast sc excretion, etc. Moreover, it should be noted that the optimal course of treatment, i.e. the treatment regimen and the number of daily doses of a compound of formula I or a pharmaceutically acceptable salt thereof for a given number of days can be confirmed by those skilled in the art using standard medical tests. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound being used, age, weight a la, general health, c, diet, time of administration, route of administration and rapid sc excretion, drug combination, and the severity of the disease state being treated. The compounds of the invention can be prepared using known chemical reactions and methods, some of the starting materials being commercially available. Compounds can be prepared from known compounds (or from starting materials which can in turn be produced from known compounds), e.g. using the general preparative methods presented below. The sc activity of a given compound in inhibiting the raf kinase can be confirmed routinely, e.g. methods disclosed later in the description. Detailed examples of compound preparation are provided below in part for the experimental. The examples are given for illustration only and are not intended or should not be construed to limit the invention in any way. All reactions were performed in flame-dried or oven-dried glass apparatus under positive pressure of dry argon or dry nitrogen and magnetic stirring, unless otherwise indicated. Sensitive liquids and solutions were transferred with a syringe or tube and introduced into the reaction vessel through a rubber septum. Unless otherwise indicated, the term "concentration under vacuum" refers to the use of a Buchi rotary evaporator at a pressure of approximately 15 mmHg. Unless otherwise indicated, the term "under" vacuum refers to a vacuum of 0.4 - 1.0 mmHg. All temperatures are reported uncorrected and in degrees Celsius (° C). Unless otherwise indicated, all parts and percentages are by weight. Technical grade reagents and solvents were used without further purification. N-cyclohexyl-N '- (methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2-methoxy-5- Ethyl (trifluoromethyl) -aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5- (trifluoromethyl) Aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; AND. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. , 3, 7995, 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 7959, 760; Chem. Abstr. 53, 7959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy -5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42025067; IBID Kogyo Kagaku Zasshi 70, 7967, 491) has been previously described. Thin layer chromatography (TLC) was performed on Whatman® glass plates factory coated with 60A F-254 silica gel, 250 µm grain size. The plaque ep visualization was carried out with one or more of the following techniques: (a) ultraviolet irradiation, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphoromolybdic acid in ethanol and followed by heating, (d) immersing the plate in a cerium sulfate solution followed by heating, and / or (e) immersing the plate in an acidic ethanolic solution of 2,4-dinitrophenylhydrazine, followed by heating. Flash column chromatography was performed using 230-400 mesh EM Science® silica gel. The melting points (t. vol. ) was determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automatic melting point apparatus and temperatures were not corrected. Fourier transform infrared spectra were recorded on a Mattson 4020 Galaxy Series spectrophotometer. Proton (1H) nuclear magnetic resonance (NMR) spectra were recorded on a General Electric GN-Omega 300 spectrometer (300 MHz) using either Me 4 Si (d 0.00) or signals from residual solvent protons ( CHCl 3 d 7.26; MeOH d 3.30; DMSO d 2.49). The nuclear (13 C) nuclear magnetic resonance (NMR) spectrum was recorded on a General Electric GN-Omega 300 spectrometer (75 MHz) using solvent signals as standard (CDCl 3 d 77.0; MeOD-d 6 d 49, 0; DMSO-d 6-8 39.5). Low-resolution (MS) and high-resolution (HRMS) mass spectra were carried out using the electrode ionization (EI) technique and the fast atom bombardment (FAB) technique. Electron ionization mass spectra (EI-MS) were obtained on a Hewlett Packard 5989A mass spectrometer equipped with a sample loading probe and a Vacumetrics Chemical Ionization Probe. The ion source was kept at 250 ° C. The ionization in the electron beam was performed with an electron energy of 70 eV and a capture current of 300 µA. Secondary Ion Mass Spectrometry (FAB-MS), a modernized version of fast atom bombardment, was performed on a Kratos Concept 1-H spectrometer. Chemical ionization mass spectrum (CI-MS) was recorded on a Hewlett Packard MS-Engine (5989A) using methane or ammonia as reacting gases (1 x 10 -4 torr to 2.5 x 10 -4 torr). Chemical Desorption Direct Chemical Ionization (DCI) probes (Vaccumetrics, Inc. ) was adjusted from 0-1.5 to 10 amps for 10 sec and held at 10 amps until trace amounts of sample disappeared (~ 1-2 min). The spectra were scanned from 50-800 times with one recording time being 2 seconds. HPLC chromatography coupled with mass spectrometry performed by electrospray technique (HPLC ES-MS) was performed on a Hewlett-Packard 1100 HPLC device equipped with a quadruple pump, detector with variable PL 203 687 B1 11 wavelength , C-18 columns and Finnigan LCQ ion-capture mass spectrometer for electrocompression. The spectra were scanned from 120-800 times using a variable ionization time according to the number of ions in the source. Gas chromatography coupled to selective mass spectrometry (GC-MS) was performed on a Hewlett Packard 5890 gas chromatograph equipped with a HP-1 methyl silicone column (0.33 µM coating; 25 mx 0.2 mm) and a Hewlett Packard 5971 model mass selective detector (70 eV ionization energy). Elemental analyzes were performed at Robertson Mikrolit Labs, Madison NJ. All compounds gave NMR, LRMS and elemental or HRMS spectra according to the assigned structures. List of abbreviations and acronyms: AcOH acetic acid anh anhydrous atm atmosphere (atmospheres) BOC tert-butoxycarbonyl CDI 1,1'-carbonyldiimidazole conc concentrated day n (days) decomposition DMAC N, N-dimethylacetamide DMPU 1,3-dimethyl -3,4,5,6-tetrahydro-2 (1H) pyrimidinone DMF N, N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol (100%) Et 2 O diethyl ether EtaN triethylamine h hour (s) HOBT 1-hydroxybenzotriazole m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. petroleum ether (boiling range 30-60 ° C) temp. temperature THF tetrahydrofuran TFA trifluoro-AcOH Tf trifluoromethanesulfonyl A. General Methods for the Synthesis of Substituted Anilines A1. General Method for Arylamine Formation via Ether Formation followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-amino-3-methoxy-naphthalene. Step 1. Methyl 3-methoxy-2-naphthoate. 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) was stirred at room temperature for 15 minutes. and then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was stirred at room temperature overnight then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated NaCl (100 mL), dried (MgSO 4), concentrated in vacuo (approx. 0.4 mmHg overnight) to provide ac 3-methoxy-2-naphthoate methyl as an amber oil (10.30 g). 1 H-NMR (DMSO-d 6) d 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (ca. t, J = 8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (approx. t, J = = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H). Stage 2. 3-methoxy-2-naphthoic acid. A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) was treated at room temperature with 1N NaOH (33.4 mL, 33.4 mmol) . The mixture was heated to reflux for 3 hours, cooled to room temperature and acidified with 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 (MgSO 4), and concentrated in vacuo. The residue was triturated with hexane 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) d 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 (broad s, 1H). Stage 3. 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene. 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 anhydrous toluene (70 mL) was stirred at room temperature for 15 minutes. then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette e. The resulting mixture was heated at 80 ° C for 2 hours. After the mixture was cooled to room temperature, a syringe was added and benzyl alcohol (2.06 mL, 20 mmol). The mixture was then heated at 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with 10% citric acid, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO 4) and concentrated in vacuo. The residue was purified by column chromatography (14% EtOAc / 86% hexane) to give ac 1- (N- (carbobenzyloxy) amino-3-methoxynaphthalene as a light yellow oil (5.1 g, 100%). 1 H-NMR (DMSO-d 6) d 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). Stage 4. 2-amino-3-methoxynaphthalene. 