HRP20010580A2 - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Download PDF

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Publication number
HRP20010580A2
HRP20010580A2 HR20010580A HRP20010580A HRP20010580A2 HR P20010580 A2 HRP20010580 A2 HR P20010580A2 HR 20010580 A HR20010580 A HR 20010580A HR P20010580 A HRP20010580 A HR P20010580A HR P20010580 A2 HRP20010580 A2 HR P20010580A2
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HR
Croatia
Prior art keywords
substituted
phenyl
optimally
halogen
heteroatoms selected
Prior art date
Application number
HR20010580A
Other languages
Croatian (hr)
Inventor
Bernd Riedl
Jacques Dumas
Uday Khire
Timothy B Lowinger
William J Scott
Roger A Smith
Jill E Wood
Mary-Katherine Monahan
Reina Natero
Joel Renick
Robert N Sibley
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Bayer Ag
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27381740&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HRP20010580(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from PCT/US2000/000648 external-priority patent/WO2000042012A1/en
Application filed by Bayer Ag filed Critical Bayer Ag
Publication of HRP20010580A2 publication Critical patent/HRP20010580A2/en
Publication of HRP20010580B1 publication Critical patent/HRP20010580B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
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    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
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    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
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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
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    • 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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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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    • A61K31/44—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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    • 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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    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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Description

Referencije koje se odnose na zahtjev References relating to the request

Ovo je neprestano-u-dijelovima Serije No.09/257.266 podnesen 25.veljače, 1999 i neprestano-u-dijelovima Serije No.60/115,877 podnesen zahtjev 13.siječnja 1999. This is continuous-in-part Serial No. 09/257,266 filed Feb. 25, 1999 and continuous-in-part Serial No. 60/115,877 filed Jan. 13, 1999.

Područje izuma Field of invention

Izum se odnosi na upotrebu skupine aril ureaze u tretiranju raf-om posredovanih bolesti i farmaceutske formulacije za upotrebu u toj terapiji. The invention relates to the use of the aryl urease group in the treatment of raf-mediated diseases and a pharmaceutical formulation for use in such therapy.

Pozadina izuma Background of the invention

Onkogen p21ras uveliko pridonosi razvoju i napretku humanih čvrstih i mutiranih u 30% svih humanih karcinoma (Bolton et al. Ann. Rep. Mađ. Chem. 1994, 29, 165-74; Bos.Cancer Res.1989, 49, 4682-9). Uobičajeni, nemutirani oblici,ras protein ključni je elemment signala transdukcijske kaskade direktno na receptor faktora rasta u svim tkivima (Avruch et al. Trends Bichem.sci. 1994, 19, 279-83). Bikemijski, ras je veza gunidin nukleotida u proteinu, i kruženje između aktiviranih GTP-veza i GTP-veza u preostalih oblika koji su precizno kontrolirani s ras' endogenom GTP-aze aktivnosti i drugih regulatora proteina. Kod ras mutanata u stanicama raka, endogene aktivnosti GTP-aze su olakšane i zato prijenos proteina, osnovni su signal rasta u daljnje efektore kao što je raf kinaza. To su okviri za rast stanica raka koje nose ti mutanti (Magnuson et al. Semin.Cancer Biol. 1994. 5, 247-53). Pokazalo se da inhibicijski učinak aktivnog ras-a inhibicijom raf kinaze daje znak za prikladan put administracije deaktiviranih protutijela za raf kinazu ili co-ekspresiju dominantnih negativnih raf kinaza ili dominantnih negativnih MEK podloga od raf kinaze, znak je za reviziju transformiranih stanica u normalan rast fenotipa (vidi: 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) imaju i daljnje inhibicije raf ekspresije s neosjetljivim RNA zapriječi se stanična proliferacija u membranom udruženih onkogena. Ista inhibicija raf kinaze (s neosjetljivim oligodeoksinukleotidama) biti će u korelaciji in vitro i in vivo s inhibicijom rasta različitih tipova humanih tomora. (Monia et al., Nat.Med. 1996, 2 668-75). Oncogene p21ras greatly contributes to the development and progression of human solid and mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Mag. Chem. 1994, 29, 165-74; Bos.Cancer Res.1989, 49, 4682-9 ). In its normal, unmutated form, the ras protein is the key element of the signal transduction cascade directly to the growth factor receptor in all tissues (Avruch et al. Trends Bichem.sci. 1994, 19, 279-83). Bichemically, ras is a bond of gunidine nucleotides in the protein, and cycling between activated GTP-bonds and GTP-bonds in the remaining forms is precisely controlled by ras' endogenous GTPase activity and other protein regulators. In ras mutants in cancer cells, the endogenous GTPase activities are facilitated and therefore the transfer of proteins, the basic growth signal to downstream effectors such as raf kinase. These are the frameworks for the growth of cancer cells carried by these mutants (Magnuson et al. Semin. Cancer Biol. 1994. 5, 247-53). It has been shown that the inhibitory effect of active ras by inhibiting raf kinase provides a sign for a suitable route of administration of deactivated antibodies for raf kinase or co-expression of dominant negative raf kinases or dominant negative MEK substrates from raf kinase, is a sign for revising transformed cells into 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) have further inhibitions raf expression with insensitive RNA inhibits cell proliferation in membrane associated oncogenes. The same inhibition of raf kinase (with insensitive oligodeoxynucleotides) will be correlated in vitro and in vivo with growth inhibition of various types of human tumors. (Monia et al., Nat.Med. 1996, 2 668-75).

Sadržaj izuma Content of the invention

Predstavljeni izum osigurava supstancije koje su inhibitori enzima raf kinaze. Budući da je enzim daljnji efektor p21ras, inhibitori su korisni u farmaceutskim formulacijama za humanu u veterinarsku upotrebu gdje inhibiraju odgovarajućim načinom raf kinazu gdje je to indicirano, npr., u tretiranju tumora i/ili rasta kanceriznih stanica koji je povezan s raf kinazom. Osobito, supstancije su korisne u tretiranju humanih ili animalnih čvrstih tumora, tj. mišji rak, budući da progresija tih karcinoma ovisi o signalu ras proteina na transdukciju kaskade sumijivom tretmnu s prekidanjem kaskade, tj. inhibicijom raf kinaze. U suglasju sa supstancijama izuma koje su korisne za tretiranje raka, uključujući i solidne zloćudne tumore, kao što su na primjer karcinomi (pluća, gušterače, tireoidee, krvi i kolona) mileoidnih poremećaja(mileoidna leukemija) ili adenomi (zloćudni adenom kolona). The present invention provides substances that are inhibitors of the raf kinase enzyme. Since the enzyme is a downstream effector of p21ras, the inhibitors are useful in pharmaceutical formulations for human and veterinary use where they appropriately inhibit raf kinase where indicated, eg, in the treatment of tumors and/or cancerous cell growth associated with raf kinase. In particular, the substances are useful in the treatment of human or animal solid tumors, i.e. mouse cancer, since the progression of these cancers depends on the signal of the ras protein on the transduction of the cascade comparable to the treatment with the interruption of the cascade, i.e. the inhibition of raf kinase. In accordance with the substances of the invention that are useful for the treatment of cancer, including solid malignant tumors, such as for example carcinomas (lung, pancreas, thyroid, blood and colon) myeloid disorders (myeloid leukemia) or adenomas (malignant colon adenoma).