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 an atmosphere of H 2 ( balloon), at room temperature, overnight. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to afford 2-amino-3-methoxynaphthalene as a light pink powder (2.40 g, 85%). 1 H-NMR (DMSO-d 6) d 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 Hz, 1H); EI-MS m / z 173 (M +). A2. Synthesis of β-carbamylaniline via the formation of carbamylpyridine followed by nucleophilic coupling with arylamines. Synthesis of 4- (2-N-methylcarbamyl-4-pyridyloxy) aniline. Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinacarboxamide via the Menisci reaction. Warning: this is a very dangerous, potentially explosive reaction. H 2 SO 4 concentrations (3.55 ml) were added to a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 ml) at room temperature to increase the heat of the reaction. To this mixture was added H 2 O 2 (30 wt% in H 2 O, 17 mL) followed by FeSO 4 • 7H 2 O (0.56 g) to further increase the heat of reaction. The resulting mixture was stirred in the dark at room temperature for 1 hour, then warmed slowly over 4 hours to 45 ° C. After the evolution of bubbles had ceased, the reaction mixture was heated at 60 ° C for 16 hours. The resulting opaque brown solution was diluted with H 2 O (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 saturated NaCl solution (3 x 150 ml), then combined, dried (MgSO 4) and filtered through a silica gel pad with 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 was crystallized at 0 ° C over 72 hours to give ac 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%). TLC (50% EtOAc / 50% hexane) R f 0.50; 1 H NMR (CDCl 3) d 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (broad s , 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1Hz, 1H); CI-MS m / z 171 ((M + H) +). Stage 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride hydrochloride via picolinic acid. Anhydrous DMF (6.0 ml) was slowly added to SOCl 2 (180 ml) at a temperature between 40 ° C and 50 ° C. The solution was stirred within this temperature range for 10 minutes. Picolinic acid (60.0 g, 487 mmol) was then added portionwise over 30 minutes. The resulting solution was heated at 72 ° C (strong SO 2 evolution) for 16 hours to form a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to a volume of 200 ml. The toluene addition / concentration process was repeated twice. The resulting almost dry residue was filtered and the solids washed with toluene (2 x 200 ml) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride hydrochloride as yellow. - orange solid body (92.0 g, 89%). Stage 2. Synthesis of methyl 4-chloropyridine-2-carboxylate hydrochloride. Anhydrous DMF (10.0 ml) was slowly added to SOCl 2 (300 ml) at 40-48 ° C. The solution was stirred at this temperature range for 10 minutes, then picolinic acid (100 g, 812 mmol) was added over 30 minutes. The resulting solution was heated at 72 ° C (strong SO 2 evolution) for 16 hours to produce a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The toluene addition / concentration process was repeated twice. The resulting almost dry residue was filtered and the solids were washed with toluene (50 ml) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride hydrochloride as a white solid. lego (27.2 g, 16%). These substances were set aside. 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 minutes, cooled to 5 ° C, and treated dropwise with Et 2 O (200 mL). The resulting solids were filtered, washed with Et 2 O (200 ml) and dried in vacuo at 35 ° C to give methyl 4-chloropyridine-2-carboxylate hydrochloride as a white solid (110 g , 65%). Melting point 108-112 ° C. 1 H-NMR (DMSO-d 6) d 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); 10.68 (broad s, 1H); HPLC ES-MS m / z 172 ((M + H) +). Stage 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate. A suspension of methyl 4-chloropyridine-2-carboxylate hydrochloride (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (1 L) with a fast retention regime of The internal temperature is below 5 ° C. The resulting mixture was stored at 3 ° C for 5 hours, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with saturated NaCl (500 ml), dried (Na 2 SO 4) and concentrated in vacuo to give ac 4-chloro-N-methyl-2-pyridinecarboxamide as light yellow crystals (71, 2 g, 97%). Melting point 41-43 ° C; 1 H-NMR (DMSO-d 6) d 2.81 (s, 3H), 7.74 (dd, J-5A, 2.2 Hz, 1H), 8.00 (d, J = 2.2, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (broad d, 1H); CI-MS m / z 171 ((M + H) +). Stage 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride 4-chloropyridine-2-carbonyl chloride hydrochloride (7.0 g, 32.95 mmol) was added portionwise to a mixture of 2.0M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 &lt; 0 &gt; C. The obtained mixture was stored at 3 ° C for 4 hours, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with saturated NaCl solution (2 x 100 mL), dried (Na 2 SO 4) and concentrated in vacuo to give ac 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88%). Melting point 37-40 ° C. Stage 4. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (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 hours. The S 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 then heated to 80 ° C. for 8 hours. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was re-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 mL), dried (Na 2 SO 4), and concentrated in vacuo. The resulting solids were dried under reduced pressure at 35 ° C for 3 hours to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9 g, 84%). 1 H-NMR (DMSO-d 6) d 2.77 (d, J = 4.8 Hz, 3H), 5.17 (broad s, 2H), 6.64, 6.86 ( AA'BB 'quartet, 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. General method for aniline synthesis by nucleophilic aromatic addition followed by reduction of nitroarene. Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione. 4-Hydroxyphthalic acid (5.0 g, 27.45 mmol) was slowly added to a mixture of ammonium egylate (5.28 g, 54.9 mmol) in concentrated AcOH (25 mL). The resulting mixture was heated at 120 ° C for 45 minutes, then a clear, light yellow mixture was heated at 160 ° C for 2 hours. The resulting mixture was kept at 160 ° C and concentrated to approximately 15 mL, then cooled to room temperature and adjusted to pH 10 with 1N NaOH. This mixture was cooled to 0 ° C and slowly acidified to pH 5 using 1N HCl solution. The resulting precipitate was collected by filtration and dried in vacuo to give ac 5-hydroxyisoindoline-1,3-dione as a light yellow powder as the product (3.24 g, 72%), 1H NMR (DMSO- d 6) d 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H). Stage 2. Synthesis of 5- (4-nitrophenoxy) isoindoline-1,3-dione To a stirred suspension of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 ° C, a solution of 5-hydroxyisoindoline was added dropwise. 1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL). The pale yellow-green mixture was allowed to return to room temperature and stirred for 1 hour, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added by syringe in 3-4 portions. The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature, slowly diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO 4) and concentrated in vacuo 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) d 7.32 (d, J = 12 Hz, 2H), 7.22-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9Hz, 2H), 11.43 (broad s, 1H); CI-MS m / z 285 ((M + H) + 100%). Stage 3. Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g, 2.11 mmol) in concentrated AcOH (12 mL) and water (0.1 mL) was stirred under an argon stream while iron powder (0.59 g, 55.9 mmol) was slowly added. This mixture was stirred at room temperature for 72 hours, then diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO 4) and concentrated in vacuo to afford 5- (4-aminophenoxy) isoindoline-1,3-dione as a tan solid (0.4 g, 75%). TLC (50% EtOAc / 50% hexane) R f 0.27; 1 H NMR (DMSO-d 6) d 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%). A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline. Step 1. Synthesis of 1- (4-tert-butyl-2-nitrophenyl) -2,5-dimethylpyrrole. To a stirred solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added a syringe of AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) . The reaction mixture was heated at 120 ° C for 72 hours, with azeotropic removal of volatiles. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (10 ml) and washed sequentially with 1N HCl (15 ml), 1N NaOH (15 ml) and saturated NaCl (15 ml), dried (MgSO 4) and concentrated under reduced pressure. The resulting orange-brown solids were purified by column chromatography (60 g SiO 2; gradient from 6% EtOAc / 94% hexane to 25% EtOAc / 75% hexane) to afford ac 1- (4-tert-butyl). 2-nitrophenyl) -2,5-dimethylpyrrole as an orange-yellow solid body (0.34 g, 49%). TLC (15% EtOAc / 85% hexane) R f 0.67; 1 H NMR (CDCl 3) d 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 = 2A Hz, 1H); CI-MS m / z 273 ((M + H) +, 50%). Stage 2. Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline Suspension 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) under an atmosphere of H 2 (balloon) were stirred for 72 hours, then filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to afford 5-tert-butyl--2- (2,5-dimethylpyrrolyl) aniline as a yellowish solid (0.30 g, 99%). TLC (10% EtOAc / 90% hexane) R f 0.43; 1 H NMR (CDCl 3) d 1.28 (s, 9h), 1.87-1.91 (m, 8H), 5.85 (broad s, 2h), 6.73-6.96 (m, 3h), 7.28 (s broad, 1H). A5 General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline hydrochloride. A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 ml) was treated with tert- potassium butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temperature until the flask reached room temperature. The contents were 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 hours. 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 (MgSO 4), and concentrated in vacuo. The remaining black oil was treated with Et 2 O (50 mL) and sonicated. The solution was then treated with HCl (1M in Et 2 O; 100 mL) and stirred at room temperature for 5 minutes. The resulting dark pink solids (7.04 g, 24.1 mmol) were removed by filtration from the solution and stored anaerobically at 0 ° C before use. 1 H NMR (DMSO-d 6) d 2.41 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (broad 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. 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 Step 1: Synthesis of 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol Zelazo (3.24 g, 58.00 mmol) was added to stirred TFA (200 ml). To this suspension was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). These gray suspensions were stirred at room temperature for 6 days. The iron was drained from the solution and the remaining material was concentrated under reduced pressure. The resulting gray precipitate was dissolved in water (20 ml). To the resulting yellow solution was added saturated NaHCO 3 solution (50 mL). The precipitated solids removed eto from the solution poorly. The filtrate reaction was slowly stopped with sodium hydrogen carbonate solution until visible separation of product from solution (determined using a small working tube). The labile yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSO 4), and concentrated in vacuo. 1H NMR analysis (DMSO-d6) showed 1: 1 nitrophenol starting material and intended product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol in a ratio of 1: 1. The crude material was used in the next step without further purification. Step 2: Synthesis of (2,2,2-trifluoro) acetamide 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloro-phenyl A solution of the 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 has 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 days. The black reaction mixture was cooled to room temperature and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The remaining brown oil was purified by column chromatography (gradient from 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether) to afford ac (2,2,2-trifluoro) acetamide 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl as a yellow solid (8.59 g, 23.0 mmol). Step 3. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline. A solution of the crude 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (8.59 g, 23.0 mmol) crude (2,2,2-trifluoro) acetamide in dry 4-dioxane ( 20 ml) was treated with 1N NaOH solution (20 ml). This brown solution was stirred for 8 hours. To this solution was added EtOAc (40 mL). 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 which solidified after standing (2.86 g, 10.30 mmol). 1 H NMR (DMSO-d 6) d 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, 1H). A7. General Method for Deprotecting an Acylated Aniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline Suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) -anisole (4.00 g, 14.95 mmol) in a 6M solution HCl (24 ml) was heated to reflux for 1 hour e. The resulting solution was allowed to cool to room temperature during which time it solidified poorly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and saturated NaHCO 3 solution until the solution was basic. The organic layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organics were dried (MgSO 4) and concentrated in vacuo to give ac 4-chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14.2 mmol). 1 H NMR (DMSO-d 6) d 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H). A8. General Method for the Synthesis of α-alkoxy-α-carboxyphenylanilines. Synthesis of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline Step 1. 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene. K 2 was added to a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid analogously to Method A13, Step 1, 12 mmol) in acetone (50 ml). CO 3 (5 g) and dimethyl sulfate (3.5 ml). The resulting mixture was refluxed overnight, then cooled to room temperature and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed into SiO 2, and purified by column chromatography (50% EtOAc / 50% hexane) to yield 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene in yellow powder form (3 g). Melting point 115-118 ° C. Stage 2. 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene. A mixture 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 it was heated to reflux for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The remaining residue was dissolved in water (50 ml) and the aqueous mixture was acidified with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO 4) and concentrated in vacuo to give ac 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g). Stage 3. 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene. To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 1.75 mmol) in CH 2 Cl 2 (12 ml) was added SOCl 2 (0.64 ml, 8.77 mmoles). The resulting solution was refluxed for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The obtained yellow solids were partially dissolved in CH 2 Cl 2 (3 ml), then the resulting solution was treated in portions with a methylamine solution (2.0M in THF, 3.5 ml, 7.02 mmol) (NOTE: evolution of e gas) and stirred at room temperature for 4 hours. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH 2 Cl 2 (25 mL). The organic layer was dried (Na 2 SO 4) and concentrated in vacuo to give ac 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene as a yellow solid ( 0.50 g, 95%). Stage 4. 4- (3- (n-methylcarbamoyl) -4-methoxyphenoxy) aniline. A suspension of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) stirred under 1 atmosphere of H 2 (balloon) for 2.5 days, then filtered through a Celite® pad. The resulting solution was concentrated under reduced pressure to afford 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as a white solid (0.68 g, 96%). TLC (0.1% Et 3 N / 99.9% EtOAc) R f 0.36. A9. General Method for Preparation of Anilines Containing β-alkylphthalimide. Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione Step 1. Synthesis of 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione. 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 ) stirred at room temperature for 1 hour then treated with methyl iodide (0.3 ml, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, then cooled to ° C and treated with water (10 mL). The resulting solids were collected and dried in vacuo to give ac 5- (4-nitrophenoxy) -2-methyl-isoindoline-1,3-dione as a light yellow solid (0.87 g, 83% ). TLC (35% EtOAc / 65% hexane) R f 0.61. Stage 2. Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione. 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 atmosphere H 2 (balloon) for night. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a SiO 2 pad (60% EtOAc / 40% hexane) to give 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. General Method for the Synthesis of α-Carbamoylarylaniline by Reaction of α-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline Step 1. Synthesis of 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine. To a solution of methyl 4-chloropyridine-2-carboxylate hydrochloride (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 ml) was added 4- (2-aminoethyl) morpholin e (2.55 ml) dropwise. , 19.4 mmol) and the resulting solution was heated to reflux for 20 hours, 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 in vacuo to give ac 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridines as a yellow oil (1.25 g, 95%). TLC (10% MeOH / 90% EtOAc) R f 0.50. Stage 2. Synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline. A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 ml) was stirred at room temperature for 2 hours, then treated sequentially for 4 hours. -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 ° C overnight, cooled to room temperature, and partitioned between EtOAc (25 mL) and saturated NaCl solution (25 mL). The aqueous layer was re-extracted 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 afford ac 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline (1.0 g, 65%). TLC (10% MeOH / 90% EtOAc) R f 0.32. A11. General Method for the Reduction of Nitroarens to Arylamines. Synthesis of 4- (3-carboxyphenoxy) aniline. 