Zato predstavljeni izum omogućuje općeniti opis supstancija kao aril uree, uključujući i aril i heteroalril analoge, koji inhibiraju put raf kineze. Izum dalje omogućuje metode za tretiranje rafom posredovana bolesna stanja u ljudi ili sisavaca. Osim toga izum se direktno odnosi na supstancije koje inhibiraju enzime raf kinaze kao i na supstancije , formulacije i metode za tretiranje rasta kancerogenih stanica s raf kinazom gdje je supstancija formule I koja je aplikabilna ili njezina farmaceutski prihvatljiva sol. Therefore, the present invention allows for a general description of substances as aryl ureas, including aryl and heteroaryl analogs, which inhibit the raf kinase pathway. The invention further provides methods for treating raffa-mediated disease states in humans or mammals. In addition, the invention directly relates to substances that inhibit raf kinase enzymes, as well as to substances, formulations and methods for treating the growth of cancerous cells with raf kinase, where the substance of formula I is applicable or its pharmaceutically acceptable salt.

A - D – B (I) A - D - B (I)

U formuli I, D je -NH-C(O)-NH-, In formula I, D is -NH-C(O)-NH-,

A je supstituirana polovica sve do 40 ugljikovih atoma u formuli -1-(M-L')q, gdje je L 5 i 6 član cikličke strukture vezan direktno na D, L' obuhvaća supstituirani cikličku polovicu koja ima najmanje 5 članova, M je skupina koja povezuje i ima najmanje jedan atom, q je cjelina od 1-3, i svaka ciklička struktura od L i L' sadržava 0 -4 članova grupe koja sadržava dušik, kisik i sumpor, i A is a substituted half of up to 40 carbon atoms in the formula -1-(M-L')q, where L is a 5 and 6 member of the cyclic structure attached directly to D, L' comprises a substituted cyclic half having at least 5 members, M is the linking group i has at least one atom, q is an integer of 1-3, and each cyclic structure of L and L' contains 0-4 members of a group containing nitrogen, oxygen, and sulfur, and

B je supstituiran i nesupstituiran, sve do tricikličkog arila ili heteroarila polovice sve od 30 atomas ugljika s najmanje 6-člava cikličke strukture koji se direktno vezuje na D koji sadržava 0-4 člana grupe koja sadržava dušik, kisik i sumpor, i B is substituted and unsubstituted, up to a tricyclic aryl or heteroaryl moiety of at least 30 carbon atoms with at least a 6-membered ring structure directly attached to D containing 0-4 members of a nitrogen, oxygen, and sulfur containing group, and

u čemu je L' supstituiran s najmanje jednim supstituentom odabranim iz skupine koja sadržava -SO2Rx i -C(NRy)Rz, wherein L' is substituted with at least one substituent selected from the group consisting of -SO2Rx and -C(NRy)Rz,

Ry vodik ili ugljik koji se osniva na polovici sve do 24 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno halosupstituiranih sve do per halo, Ry hydrogen or carbon that is based on half up to 24 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally halo-substituted up to per halo,

Rz je vodik i ugljik koji se osnova na polovici sve do 30 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O ioptimalno supstitiuranog halogenom, hidroksi i ugljikom na osnovu supstituenata iznad 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i oni su optimalno supstituirani s halogenima Rx je Rz ili NRaRb gdje su Ra i Rb Rz is hydrogen and carbon based on half of up to 30 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on substituents above 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and they are optimally substituted with halogens Rx is Rz or NRaRb where Ra and Rb

a) samostalni vodik a) independent hydrogen

ugljik na osnovu djela sve do 30 ugljikovih atoma koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi i ugljikom na osnovu supstituenata sve do 24 atoma ugljika, koji sadržavaju optimalno odabrane između N, S i O i optimalno su supstituirani halogenom, ili carbon based on up to 30 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on substituents up to 24 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted by halogen, or

-OSi(Rf)3 gdje je Rf vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi i ugljikom na osnovu supstituenata sve do 24 atoma ugljika, koji sadržavaju heteroatome optimalno odabrane između N, S i O i optimalno su supstituirani halogenom; ili -OSi(Rf)3 where Rf is hydrogen or carbon based on half up to 24 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on substituents up to 24 carbon atoms, containing heteroatoms optimally selected from N, S and O and optimally substituted by halogen; or

b) Ra je Rb zajedno oblika s 5-7 članova heterocikličke strukture od 1-3 heteroatoma odabranih između N, S i O, ili supstituiranih 5-7 članova heterociklične strukture s 1-3 heteroatoma odabranih između N, S i O suptituiranih halogenom, vodikom ili ugljikom na osnovu supstitueneta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i koji su optimalno supstituirani halogenom, ili b) Ra is Rb together of the form with 5-7 members of the heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or substituted 5-7 members of the heterocyclic structure with 1-3 heteroatoms selected from N, S and O substituted by halogen, hydrogen or carbon based on substituents up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and which are optimally substituted by halogen, or

c) jedan od Ra ili Rb je -C(O)-, C1-C5 divalentna alkilna skupina ili supstituirani C1-C5 divalentna alkilna grupa povezana s polovicom L oblika ciklične strukture s najmanje 5 članovam gdje je supstituent supstituirane C1-C5 divalentne alkiIne skupine odabran iz grupe koja sadržava halogen vodik, i ugljik na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i oni su optimalno supstituirani halogenom; c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkyl group or a substituted C1-C5 divalent alkyl group connected to half of the L form of a cyclic structure with at least 5 members where the substituent is a substituted C1-C5 divalent alkyl group selected from the group consisting of hydrogen halogen, and carbon based substituents of up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted with halogen;

gdje je B supstituiran s L supstituiran ili je L' dodatno supstituiran, a supstituent je odabran iz skupine koja sadržava halogen, sve do per-halo, i Wn, gdje je n 0-3; where B is substituted with L substituted or L' is additionally substituted, and the substituent is selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