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 an atmosphere of H 2 (balloon) during 2 days. The resulting mixture was filtered through a Celite® layer, then concentrated under reduced pressure to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48% ). TLC (10% MeOH / 90% CH 2 Cl 2) R f 0.44 (smear). A12. General Method for the Synthesis of Isoindolinone Containing Anilines. Synthesis of 4- (1-oxoisoindolin-5-yloxy) aniline. Level 1. Synthesis of 5-hydroxyisoindolin-1-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 ml) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated to a at reflux for 40 minutes, filtered hot and concentrated in vacuo. The reaction was repeated on the same scale and the combined oily residues were purified by column chromatography (1.1 kg SiO 2; gradient from 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to yield ac 5-hydroxyisoindolin-1-one (3.77 g). TLC (100% EtOAc) R f 0.17; HPLC ES-MS m / z 150 ((M + H) +). Stage 2. Synthesis of 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene. 5-Hydroxy-isoindolin-1-one (2.0 g, 13.4 mmol) was added portionwise to a suspension of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C. The resulting suspension was allowed to warm to room temperature and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and then the mixture was heated at 70 ° C for 3 hours. The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate was formed. The precipitated solid was collected, yielding 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%). TLC (100% EtOAc) R f 0.35. Stage 3. Synthesis of 4- (1-oxoisoindolin-5-yloxy) aniline. A suspension of 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 ml) was stirred under an atmosphere of H 2 (balloon) for 4 hours, then filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to give 4- (1-oxoisoindolin-5-yloxy) aniline as a dark yellow solid. TLC (100% EtOAc) R f 0.15. A13. General Method for the Synthesis of α-carbamoyl-aniline by Amide Formation via EDCI followed by Nitroarene Reduction. Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline. Level 1. Synthesis of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (16 ml, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol) and K 2 CO 3 (41 g, 300 mmol) in DMF (125 mL) was refluxed overnight, cooled to room temperature and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed successively with water (3 x 100 ml) and a saturated NaCl solution (2 x 100 ml), dried (Na 2 SO 4) and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc / 90% hexane) to give 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene as an oil (38 g). Stage 2. Synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene For 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) A solution of LiOH.H2O (1.50 g, 35.8 mmol) in water (36 mL) was added. The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure and adjusted to pH 2 with 1M HCl. The resulting light yellow solids were removed by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%). Step 3. Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene. 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 (2.0M in THF; 8 mL, 16 mmol) in CH 2 Cl 2 (45 mL) was stirred at room temperature for 3 days then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with 1M HCl (50 mL). The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaCl (50 ml), dried (Na 2 SO 4) and concentrated in vacuo to give ac 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene as an oil (1.89 g). Stage 4. Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) aniline 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) was stirred under an atmosphere of H 2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / 95% CH 2 Cl 2). The resulting oil solidifies under reduced pressure overnight to give 4- (3- (N-methylcarbamoyl) phenoxy) aniline as a yellow solid (0.95 g, 56%). A14. General Method for the Synthesis of β-Carbamoylaniline by Amide Formation via EDCI followed by Nitroarene Reduction. Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) aniline Step 1. Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. 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 ° C overnight, cooled to room temperature, and treated. MeOH (5 mL) followed by aqueous (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane) to give ac 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g). Stage 2. Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline Suspension of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred under an atmosphere of H 2 (balloon) for 72 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was 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) d 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (1H), 8.51 (d, 1H) , 8.87 (d, 1H). PL 203 687 B1 23 A15. Aniline synthesis by electrophilic nitration followed by reduction. Synthesis of 4- (3-methylsulfamoylphenoxy) aniline Step 1. Synthesis of N-methyl-S-bromobenzenesulfonamide. Methylamine e (2.0M in THF; 28 ml, 56 mmol) was added to a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mol) in THF (15 ml) at 0 ° C. The resulting solution was allowed to warm to room temperature and was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1M HCl (25 mL). The aqueous phase was re-extracted with EtOAc (2 x 25 mL). The combined organic phases were washed sequentially with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4) and concentrated in vacuo to give N-methyl-3-bromobenzenesulfonamide as a white solids (2.8 g, 99%). Stage 2. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene For a suspension of phenol (1.9 g, 20 mol), 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 overnight, cooled to room temperature, and partitioned between EtOAc (50 mL) and 1N. HCl solution (50 ml). The aqueous layer was re-extracted 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 (MgSO 4) and concentrated in vacuo. The residual oil was purified by column chromatography (30% EtOAc / 70% hexane) to give ac 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g). Stage 3. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene. NaNO 2 (0.097 g, 1.14 mmol) was added portionwise to a solution of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 ml) at -10 ° C. ) for 5 minutes. The resulting solution was stirred at -10 ° C for 1 hour, then allowed to warm to room temperature, and concentrated under reduced pressure. The remainder of the mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed successively with water (10 ml) and saturated NaCl (10 ml), dried (MgSO 4) and concentrated in vacuo to give 4- (3- (N-methylsulfamoyl) phenyloxy ) -1-nitrobenzene (0.20 g). These materials were used in the next step without further purification. Stage 4. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) aniline. 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 an atmosphere of H 2 (balloon) overnight . The resulting mixture was filtered through a layer of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane) to give ac 4- (3- (N-methylsulfamoyl) phenyloxy) aniline (0.070 g). PL 203 687 B1 24 A16. Modification of? -Ketones. Synthesis of 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride To a slurry of 4- (4-acetylphenoxy) aniline hydrochloride (prepared analogously 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 hydrochloride (0.65 g, 7.78 mmol, 2.0 eq.) was added. The resulting solution was refluxed for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The resulting solids were triturated with water (10 ml) and washed with water to give 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride as a yellow solid (0.85 g ). TLC (50% EtOAc / 50% petroleum ether) R f 0.78; 1 H NMR (DMSO-d 6) d 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 ((M + H) +). A17. Synthesis of N - ((o-silyloxyalkyl) amides. Synthesis of 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline Step 1. 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared analogously to Method A2, Step 3b; 1.5 g, 7.4 mmol) in dry DMF (7 ml) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 eq. Disappear) and imidazole (1.12 g, 16.4 mmol, 2.2 eq.). The resulting yellow solution was stirred for 3 hours at room temperature then concentrated under reduced pressure. The remaining residue was partitioned 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 in vacuo to give ac 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) pyridine carboxamide as an orange oil (2.32 g, 88%). This material was used for the next step without further purification. Stage 2. 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline. To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 ml) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 eq. and c to warm the reaction mixture. When this mixture was cooled to room temperature, the solution was added 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 eq disappears). 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 an additional 4 hours. The mixture was cooled to 0 ° C in an ice / water bath, then water was added slowly dropwise (approximately 1 ml). 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 (MgSO 4), and concentrated in vacuo. The brown oily residue was purified by column chromatography (SiO 2; 30% EtOAc / 70% petroleum ether) to afford 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridine oxyaniline or as a clear light brown oil (0.99 g, 38%). PL 203 687 B1 25 A18. Synthesis of 2-pyridine carboxylate esters by oxidation of 2-methylpyridines. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline Step 1. 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. A mixture 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 eq.) In DMF (100 mL) was heated to reflux overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed sequentially with water (2 x 100 mL) and saturated NaCl ((100 mL), dried (MgSO 4) and concentrated in vacuo to afford 4- (5- (2-methyl) - pyridyloxy) -1-nitrobenzene in the form of a brown solid (12.3 g). Stage 2. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. A mixture 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 eq.) In pyridine (20 mL) was refluxed for 5 hours and then cooled to room temperature. The resulting suspension was filtered and then concentrated under reduced pressure. The remaining residue was dissolved in MeOH (100 mL). The solution was treated with a concentrated HCl solution (7 mL), then heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 1N NaOH (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed sequentially with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4) and concentrated in vacuo. The remainder of the sc was purified by column chromatography (SiO 2; 50% EtOAc / 50% hexane) to give ac 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.70 g). Stage 3. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. 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 H 2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2; 70% EtOAc / 30% hexane) to provide 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g). A19. Synthesis of β-sulfonylphenylanilines. Synthesis of 4- (4-methylsulfonylphenyoxy) aniline Step 1. 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. 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, m-CPBA (57-86%, 4.0 g) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was treated with a 1N NaOH solution (25 mL). The organic layer was washed sequentially with 1N NaOH (25 mL), aq. (25 mL), and a saturated NaCl solution (25 mL), dried (MgSO 4), and concentrated in vacuo to give 4- (4- methylsulfonylphenoxy) -1-nitrobenzene as a solid (2.1 g). Step 2. 4- (4-methylsulfonylphenoxy) -1-aniline. 4- (4-methylsulfonylphenoxy) -1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A18, step 3. B. Synthesis of urea precursors B1. General Method for the Synthesis of Isocyanates from Aniline Using CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate. Step 1. Synthesis of 4-bromo-3- (trifluoromethyl) aniline hydrochloride. A solution of HCl (1M in Et 2 O; 300 ml) was added dropwise to a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et 2 O (500 ml) and the resulting mixture was stirred in room temperature for 16 hours. The resulting pink-white precipitate was removed by filtration and washed with Et 2 O (50 ml) to give 4-bromo-3- (trifluoromethyl) aniline hydrochloride (73 g, 98%). Stage 2. Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate. A suspension of 4-bromo-3- (trifluoromethyl) aniline hydrochloride (36.8 g, 133 mmol) in toluene (278 ml) was treated dropwise with trichloromethyl chloroformate and the resulting mixture was heated. at boiling point for 18 hours. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL) then concentrated under reduced pressure. The remainder was treated with CH 2 Cl 2 (500 mL) then concentrated under reduced pressure. The CH 2 Cl 2 treatment / concentration cycle was repeated and the resulting amber oil was stored at -20 ° C for 16 hours, yielding 4-bromo-3- (trifluoromethyl) phenyl isocyanate as a brown solid (35.1 g, 86%). GC-MS m / z 265 (M +). C. Methods of obtaining urea C1a. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 4-chloro-3- (trifluoromethyl) isocyanate solution phenyl (14.60 g, 65.90 mmol) in CH 2 Cl 2 (35 ml) was added dropwise to a suspension of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (Method A 2, 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 hours. The resulting yellow solids were removed by filtering, then washed with CH 2 Cl 2 (2 x 30 mL) and dried in vacuo (approx. 1 mmHg) to give N- (4-chloro -3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) urea as a white solid (28.5 g, 93% ). Melting point 207-209 ° C; 1 H-NMR (DMSO-d 6) d 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 (broad d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 465 ((M + H) +). PL 203 687 B1 27 C1b. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 4-bromo-3- (trifluoromethyl) isocyanate solution phenyl (Method B1, Step 2; 8.0 g, 3 0.1 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 hours. The resulting yellow solids were removed by filtering, then washed with CH 2 Cl 2 (2 x 50 mL) and dried in vacuo (approx. 1 mmHg) at 40 ° C to give N - (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea in the form of a light yellow solid (13, 2 g, 90%). Mp. 203-205 ° C; 1 H-NMR (DMSO-d 6) d 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. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea. A solution of 2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.11 g, 0.45 mmol) in CH 2 Cl 2 (1 ml) was treated with Et 3 N (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 days then treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO 4) and concentrated in vacuo to give ac 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) d 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 (approx. d, 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. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) -phenyl) -N '- (4-aminophenyl) urea For 4-chloro-3- (trifluoromethyl) phenyl isocyanate solution (2.27 g, 10.3 mmol) N-phenylenediamine (3.32 g, 30.7 mmol) was added in CH 2 Cl 2 (308 mL) in one portion. The resulting mixture was stirred at room temperature for 1 hour, 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 0.05N HCl. The organic layer was concentrated under reduced pressure to give impure N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea (3.3 g). TLC (100% EtOAc) R f 0.72. C1e. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 ml ) 4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol) was added and the solution was stirred at room temperature overnight. The resulting suspension was diluted with CH 2 Cl 2 (50 ml) and filtered to give ac N- (4-chloro-3- - (trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea as a white body la solid (5.93 g, 97%). TLC (40% EtOAc / 60% hexane) R f 0.44. C1f. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea 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 stirring was continued for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting brown solid was triturated with a 1: 1 EtOAc / hexane solution to give ac N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea as a white body la solid (1.21 g, 76%). C2a. General Method for the Synthesis of Urea by Reaction of an Aniline with N, N'-carbonyldiimidazole followed by Addition of a Second Aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea For 2-methoxy-5- (trifluoromethyl) solution aniline (0.15 g) in anhydrous CH 2 Cl 2 (15 ml), at 0 ° C, CDI (0.13 g) was added. The resulting solution was allowed to warm to room temperature over 1 hour, stirred at room temperature for 16 hours, then treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours then treated with H 2 O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgSO 4), and concentrated in vacuo. The remaining residue was triturated (90% EtOAc / 10% hexane). The resulting solid white was 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 afford N- (2-methoxy-). 5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a light brown solid (0.098 g, 30%). TLC (100% EtOAc) R f 0.62; 1 H NMR (DMSO-d 6) d 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. General Method for the Synthesis of Urea by Reaction of an Aniline with N, N'-carbonyldiimidazole followed by Addition of a Second Aniline. Symmetrical ureas as by-products of N, N'-carbonyldiimidazole reaction. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea For a mixed solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 ml) at 0 [Deg.] C CDI (0.13 g) was added. The resulting solution was allowed to warm to room temperature over 1 hour then stirred at room temperature for 16 hours. 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 hours 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 (MgSO 4) and concentrated under reduced pressure. The remaining residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give ac bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%). TLC (100% EtOAc) R f 0.50; 1H NMR (DMSO-d6) d 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. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with Anilines. Synthesis of N- (2-methoxy-5- - (trifluoromethyl) -phenyl-N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea For a mixed solution of 2-methoxy-5- (trifluoromethyl) isocyanate phenyl (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 ml) was added 5- (4-aminophenoxy) isoindoline-1,3-dione in one portion (Method A3, Step 3; 0.12 g , 0.47 mmol). The resulting mixture was stirred for 12 hours then treated with CH 2 Cl 2 (10 mL) and MeOH (5 mL). The resulting mixture was washed sequentially with 1N HCl (15 mL) and saturated NaCl (15 mL), dried (MgSO 4), and concentrated in vacuo to yield ac N- (2-methoxy-5- (trifluoromethyl) ) phenyl-N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea in the form of a white solid (0.2 g, 96%). TLC (70% EtOAc / 30% hexane) R f 0.50; 1 H NMR (DMSO-d 6) d 3.9 (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. General Method for the Synthesis of Urea by Reaction of an Aniline with N, N'-carbonyldiimidazole 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 PL 203 687 B1 5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) aniline (Method A4 , Step 2; 0.30 g, 1.24 mmol). The resulting mixture was stirred at room temperature for 4 hours, then 4- (2- - (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added in one 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 sequentially with water (15 mL) and 1N HCl (15 mL), dried (MgSO 4), and filtered through a silica gel pad (50 g) to yield N- (5- (tert. - -butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea in the form of a yellowish solid (0.033 g, 24%). TLC (40% EtOAc / 60% hexane) R f 0.24; 1H NMR (acetone-d6) d 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8Hz, 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 = 5AHz, 1H), 8.57 d, J = 2.1 Hz, 1H), 8.80 (broad s, 1H); HPLC ES-MS 512 ((M + H) +, 100%). C3. Combinatorial method for the synthesis of diphenylureas using triphosgene. One of the conjugated anilines was dissolved in dichloroethane (0.10M). This solution was added to an 8 ml tube (0.5 ml) containing dichloroethane (1 ml). Thereto was added a solution of bis (trichloromethyl) carbonate (0.12M in dichloroethane, 0.2ml, 0.4eq. Disappear) followed by diisopropylethylamine (0.35M in dichloroethane, 0.2ml, 1.2 eq. Disappears). The tubes were sealed and heated at 80 ° C for 5 hours then allowed to cool to room temperature for approximately 10 hours. Second aniline (0.10M in dichloroethane, 0.5 ml, 1.0 eq. Disappear) was added, followed by diisopropylethylamine (0.35M in dichloroethane, 0.2 ml, 1.2 eq. Disappearing). 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. General Method for the Synthesis of Urea by Reaction of 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 For a mixed solution of phosgene (1.9M in toluene; 2.07 ml, 0.11 g, 1.30 mmol) in CH 2 Cl 2 (20 ml) at 0 ° C was added anhydrous pyridine e (0.32 ml) followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to warm to room temperature resulting in the formation of a precipitate. The yellow mixture was stirred for 1 hour, then concentrated under reduced pressure. The resulting solids were treated with anhydrous toluene (20 ml) followed by 4- (2- - (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared as described in Method A2; 0.30 g) and yielded The scan of the suspension was heated at 80 ° C for 20 hours, then allowed to cool to room temperature. The resulting mixture was diluted with water (100 ml), then made basic with saturated NaHCO 3 solution (2-3 ml). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separated, washed with a saturated NaCl solution, combined, dried (MgSO 4), and concentrated in vacuo. The resulting pink-brown residue was dissolved in MeOH and absorbed onto SiO 2 (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) and then concentration under reduced pressure at 45 ° C gave a warm, concentrated EtOAc solution which was treated with hexane (10 ml) to slowly form N- (2-methoxy-5-trifluoromethyl) crystals phenyl) -N '- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.44 g). TLC (1% Et 3 N / 99% EtOAc) R f 0.40. PL 203 687 B1 31 D. Transformation of ureas D1a. Conversion of α-aminophenylureas to α- (aroylamino) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea For N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N solution '- (4-aminophenyl) urea (Method C1d; 0.050 g, 1.52 mmol), mono-methylisophthalate (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) were added EDCI.HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated NaHCO 3 (25 mL). The organic layer was dried (Na 2 SO 4) and concentrated in vacuo. The resulting solids were triturated with EtOAc (80% EtOAc / 20% hexane) to give ac N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%). Melting point 121-122 ° C; TLC (80% EtOAc / 20% hexane) R f 0.75. D1b. Conversion of α-carboxyphenylureas to α- (arylcarbamoyl) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) -carbamoylphenyl) urea For a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (3-methylcarbamoylphenyl) carboxamino-phenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoyl aniline (0.080 g, 0.53 mmol), HOBT • H 2 O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL), added EDCI.HCl (0.10 g, 0.53 mmol) at 0 ° C . The resulting mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was treated with aq (10 mL) and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow portions were continuously dissolved in EtOAc (3 mL) then filtered through a silica gel pad (17 g, gradient from 70% EtOAc / 30% hexane to 10% MeOH / 90% EtOAc) to yield 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. Combinatorial Approach to Convert α-carboxyphenylureas to α- (arylcarbamoyl) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea Mixtures 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 CH 2 Cl 2 (1M; 0.074 ml, 0.074 mmol) (in the case of no dissolution or if it became dimmed, only a small amount of DMSO was added). The resulting EPL mixture was heated at 36 ° C overnight. The mixture was then treated with THF (1 mL) and heating was continued for 18 hours. The resulting mixtures were treated with poly (4- (isocyanatomethyl) styrene) (0.040 g) and the resulting mixture was stirred at 36 ° C for 72 hours, then cooled to room temperature and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure gave 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. Conversion of α-carboalkoxyarylureas to α-carbamoylarylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea For sample N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-Carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2M in THF; 1 mL, 1.7 mmol) and a mixture of stirred at room temperature overnight, then concentrated in vacuo to give ac N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea as lego white body. Melting point 247 ° C; TLC (100% EtOAc) R f 0.35. D3. Conversion of α-carboxalkoxyarylureas to α-carboxyarylureas. Synthesis of N- (4-chloro-3- - ((trifluoromethyl) -phenyl) -N '- (4-carboxyphenyl) urea For the suspension of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N' - ( 4-ethoxycarbonylphenyl) urea (Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 ml) was added an aqueous solution of KOH (2.5N, 10 ml, 23 mmol). The resulting mixture was refluxed for 12 hours, cooled to room temperature, and concentrated in vacuo. The residue was diluted with water (50 mL), then treated with 1N HCl to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) - -N '- (4-carboxyphenyl) urea as a white solid (5 0.05 g, 92%). D4. General Method for the Conversion of α-Alkoxyesters to α-Alkylamides. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea Step 1. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea N- (4-chloro-3- (trifluoromethyl) phenyl) -N '((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea was synthesized from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- (5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a way analogous to the C1a Method. 