u čemu svaki W je neovisno odabran iz grupe koja sadržava -CN, -CO2R7, -C(O)NR7R7, -C(O)-R7, -N02, -OR7, -SR7,-NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -O-Ar i ugljik baziran na polovici sve do 14 atoma ugljika, optimalni sadržaj heteroatoma odabran je između N, S i O i optimalno supstituiran s jednim ili više supstituenata slobodno odabranih iz grupe koja sadržava -CN, -CO2R7, -C (O) R7, -C(O)NR7R7, -OR7, -SR7, NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, halogen sve do per-halo, sa svakim R7 nasumce odabranim između H ili ugljikom baziranim na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava hetero atome odabrane između N, S i O i optimalno supstituiranim halogenom; wherein each W is independently selected from the group consisting of -CN, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7 , -NR7C(O)R7, -O-Ar and carbon based on half of up to 14 carbon atoms, the optimal heteroatom content is selected from N, S and O and optimally substituted with one or more substituents freely selected from the group containing -CN , -CO2R7, -C (O)R7, -C(O)NR7R7, -OR7, -SR7, NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, halogen up to per-halo, with each R 7 randomly selected from H or carbon based on half of up to 24 carbon atoms, optimally containing hetero atoms selected from N, S and O and optimally substituted with halogen;

gdje je Q -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-; -CH(OH)-; -(CH2)mO-, -(CH2)mS-,-(CH2)mN(R7)-, -O(CH2)m-CHXa-, -CXa2-,-S-(CH2)m- i -N(R7)(CH2)m-, gdje je m= 1-3 a Xa je halogen; i where Q is -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-; -CH(OH)-; -(CH2)mO-, -(CH2)mS-,-(CH2)mN(R7)-, -O(CH2)m-CHXa-, -CXa2-,-S-(CH2)m- and -N( R7)(CH2)m-, where m= 1-3 and Xa is halogen; and

Ar je 5- ili 6-član aromatske strukture koji sadržava 0-2 člana odabrana oiz skupine koja sadržava, dušik, kisik i sumpor, koji su optimalno supstituirani halogenom, sve do per-halo, i optimalno supstituirani s Zni, gdje ni je 0 do 3 i svaki Z je slobodno odabran iz grupe koja sadržava -CN, -CO2R7, -C(O)R7, -C(O)NR7R7,-NO2, -OR7, -SR7,-NR7R7, -NR7C(O)R7, -NR7C(O)OR7,i ugljikom baziranim na osnovu polovice sve do 24 atoma ugljika, optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane s jednim ili više supstituenata iz skupine -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7 i -NR7C(O)OR7, s R7 koji ima gore definirano značenje. Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which are optimally substituted with halogen, up to per-halo, and optimally substituted with Zni, where ni is 0 to 3 and each Z is freely selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)R7 , -NR7C(O)OR7, and carbon based on half up to 24 carbon atoms, optimally contain heteroatoms selected from N, S and O and optimally substituted with one or more substituents from the group -CN, -CO2R7, -COR7, - C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7 and -NR7C(O)OR7, with R7 having the meaning defined above.

U formuli I, odgovarajuće hetaril skupine uključuju, ali nije ograničeno na, 5-12 atoma ugljika aroamtskog prstena ili prsten sistema koji sadržava 1-3 prstena, najmanje jedan je aromatski, u kojem je jedan ili više, npr., 1-4 toma ugljika se jedan ili više prstenova može zamjeniti s atomom kisika, dušika ili sumpora. Svaki prsten ima 3-7 atoma. Na primjer, B može biti 2- ili 3-furil, 2- ili 3-tienil, 2- ili 4-triazinil, 1-, 2- ili 3-pirolil, 1-, 2-, 4- ili 5-imidazolil, 1-, 3-, 4- ili 5-pirazolil, 2-, 4- ili 5-oksazolil, 3-, 4-ili 5-izoksazolil, 2-, 4-, ili 5 tiazolil, 3-, 4- ili 5-izotiazolil, 2-, 3- ili 4-piridil, 2-, 4-, 5- ili 6-pirimidinil, 1,2,3-triazol-1-, -4- ili -5-il, 1,2,4-triazol-1-, -3- ili -5-tetrazolil, 1,2,3-oksadiazol-4- ili -5-il, 1,2,4-oksadiazol-3- ili -5-il, 1,3,4-tiadiazol-2- ili -5-il, 1,2,4-oksadiazol-3- ili -5-il, 1,3,4-tiadiazol-2- ili -5-il, 1,3,4-tiadiazol-3- ili -5-il, 1,2,3-tiadiazol-4- ili -5-il, 2-, 3-, 4-, 5- ili 6-2H-tiopiranil, 2-, 3- ili -4-4H-tiopiranil, 3- ili 4-piridazinil, pirazinil, 2-,3-,4-,5-,6-ili 7-benzofluril, 2-,3-,4-,5-,6- ili 7-benzotienil, 1-,2-,3-,4-,5-,6- ili 7-indolil, 1-,2-,4- ili 5-benzimidazolil, 1-,3-,4-,5-,6- ili 7-benzopirazolil, 2-,4-,5-,6- ili 7-benzoksazolil,2-, 4-, 5-, 6- ili 7-benz-1, 3-oksadiazolil, 2-, 3-, 4-, 5-, 6-, 7- ili 8-kvinolinil, 1-,3-, 4-, 5-, 6-, 7-, 8-izokvinolinil, 1-, 2-, 3-, 4- ili 9-karbazolil, 1-,2-, 3-, 4-, 5-, 6-, 7-, 8- ili 9-akridinil, ili 2-, 4-, 5-, 6-, 7-ili 8-kvinazolinil, ili dodatno optimalno supstituiran fenil, 2- ili 3- tienil, 1,3,4-tiadiazolil, 3-piril, 3-pirazolil, 2-tiazolil ili 5-tiazolil itd. Na primjer, B može biti 4-metil-fenil, 5-metil-2-tienil, 4-metil-2-tienil, 1-metil-3-piril, 1-metil-3-pirazolil, 5-metil-2-tiazolil ili 5-metil-1,2,4-tiadiazol-2-il. In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon atoms of an aromatic ring or a ring system containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 atoms one or more carbon rings can be replaced by an oxygen, nitrogen or sulfur atom. Each ring has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4- or 5 -isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2, 4-triazol-1-, -3- or -5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3, 4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3 - or -4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-,3-,4-,5-,6-or 7-benzofluril, 2-,3-,4-,5-,6 - or 7-benzothienyl, 1-,2-,3-,4-,5-,6- or 7-indolyl, 1-,2-,4- or 5-benzimidazolyl, 1-,3-,4-, 5-,6- or 7-benzopyrazolyl, 2-,4-,5-,6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benz-1, 3-oxadiazolyl, 2- , 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-,3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2 -, 4-, 5-, 6-, 7-or 8-quinazolinyl, or additionally optimally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

Odgovarajuće aklil skupine i alkil djelovi skupine, npr. alkoksi, itd sve vrijeme uključuje metil, etil, propil, butil, itd., uključujući i čvrsti lanac i razgranate izomere kao što su izopropil, izobutil, sec-butil, tert-butil, itd. Odgovarajuće aril skupine koje ne sadržavaju heteroatome, na primjer fenil i 1- i 2-naftil. Suitable acyl groups and alkyl moieties, eg alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including both straight chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc. Suitable aryl groups which do not contain heteroatoms, for example phenyl and 1- and 2-naphthyl.

Ovdje upotrebijen termin "cikloalkil" odnosi se na cikličnu strukturu sa ili bez alkil supstituenata kao što su, na primjer, "C4 cikloalkil" uključuje metil supstituiranu ciklopropil skupinu kao što je ciklobutil skupina. Pojam "cikloalkil", kao što je ovdje upotrebijen uključuje i zasićenu heterocikličnu skupinu. As used herein, the term "cycloalkyl" refers to a cyclic structure with or without alkyl substituents such as, for example, "C4 cycloalkyl" includes a methyl substituted cyclopropyl group such as a cyclobutyl group. The term "cycloalkyl" as used herein includes a saturated heterocyclic group.

Odgovarajuća halogena skupina uključuje F, Cl, Br, i/ili, jednu od per-supstitucija (tj. svi H atomi u grupi zamijene se atomom halogena) moguće je kada je alkil skupina supstituitrana halogenom, miješana supstitucija tipa halogen atoma također je moguća i daje polovicu. The corresponding halogen group includes F, Cl, Br, and/or, one of the per-substitutions (i.e., all H atoms in the group are replaced by a halogen atom) is possible when the alkyl group is substituted with a halogen, a mixed substitution of the halogen atom type is also possible and gives half.

Izum se odnosi i na supstancije per se, formule I. The invention also relates to substances per se of formula I.

Izneseni izum odnosi se i na farmaceutski prihvatljive soli formule I. Odgovarajuće farmaceutski prihvatljive soli su dobro poznate stručnjacima i uključuju bazične soli anorganskih i organskih kiselina, kao što su klorovodična kiselina, bromovodična kiselina, sumporna kiselina, fosforna kiselina, metansulfonska kiselina, trifluorometansulfonska kiselina, benzensulfonska kiselina, p-toluensulfonska kiselina, 1-naftalensulfonska kiselina, 2-naftalensulfonska kiselina, octena kiselina, trifluorotena kiselina, jabučna kiselina, vinska kiselina, limunska kiselina, mliječna kiselina, oksalna liselina, sukcinska kiselina, fumarna kiselina, maleična kiselina, benzoična kiselina, salicilna kiselina, feniloctena kiselina, i bademova kiselina. U dodatku, farmaceutski prihvatljive soli uključuju soli kiselina anorganskih baza, kao što je su soli koje sadržavaju aklalne katione (npr. Li+, Na+ ili K+), zemljane alkalne katione (npr. Mg+2, Ca+2,ili Ba+2), katione amonijaka, kao što su soli kiselina organskih baza, uključujući alifate i aromate supstituirane amonijem, i karternim amonijevim kationima, koji potječu od protonacije ili peralkilacije trietilamina, N,N-dietilamin, N,N-dicikloheksilamin, lizin, piridin, N,N-dimetilaminopiridin (DMAP); 1,4-diazabiclo[2.2.2]oktan (DABCO), 1,5-diazabiciklo[4.3.0]non-5-en (DBN)i 1,8-diazabi-ciklo[5.4.0]undec-7-en (DBU). The present invention also relates to pharmaceutically acceptable salts of formula I. Appropriate pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluorothenic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid , salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include salts of acids with inorganic bases, such as salts containing alkaline cations (eg Li+, Na+ or K+), alkaline earth cations (eg Mg+2, Ca+2, or Ba+2) , ammonium cations, such as acid salts of organic bases, including ammonium-substituted aliphatics and aromatics, and quaternary ammonium cations, derived from the protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMAP); 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7- en (DBU).

Broj supstancija formule I koje posjeduju asimetrični ugljik a on može biti u racemičnom obliku ili optički aktivnom obliku. Metode odvajanja enantiomera i diastereomeričnih smjesa dobro su poznate stručnjacima. Predstavljeni izum sadržava sve izolirane racemične i optički aktivne oblike supstancija opisane u formuli I koje posjeduju raf inhibitorno djelovanje. The number of substances of formula I that have asymmetric carbon and it can be in racemic form or optically active form. Methods for separating enantiomers and diastereomeric mixtures are well known to those skilled in the art. The present invention contains all isolated racemic and optically active forms of the substances described in formula I, which possess raf inhibitory activity.

Opće metode pripremanja General preparation methods

Supstancije Formule I mogu se pripremiti korištenjem poznatih kemijskih reakcija i postupaka, neki od polaznih materijala su komercijalno dostupni. Unatoč tomu, metode opće pripreme provode se uz pomoć stručnjaka za sintezu tih supstancija, s više detalja u primjerima koji su u Eksperimentalnom djelu koji slijedi. Formula I substances can be prepared using known chemical reactions and procedures, some of the starting materials being commercially available. Nevertheless, general preparation methods are carried out with the help of experts in the synthesis of these substances, with more details in the examples in the Experimental Work that follows.