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 hour e. The pH of the resulting mixture was adjusted to 5 with a 1N HCl solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL), and the resulting solution was concentrated under reduced pressure. The procedure ePL 203 687 B1 33 EtOH / concentration was repeated twice, yielding N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0 18 g, 71%). Stage 2. Synthesis of N- (4-chloro-3-trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea. 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 partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 ml), dried (MgSO 4) and concentrated in vacuo. The residue was dissolved in the minimum amount of CH 2 Cl 2 (approximately 2 mL). The resulting solution was treated dropwise with Et 2 O, yielding ac N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea as a white solid (0.48 g, 84%). 1H NMR (DMSO-d6) d 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. General Method for the Deprotection of N- (α-silyloxyalkyl) amides. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea. To a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared by a method analogous to Method C1a; 0.25 g, 0.37 mmol) in dry THF (2 ml) was added tetrabutylammonium fluoride (1.0M in THF; 2 ml). The mixture was stirred at room temperature for 5 minutes, then was treated with water (10 ml). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgSO 4) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2; gradient from 100% hexane to 40% EtOAc / 60% hexane) to give ac N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N'- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxy phenyl) urea as a white solid (0.019 g, 10%). The compounds synthesized according to the detailed experimental methods described previously are presented below. Entry 1: 4- (2-N-methylcarbamyl-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 give ac urea. Item 2: 4-chloropyridine-2-carbonyl chloride hydrochloride was reacted with ammonia according to Method A2, Step 3b, to give ac 4-chloro-2-pyridine carboxamide. The 4-chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give ac 4- (2-carbamoyl-4-pyridyloxy) aniline. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline according to Method C1a to give ac urea. Item 3: 4-chloropyridine-2-carbonyl chloride hydrochloride was reacted with ammonia according to Method A2, Step 3b, to give ac 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4, to give ac 3- (2-carbamoyl-4-pyridyloxy) aniline. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline according to Method C1a to give ac urea. Item 4: 4-chloro-N-methyl-2-pyridine carboxamide which was synthesized according to Method A2, Step 3a, reacted with 3-aminophenol according to Method A2, Step 4, give ac 3- (2 - (N-methylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to give ac urea. Entry 5: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give ac urea according to Method C1a. Entry 6: 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. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea. Entry 7: 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. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give ac urea according to Method C1a. Entry 8: 4-amino-2-chlorophenol reacted according to Method A2, Step 4 with 4-chloro-N-methyl-2-pyridine carboxamide which was synthesized according to Method A2, Step 3b, give ac 4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline e. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give ac urea according to Method C1a. Item 9: 4-chloro-N-methyl-2-pyridinecarboxamide which was synthesized according to Method A2, Step 3a, reacted with 3-aminophenol according to Method A2, Step 4, give ac 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. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to give ac urea. Entry 10: 4-chloro-N-methylpyridine carboxamide was synthesized according to Method A2, Step 3b. The chloropyridines were reacted with 3-aminothiophenol according to Method A2, Step 4, to give ac 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method C1a to give urea. Entry 11: 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-non-oxy--5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. 4-Chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- - (N-methylcarbamoyl) -4-pyridyloxy) aniline to give ac urea according to Method C1a. Entry 12: 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. 4-Chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline and according to Method C1a, give ac urea. Tables 1-3 below list the compounds that were synthesized according to the detailed experimental methods and their characteristics are given: T a b l and c a 4. 3- (trifluoromethyl) -4-chlorophenylureas T a b 1 and c a 2. 3- (trifluoromethyl) -4-bromophenylureas T a b 1 and c a 3. 5- (trifluoromethyl) -4-chloro-2-methoxyphenylureas PL PL PL

Claims (18)

1. Zastrze zenia patentowe 1. Zwi azek wybrany z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik,PL 203 687 B1 38 N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalna sól.1. Claims 1. A compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, PL 203 687 B1 38 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 -chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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. 2. Zwi azek wed lug zastrz. 1, znamienny tym, ze jest farmaceutycznie dopuszczaln a sola wy- bran a z grupy obejmuj acej a) zasadowe sole kwasów organicznych i kwasów nieorganicznych wybranych z grupy obejmu- jacej kwas chlorowodorowy, kwas bromowodorowy, kwas siarkowy, kwas fosforowy, kwas metanosul- fonowy, kwas trifluorosulfonowy, kwas benzenosulfonowy, kwas p-toluenosulfonowy (tosylan), kwas 1-naftalenosulfonowy, kwas 2-naftalenosulfonowy, kwas octowy, kwas trifluorooctowy, kwas jab lkowy, kwas winowy, kwas cytrynowy, kwas mlekowy, kwas szczawiowy, kwas bursztynowy, kwas fumarowy, kwas maleinowy, kwas benzoesowy, kwas salicylowy, kwas fenylooctowy i kwas migda lowy; i b) kwa sne sole organicznych i nieorganicznych zasad zawieraj ace kationy wybrane z grupy obejmuj acej kationy metali alkalicznych, kationy metali ziem alkalicznych, kation amonowy, alifatycz- nie podstawiony kation amoniowy i aromatycznie podstawiony kation amoniowy.2. Compound according to claim A salt according to claim 1, characterized in that it is a pharmaceutically acceptable salt selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, jaalic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, acid fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium, aliphatic substituted ammonium and aromatically substituted ammonium. 3. Kompozycja farmaceutyczna zawieraj aca substancj e aktywn a oraz fizjologicznie dopuszczal- ny no snik, znamienna tym, ze substancj a aktywn a jest zwiazek okre slony w zastrz. 1 lub jego farma- ceutycznie dopuszczalna sól.3. A pharmaceutical composition containing an active ingredient and a physiologically acceptable carrier, characterized in that the active ingredient is a compound as defined in claim 1. 1 or a pharmaceutically acceptable salt thereof. 4. Zwi azek wed lug zastrz. 1, znamienny tym, ze jest zwi azkiem wybranym z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydylo- ksy))fenylo)mocznik, lub jego farmaceutycznie dopuszczalna sól.4. A compound according to claim The compound of claim 1, which is a compound selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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 '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - (4 - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 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. 5. Zwi azek wed lug zastrz. 4, znamienny tym, ze jest farmaceutycznie dopuszczaln a sola wy- bran a z grupy obejmuj acej a) zasadowe sole kwasów organicznych i kwasów nieorganicznych wybranych z grupy obejmuj acej kwas chlorowodorowy, kwas bromowodorowy, kwas siarkowy, kwas fosforowy, kwas metanosulfonowy, kwas trifluorosulfonowy, kwas benzenosulfonowy, kwas p-toluenosulfonowy (tosylan), kwas 1-naftaleno- sulfonowy, kwas 2-naftalenosulfonowy, kwas octowy, kwas trifluorooctowy, kwas jab lkowy, kwas winowy, kwas cytrynowy, kwas mlekowy, kwas szczawiowy, kwas bursztynowy, kwas fumarowy, kwas maleinowy, kwas benzoesowy, kwas salicylowy, kwas fenylooctowy i kwas migda lowy; i b) kwa sne sole organicznych i nieorganicznych zasad zawieraj ace kationy wybrane z grupy obejmuj acej kationy metali alkalicznych, kationy metali ziem alkalicznych, kation amonowy, alifatycz- nie podstawiony kation amoniowy i aromatycznie podstawiony kation amoniowy.5. A compound according to claim 4. The method of claim 4, characterized in that it is a pharmaceutically acceptable salt selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, jaalic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid , maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium, aliphatic substituted ammonium and aromatically substituted ammonium. 