Supstitucija anilina može se provesti korištenjem standardnih metoda (March. Advanced Organic Chemisty, 3rd Ed.; John Wiley: New York (1985). Laroc.Comprehensive Organic Transformations, VCH Publishers: New York (1989)). Kao što je prikazano u Shemi I, aril amini se uobičajeno sintetiziraju redukcijom nitroarila korištenjem metala kao katalizatora, kao što si Ni, Pd ili Pt, i H2 ili hidrida kao sredstva za transfer, kao što su format, cikloheksadin, ili borohidrid (Rylander. Hydrogenation Metods; Academic Press: London, UK(1985)). Nitroarili mogu se isto direktno reducirati s jakim izvorom hidrida, kao što je LiAlH4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publichers: New York (1991)), ili korištenjem nula valentnih metala, kao što su Fe, Sn ili Ca, često u kiselom mediju. Postoje brojne metode za sintezu nitroarila (March. Advanced Organic Chemisty, 3rd Ed. ; John Wiley: New York (1985). Laroc.Comprehensive Organic Transformations, VCH Publishers: New York (1989)). Aniline substitution can be carried out using standard methods (March. Advanced Organic Chemisty, 3rd Ed.; John Wiley: New York (1985). Laroc. Comprehensive Organic Transformations, VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using metals as catalysts, such as Ni, Pd, or Pt, and H2 or hydrides as transfer agents, such as formate, cyclohexadine, or borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls can also be directly reduced with a strong hydride source, such as LiAlH4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using zero-valent metals, such as Fe, Sn or Ca, often in an acidic medium. There are numerous methods for the synthesis of nitroaryls (March. Advanced Organic Chemisty, 3rd Ed. ; John Wiley: New York (1985). Laroc. Comprehensive Organic Transformations, VCH Publishers: New York (1989)).

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Shema I Redukcija nitroarila u aril amine Scheme I Reduction of nitroaryls to aryl amines

Nitroarili uobičajeno se formiraju s elektrolitičkom aromatskom nitracijom korištenjem HNO3, ili nekim od alternativnih NO2- izvora. Nitroarili mogu se dalje poboljšati prije redukcije. Nitroarili mogu se supstituirati s Nitroaryls are commonly formed with electrolytic aromatic nitration using HNO3, or one of the alternative NO2- sources. Nitroaryls can be further refined before reduction. Nitroaryls can be substituted with

[image] [image]

Potencijalnom ostatnom skupinom (npr. F, Cl, Br, itd.) mogu se podvrći reakciji supstitucije ili tretmanu s nukleofilima, kao što je tiolat (prikazan U Shemi II) ili peroksid. Nitroarili mogu se isto podvrći Ullman-ovom tipu reakcije spajanja (Shema II) A potential remaining group (eg, F, Cl, Br, etc.) can be subjected to a substitution reaction or treatment with a nucleophile, such as a thiolate (shown in Scheme II) or a peroxide. Nitroaryls can also undergo an Ullman-type coupling reaction (Scheme II).

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Shema II Odabrana nukleofilična aromatična supstitucija upotrebom nitroarila Scheme II Selective nucleophilic aromatic substitution using nitroaryls

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Nitroarili mogu se podvrći tranziciji metala koristeći reakciju unakrsnog spajanja. Za primjer, nitroaril electrofili, kao što su nitroaril bromidi, jodidi ili triflati, postiže se unakrsnom reakcijom vezanja posredovanjem s paladijem s aril nukleofilima , kao što je arilborna kiselina (Suzuki reakcija, prikazana kasnije), ariltins (Stille reakcija) ili arilcink (Negishi reakcija) da se dobije biaril (5). Nitroaryls can undergo transition metals using a cross-coupling reaction. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides, or triflates, are achieved by palladium-mediated cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (the Suzuki reaction, shown later), aryltins (the Stille reaction), or arylzincs (Negishi reaction) to give the biaryl (5).

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Isto tako nitroarili ili anilini mogu se pretvoriti u odgovarajući arensulfonil klorid (7) obradom s klorsulfonskom kiselinom. Reakcija sulfonil klorida s izvorom fluorida, kao što je KF da se dobije sulfonil klorid (8). Reakcija sulfonil fluorida 8 s trimetilsilil trif luorometanom uz izvor fluorida, kao što je tris (dimetilamino) sulfonium difluorotrimetilsilikonata (TASF) vodi u odgovarajući trifluormetilsulfon (9). Alternativno, sulfonil klorid 7 može se reducirati na arenetiol (10), na primjer s cinkovim amalgamom. Reakcija tiol 10 s CHCIF2 u prisustvu baze daje difluormetil merkaptam (11), koji se može oksidirati u sulfon (12) s jednim od različitih oksidanata, uključujući CrO3-octeni anhidrid (Sedova et al.Zh.Org.Khim,1970, 6 (568). Likewise, nitroaryls or anilines can be converted to the corresponding arenesulfonyl chloride (7) by treatment with chlorosulfonic acid. Reaction of sulfonyl chloride with a fluoride source, such as KF, to give sulfonyl chloride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane with a fluoride source such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to the arenethiol (10), for example with zinc amalgam. Reaction of thiol 10 with CHCIF2 in the presence of a base affords the difluoromethyl mercaptam (11), which can be oxidized to the sulfone (12) with one of a variety of oxidants, including CrO3-acetic anhydride (Sedova et al.Zh.Org.Khim,1970, 6 ( 568).

Shema III Odabrane metode sinteze fluoriniranog aril sulfona Scheme III Selected methods of fluorinated aryl sulfone synthesis

Kao što je prikazano u shemi IV, ne-simetrične urea formacije mogu biti uključene u reakciju aril izocianata (14) s aril aminom (13). Heteroaril izocianat može se sintetizirati iz heteroarilamina obradom s fosgenom ili fosgenovom ekvivalentom, kao što je triklor metil klorformat (difosgen), bis(triklormetil) karbonat (trifosgen) ili N,N'-karbonil diimidazol (CDI). Izocianat se isto može derivirati iz dobro derivirane heterolitične karboksilne kiseline, kao što je ester, kiseli halid ili anhidrid od Curtius -tip pretvaranja. Ta reakcija deriviranja kiseline 16 je izvor azida, slijedeće pretvaranje da se dobije izocianat. Odgovarajuća karboksilna kiselina (17) isto može biti predmet Curtius-tipa pretvaranja koristeći difenilfosforil azida(DPPA) ili sličnog reagensa. As shown in Scheme IV, non-symmetric urea formations can be involved in the reaction of aryl isocyanate (14) with aryl amine (13). A heteroaryl isocyanate can be synthesized from a heteroarylamine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N,N'-carbonyl diimidazole (CDI). The isocyanate can also be derived from a well-derivatized heterolytic carboxylic acid, such as an ester, acid halide, or anhydride by Curtius-type conversion. This acid derivatization reaction 16 is the source of the azide, following conversion to give the isocyanate. The corresponding carboxylic acid (17) can also be subjected to a Curtius-type conversion using diphenylphosphoryl azide (DPPA) or a similar reagent.

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Shema IV Odabrane metode formiranja ne-simetrične uree Scheme IV Selected methods of non-symmetrical urea formation

Na kraju, ureama može se dalje manipulirati koristeći metode poznate stručnjacima. Finally, the ureas can be further manipulated using methods known to those skilled in the art.

Izum uključuje i farmaceutske kompozicije koje uključuju supstanciju Formule I, i fiziološki prihvatljivog nosača. The invention also includes pharmaceutical compositions that include a substance of Formula I, and a physiologically acceptable carrier.

Supstancije se mogu aplicirati oralno, topički, parenteralno, inhalacijom ili sprejem ili rektalno u jedinici, doze ovisno o formulaciji. Pojam "aplikacija injekcijom" uključuje intravenoznu, intramuskularnu, supkutanu i parentralnu injekciju, kao što je i postupak infuzije. Jedna ili više supstancija mogu biti udružene s jednim ili više netoksičnih farmaceutski prihvatljivih nosača iako se traži druge aktivne supstancije. Substances can be applied orally, topically, parenterally, by inhalation or spray, or rectally in a unit, doses depending on the formulation. The term "administration by injection" includes intravenous, intramuscular, subcutaneous and parenteral injection, as well as the infusion procedure. One or more substances may be combined with one or more non-toxic pharmaceutically acceptable carriers, although other active substances are required.

Sastav namijenjen za oralnu upotrebu može se pripremiti odgovarajućom metodom poznatoj u proizvodnji farmaceutskih pripravaka. Takav sastav može sadržavati jednu ili više tvari odabranih između otapala, zaslađivača, aroma, boje i konzervansa tako da se postigne dobra palatabilnost proizvoda. Tablete sadržavaju aktivnu supstanciju i smjesu netoksičnih farmaceutski prihvatljivih ekscipienasa koji odgovaraju za proizvodnju tableta. Ti ekscipienti mogu biti, na primjer inertni razrjeđivači, kao što je kalcijev karbonat, natrijev karbonat, kalcijev fosfat ili natrijev fosfat, sredstva za granuliranje i dezintegraciju, na primjer kukuruzni škrob, ili alginična kiselina, veziva, na primjer magnezijev stearat, stearinska kiselina ili talk. Tablete mogu biti nepresvućene ili mogu biti presvučene poznatim tehnikama da sprečavaju dezintegraciju i absorpciju u probavnom traktu i omogućavaju odgovarajuću aktivnost kroz duže razdoblje. Na primjer, materijal koji utječe na otpuštanje, mogu se koristiti, na primjer gliceril monostearat ili gliceril distearat. Te tvari mogu se pripremiti u krutom, brzo otpuštajućem obliku. The composition intended for oral use can be prepared by a suitable method known in the production of pharmaceutical preparations. Such a composition may contain one or more substances selected from solvents, sweeteners, aromas, color and preservatives so as to achieve a good palatability of the product. The tablets contain an active substance and a mixture of non-toxic pharmaceutically acceptable excipients suitable for the production of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch, or alginic acid, binders, for example magnesium stearate, stearic acid or talc. Tablets can be uncoated or they can be coated using known techniques to prevent disintegration and absorption in the digestive tract and enable adequate activity over a longer period. For example, a material that affects the release can be used, for example glyceryl monostearate or glyceryl distearate. These substances can be prepared in a solid, quick-release form.

Formulacije za oralnu upotrebu mogu biti predstavljene u tvrdim želatinoznim kapsulama u kojima je aktivna tvar pomiješana s inertnim krutim diluentom, na primjer, kalcijev karbonat, kalcijev fosfat, kaolin, ili u mekim želatinoznim kapsulama gdje je aktivna tvar pomiješana s vodom ili uljnim medijem, na primjer uljem kikirikija, tekućim parafinom ili maslinovim uljem. Formulations for oral use may be presented in hard gelatin capsules in which the active substance is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin, or in soft gelatin capsules in which the active substance is mixed with water or an oily medium, on for example with peanut oil, liquid paraffin or olive oil.

Vodene suspenzije sadržavaju aktivne tvari u smjesi s ekscipiensom odgovarajućim za proizvodnju vodenih suspenzija. Takav ekscipiens je suspenzioni posrednik, na primjer natrijeva karboksimetilceluloza, metilceluloza, hidroksi-propil metilceluloza, natrijev alginat, polivinilpirolidon, gumeni tragakant i gumena akacia; sredstva za disperziju i močenje mogu se javljati i prirodni fosfatidi, na primjer lecitin, ili sredstva za zgušćivanje ili alkilen oksid masnih kiselina, na primjer polioksietilen stearat, ili sredstvo za zgušćivanje produkta od etilen oksida s dugim lancem alifatskih alkohola, na primjer heptadekaetilen oksicetanol, ili sredstva za zgušćivanje od etilen oksida s djelomičnim esterima nastalim od masnih kiselina i heksitola kao što je polioksietilen sorbitol monooleat, ili stedstva za zgušćivanje od etilen oksida s djelomičnim esterima nastalim od masnih alkohol i heksitola anhidrida, na primjer polietilen sorbitan monooleat. Vodene suspenzije isto mogu sadržavati jedan ili više konzervanasa, na primjer etil, ili n-propil p-hidroksibenzoat, jednu ili više tvari za bojenje, jednu ili više aroma, i jedan ili više zaslađivača, kao što su šećer ili saharin. Aqueous suspensions contain active substances in a mixture with an excipient suitable for the production of aqueous suspensions. Such an excipient is a suspending agent, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; Dispersing and wetting agents may also be natural phosphatides, for example lecithin, or thickening agents or alkylene oxides of fatty acids, for example polyoxyethylene stearate, or thickening agents for ethylene oxide products with long chain aliphatic alcohols, for example heptadecaethylene oxyethanol, or ethylene oxide thickeners with partial esters of fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or thickeners of ethylene oxide with partial esters of fatty alcohol and hexitol anhydride, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring matter, one or more flavors, and one or more sweeteners, such as sugar or saccharin.

Vodotopivi prašci i granule koji su prikladni za pripremanje vodenih suspenzija nakon dodavanja u vodu osiguravaju aktivnu tvar i smjesu sa sredstvima za raspršivanje ili vlaženje, sredstva za suspendiranje i jedan ili više konzervanasa. Odgovarajuća sredstva za raspršivanje i vlaženje i sredstvo za suspendiranje biti će izneseni kasnije u primjerima. Dodatni ekscipiensi, na primjer, zaslađivači, arome i boje, mogu biti prisutni. Water-soluble powders and granules suitable for the preparation of aqueous suspensions after addition to water provide the active substance and mixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing and wetting agents and suspending agents will be set forth later in the examples. Additional excipients, for example, sweeteners, flavors and colors, may be present.