6. Kompozycja farmaceutyczna zawieraj aca substancj e aktywn a oraz fizjologicznie dopuszczal- ny no snik, znamienna tym, ze substancj a aktywn a jest zwiazek okre slony w zastrz. 4 lub jego farma- ceutycznie dopuszczalna sól.6. A pharmaceutical composition containing an active substance and a physiologically acceptable carrier, characterized in that the active substance is a compound as defined in claim 1. 4 or a pharmaceutically acceptable salt thereof. 7. Zastosowanie zwi azku okre slonego w zastrz. 1, wybranego z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik,PL 203 687 B1 39 N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia rozwoju rakowa- tych komórek, w którym po sredniczy kinaza raf.7. The use of a compound as defined in claim 1, selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N -methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) ) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbam oilo) (4-pyridyloxy)) phenyl) - urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) )) phenyl) - urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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, in the manufacture of a medicament for the treatment of cancer cell development mediated by raf kinase. 8. Zastosowanie zwi azku okre slonego w zastrz. 1, wybranego z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; i 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fe- nylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia raka p luc, trzust- ki, tarczycy, p echerza, okr eznicy, przewlek lej bia laczki szpikowej, lub kosmkowego gruczolaka okr eznicy.8. The use of a compound as defined in claim 1 1, selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4 -pyridyloxy)) phenyl) - urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyl xy)) phenyl) - urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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, in the manufacture of a medicament for the treatment of cancer of the lung, pancreas, thyroid gland, pectoris, colon, chronic myeloid leukemia, or villous colonic adenoma. 9. Zastosowanie zwi azku okre slonego w zastrz. 1, wybranego z grupy sk ladaj acej si e z 4-chloro-3-(trifluorometylo)fenylomoczników: N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik i N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, 4-bromo-3-(trifluorometylo)fenylomoczników: N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-(2-(N-metylokarbamoilo)-4-pirydylotio)fenylo)mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik i N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(3-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik; iPL 203 687 B1 40 2-metoksy-4-chloro-5-(trifluorometylo)fenylomoczników: N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))- fenylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia nowotworów.9. Use of a compound as defined in claim 1 1, selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylureas: 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 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4 -pyridyloxy)) phenyl) - urea, 4-bromo-3- (trifluoromethyl) phenylureas: 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- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyl xy)) phenyl) - urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) - urea; iPL 203 687 B1 40 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: 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, in the manufacture of a medicament for the treatment of tumors. 10. Zastosowanie zwi azku okre slonego w zastrz. 4 wybranego z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))- fenylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia rozwoju rakowa- tych komórek, którym po sredniczy kinaza raf.10. The use of a compound as defined in claim 1 4 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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' - (2-chloro -4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) ) -4-pyridyloxy) phenyl) urea, 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, in the manufacture of a medicament for treating cancer cell growth mediated by raf kinase. 11. Zastosowanie zwi azku okre slonego w zastrz. 4 wybranego z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))- fenylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia raka p luc, trzust- ki, tarczycy, p echerza, okr eznicy, przewlek lej bia laczki szpikowej, lub kosmkowego raka okr eznicy.11. The use of a compound as defined in claim 1 4 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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' - (2-chloro -4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) ) -4-pyridyloxy) phenyl) urea, 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, in the manufacture of a medicament for the treatment of lung, pancreatic, thyroid, bladder, colon, chronic myeloid leukemia, or villous colon cancer. 12. Zastosowanie zwi azku okre slonego w zastrz. 4, wybranego z grupy obejmuj acej N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik, N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))fenylo)- mocznik, N-(4-bromo-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)- mocznik, N-(2-metoksy-4-chloro-5-(trifluorometylo)fenylo)-N'-(2-chloro-4-(2-(N-metylokarbamoilo)(4-pirydyloksy))- fenylo)mocznik, lub jego farmaceutycznie dopuszczalnej soli, do wytwarzania leku do leczenia nowotworów.12. Use of a compound as defined in Claim 4, selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (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' - (2- chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 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, in the manufacture of a medicament for the treatment of tumors. 13. Zwi azek wed lug zastrz. 1, znamienny tym, ze jest nim N-(4-chloro-3-(trifluorometylo)fenylo)- -N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik.13. A compound according to claim The process of claim 1, wherein it is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea. 14. Zwi azek wed lug zastrz. 1, znamienny tym, ze jest nim N-(4-chloro-3-(trifluorometylo)fenylo)- -N'-(4-(2-(N-metylokarbamoilo)-4-pirydyloksy)fenylo)mocznik.14. A compound according to claim The process of claim 1, wherein it is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. 15. Kompozycja farmaceutyczna zawieraj aca substancj e aktywn a oraz fizjologicznie dopusz- czalny no snik, znamienna tym, ze substancj a aktywn a jest N-(4-chloro-3-(trifluorometylo)fenylo)-N'- -(4-(2-karbamoilo-4-pirydyloksy)fenylo)mocznik lub jego farmaceutycznie dopuszczalna sól.15. A pharmaceutical composition containing the active substance and a physiologically acceptable carrier, characterized in that the active substance is N- (4-chloro-3- (trifluoromethyl) phenyl) -N'- - (4- ( 2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof. 16. Kompozycja farmaceutyczna zawieraj aca substancj e aktywn a oraz fizjologicznie dopusz- czalny no snik, znamienna tym, ze substancj a aktywn a jest N-(4-chloro-3-(trifluorometylo)fenylo)-N'- -(4-(2-(N-metylo-karbamoilo)-4-pirydyloksy)fenylo)mocznik lub jego farmaceutycznie dopuszczalna sól.16. A pharmaceutical composition containing the active substance and a physiologically acceptable carrier, characterized in that the active substance is N- (4-chloro-3- (trifluoromethyl) phenyl) -N'- - (4- ( 2- (N-methyl-carbamoyl) -4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof. 17. Zastosowanie N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-karbamoilo-4-pirydyloksy)fenylo)- mocznika do wytwarzania leku do leczenia rozwoju rakowatych komórek, w którym po sredniczy kinaza raf.17. The use of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) - urea in the manufacture of a medicament for the treatment of cancerous cell development in which it mediates raf kinase. 18. Zastosowanie N-(4-chloro-3-(trifluorometylo)fenylo)-N'-(4-(2-(N-metylokarbamoilo)-4-pirydylo- ksy)fenylo)mocznika do wytwarzania leku do leczenia rozwoju rakowatych komórek, w którym po sred- niczy kinaza raf. Departament Wydawnictw UP RP Cena 6,00 z l. PL PL PL18. Use of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea in the manufacture of a medicament for the treatment of cancerous cell development wherein the intermediate raf kinase. Publishing Department of the UP RP Price 6.00 PLN per PL PL PL
PL360085A 1999-01-13 2000-01-12 Compounds from the group of diphenylureas, pharmaceutical compositions containing them and their use PL203687B1 (en)

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US11587799P 1999-01-13 1999-01-13
US60/115,877 1999-01-13
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US42522899A 1999-10-22 1999-10-22
US09/425,228 1999-10-22
PCT/US2000/000648 WO2000042012A1 (en) 1999-01-13 2000-01-12 φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS

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