Supstancije također mogu biti formulirane u obliku ne-vodenih otopina, tj., uljnih suspenzija koje se mogu formulirati suspendiranjem aktivne tvari u biljnom ulju, na primjer, arahidno ulje, maslinovo ulje, sezamovo ulje, ulje kikirikija, ili mineralno ulje kao što je tekući parafin. The substances can also be formulated in the form of non-aqueous solutions, i.e., oil suspensions that can be formulated by suspending the active substance in a vegetable oil, for example, arachidonic oil, olive oil, sesame oil, peanut oil, or a mineral oil such as liquid paraffin.

Uljne suspenzije mogu sadržavati podloge, na primjer pčelinji vosak, kruti parafin ili cetilni alkohol. Zaslađivači kao sto su gore spomenuti, i arome mogu se dodati da se dobije dobra palatabilnost preparata. Sastav se može konzervirati dodavanjem antioksidanta kao što je askorbinska kiselina. Oil suspensions can contain supports, for example beeswax, solid paraffin or cetyl alcohol. Sweeteners such as those mentioned above, and aromas can be added to obtain a good palatability of the preparation. The composition can be preserved by adding antioxidants such as ascorbic acid.

Farmaceutske kompozicije su isto predmet ovog izuma i mogu biti u tipu emulzije ulje-u- vodi. Uljna faza može biti od biljnog ulja, na primjer maslinovog ili arahidnog, ili mineralnog ulja, na primjer tekući parafin ili smjese istih. Odgovarajuća sredstava za emulgiranje mogu biti gume-prirodnog podrijetla, na primjer guma akacije ili gumeni tragakant, fosfetidi prirodnog porijekla, na primjer zrno soje, lecitin i esteri ili dijelovi estera nastali derivacijom masnih kiselina i heksitol anhidrida, na primjer sorbitan monooleat, i tvari za zgušćivanje od postranih djelomičnih estera s etilen oksidom, na primjer polioksietilen sorbitan monooleat. Emulzije mogu sadržavati i zaslađivače i arome. Pharmaceutical compositions are also the subject of this invention and can be in the oil-in-water emulsion type. The oil phase can be of vegetable oil, for example olive or arachid, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums of natural origin, for example gum acacia or gum tragacanth, phosphatides of natural origin, for example soybean, lecithin and esters or ester fractions derived from the derivatization of fatty acids and hexitol anhydride, for example sorbitan monooleate, and substances for thickening from side partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavorings.

Sirupi i eliksiri mogu se formulirati sa zaslađivačima, na primjer glicerolom, propilen glikolom, sorbitolom ili laktoze. Neke formulacije mogu sadržavati i sredstva za ublažavanje, konzervanse i arome i boje. Syrups and elixirs can be formulated with sweeteners, for example glycerol, propylene glycol, sorbitol or lactose. Some formulations may also contain emollients, preservatives, and flavors and colors.

Supstancije se isto mogu aplicirati i u obliku supozuitorija za rektalnu primjenu lijeka. Te kompozicije mogu se pripremiti miješanjem lijeka s odgovarajućim ekscipientom koji ne nadražuje, koji je krut na običnoj temperaturi a tekući na rektalnoj temperaturi i tamo se rastopi i u rektumu otpusti ljekovitu tvar. Takvi materijali obuhvaćaju kakao maslac i polietilen glikole. The substances can also be applied 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 temperature and liquid at rectal temperature and melts there and releases the medicinal substance in the rectum. Such materials include cocoa butter and polyethylene glycols.

Za sve načine upotrebe koji su ovdje navedeni za supstanciju Formule I, poželjna dnevna oralna doza poželjno je da se kreće od 0.01 do 200 mg/kg ukupne tjelesne mase. Dnevne doze za aplikaciju putem injekcija, uljučujući i intravenoznu, intramuskularnu, supkutanu i peranteralne injekcije, i upotrebu putem infuzije poželjno je da su 0.01 do 200 mg/kg ukupne tjelesne mase. Poželjno je da se preporučena rektalna doza kreće od 0.01 do 200 mg/kg ukupne tjelesne mase. Preporučena dnevna topička doza poželjno je da se kreće između 0.1 i 200 mg aplicirano između jedan i četiri puta dnevno. Preporučena dnevna inhalacijska doza poželjno je da se kreće od 0.01 do 10 mg/kg ukupne tjelesne mase. For all of the uses listed herein for the substance of Formula I, the preferred daily oral dose preferably ranges from 0.01 to 200 mg/kg of total body weight. Daily doses for administration by injection, including intravenous, intramuscular, subcutaneous and perenteral injection, and use by infusion are preferably 0.01 to 200 mg/kg of total body weight. It is preferable that the recommended rectal dose ranges from 0.01 to 200 mg/kg of total body weight. The recommended daily topical dose is preferably between 0.1 and 200 mg applied between one and four times a day. The recommended daily inhalation dose preferably ranges from 0.01 to 10 mg/kg of total body weight.

Kada bi stručnjaci ocjenjivali koji način aplikacije primjeniti, to bi ovisilo o različitim faktorima, koji se smatra najprikladnijim za rutinsku aplikaciju lijeka. Kada bi ocjenjivali stručnjaci specifične doze koje se daju pacijentima koje ovise o različitim faktorima, uključujući i aktivnost aplicirane supstancije, starosti, tjelesnoj masi, zdravstvenom stanju, spolu, dijeti, vremenu i načinu aplikacije, ekskreciji itd. Ukoliko bi dalje stručnjaci ocjenjivali optimalni put tretiranja, tj. način aplikacije i broj dnevnih doza supstancije Formule I ili farmaceutski prihvatljive njezine soli za definiranje broja dana, mogli bi stručnjaci ustanoviti korištenjem uobičajenih ispitivanja. If experts were to evaluate which method of application to apply, it would depend on various factors, which is considered the most suitable for routine application of the drug. If experts were to evaluate the specific doses given to patients that depend on various factors, including the activity of the applied substance, age, body weight, state of health, sex, diet, time and method of application, excretion, etc. If experts were to further evaluate the optimal route of treatment , i.e., the method of application and the number of daily doses of the substance of Formula I or a pharmaceutically acceptable salt thereof to define the number of days, could be established by experts using conventional tests.

Ukoliko nebi razumjeli, da specifični nivo za određene pacijente ovisi o različitim faktorima, uključujući aktivitet specifične tvari koja se koristi, starosti, tjelesne mase, općenitog stanja zdravlja, dijeti, vremenu administracije, putu administracije, putu ekskrecije, kombinaciji tvari i brojnim uvjetima pod kojima se provodi terapija. If they did not understand, that the specific level for certain patients depends on various factors, including the activity of the specific substance used, age, body weight, general state of health, diet, time of administration, route of administration, route of excretion, combination of substances and numerous conditions under which therapy is carried out.

Ukupni prilog svim aplikacijama, patenti i publikacije navedeni gore i poslije su ovdje uklopljeni s referencama, uključujući privremenu aplikaciju Serial No. 60/115,877 podnesenu 13. siječnja 1999 i ne-privremenu aplikaciju Serial No. 09/257, 266 podnesenu 25.veljače 1999. The entirety of all applications, patents and publications listed above and hereinafter are incorporated herein by reference, including provisional application Serial No. 60/115,877 filed Jan. 13, 1999 and non-provisional application Serial No. 09/257, 266 filed on February 25, 1999.

Supstancije se mogu proizvoditi iz poznatih supstancija (ili iz polaznih materijala koji, ili se mogu proizvesti od poznatih supsatncija) tj. putem općih metoda pripremanja koje su dalje prikazane. Aktivnost datih tvari za inhibiciu raf kinaze mogu se rutinski mjeriti tj. u skladu s postupcima koji će biti pokazani kasnije. Slijedeći primjeri su dati samo u ilustrativne svrhe i nisu namijenjeni, i ne predstavljaju granice ni u kojem smjeru za izum. Substances can be produced from known substances (or from starting materials which, or can be produced from known substances), i.e. through the general methods of preparation that are shown below. The activity of the given substances for inhibition of raf kinase can be measured routinely, i.e. according to the procedures that will be shown later. The following examples are provided for illustrative purposes only and are not intended to, and do not represent limits in any direction to the invention.

PRIMJERI EXAMPLES

Sve reakcije se provode u Flame-dried ili oven-dried staklenom sudu pod pozitivnim tlakom suhog argona ili suhog dušika, miješa se magnetskom miješalicom osim ako je drugačije indicirano. Osjetljive tekućine i otopine prenose se štrcaljkom ili kanilom, i uvode se u reakcionu posudu preko gumenog septa. Ukoliko nije drugačije određeno pojam "koncentracija pod smanjenim tlakom" odnosi se na BUCHY rotacioni evaporator pod aproksimativnim tlakom od 15 mmHg. Ukoliko nije drugačije određeno pojam "pod visokim tlakom" odnosi se na vakum od 0.4 - 1.0 mmHg. All reactions are carried out in a flame-dried or oven-dried glass vessel under a positive pressure of dry argon or dry nitrogen, stirred with a magnetic stirrer unless otherwise indicated. Sensitive liquids and solutions are transferred with a syringe or cannula, and introduced into the reaction vessel through a rubber septum. Unless otherwise specified, the term "concentration under reduced pressure" refers to the BUCHY rotary evaporator under an approximate pressure of 15 mmHg. Unless otherwise specified, the term "under high pressure" refers to a vacuum of 0.4 - 1.0 mmHg.

Sve navedene temperature nisu korigirane i izražene su u °C. Osim ako nije drugačije određeno, svi djelovi i postoci odnose se na težinu. All stated temperatures are not corrected and are expressed in °C. Unless otherwise specified, all parts and percentages are by weight.

Koristi se komercijalna kvaliteta reagensa i bez daljnje purif ikaci jeotapala. N-cikloheksil-N'-(metilpolistiren) karbo diimid nabavljen je od Calbiochem-Novabiochem Corp. 3-tert-butilanilin, 3-tert-butil-2-metoksianilin, 4-bromo-3-(trifluormetil)anilin, 4-kloro-3-(trifluorometil)anilin 2-metoksi-5- trifluormetil)anilin, 4-tert-butil-2-nitroanilin, 3-amino-2-naftol, etil 4-izocianatbenzoat, N-acetil-4-kloro-2-metoksi-5-(trifluormetil)anilin i 4-kloro-3-(trifluor metil)fenil izocianat nabavljeni su i korišteni bez daljnje purifikacije. Sinteza 3-amino-2-metoksikvinolina (E.Cho et al W0 98/00402; A. Cori et al. EP 542,609 IBID Bioorg. Med.Chem.. 3, 1995, 129), 4-(3-karbamoksilfenoksi)-1-nitrobenzen (K.Ikava Vakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butilfenil izocianat (O. Rohr et al. DE 2,436,108) i 2-metoksi-5-(trifluorometil)fenil izocianat (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) prije su bili opisani. Commercial quality reagents are used without further purification of the solvent. N-cyclohexyl-N'-(methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-butylaniline, 3-tert-butyl-2-methoxyaniline, 4-bromo-3-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-trifluoromethyl)aniline, 4-tert -butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatebenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were obtained and used without further purification. Synthesis of 3-amino-2-methoxyquinoline (E.Cho et al WO 98/00402; A. Cori et al. EP 542,609 IBID Bioorg. Med.Chem.. 3, 1995, 129), 4-(3-carbamoxylphenoxy)- 1-nitrobenzene (K.Ikava Vakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 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 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) were previously described.

Tankoslojna kromatografija (TLC) provodi se upotrebom Watman® -ovog silica gela 60A F-254 250 hiti presvučenim pločama. Vizualizacija ploča postiže jednom ili s više nabrojanih tehnika: (a) ultravioletnom ilumunacijom, (b)izlaganje parama joda, (c) uranjanjem ploča u 10% otopinu fosforomolibdićne kiseline nakon zagrijavanja, (d) uranjanjem ploča u otopinu cerijevog sulfata nakon zagrijavanja, i/ili (e) uranjanjem ploča u otopinu i 2.4-dinitrofenilhidrazina u kiselom etanolu nakon zagrijavanja. U kolonskoj kromatografiji (flash chromatography) koristi se 230-400 mash EM Science® silika gel. Thin layer chromatography (TLC) is performed using Watman® silica gel 60A F-254 250 hiti coated plates. Visualization of plates is achieved by one or more of the listed techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of plates in a 10% solution of phosphoromolybdic acid after heating, (d) immersion of plates in a solution of cerium sulfate after heating, and /or (e) by immersing the plates in a solution of 2,4-dinitrophenylhydrazine in acid ethanol after heating. In column chromatography (flash chromatography) 230-400 mash EM Science® silica gel is used.

Točke vrenje (mp) navedene su nekorigirane, a određuju se korištenjem Thomas-Hoover aparature za određivanje točke vrenja, ili Mettler FP66 aparata za automatsko određivanje točke vrenja. Četverostruka transformacija infracrvenog spektra postiže se upotrebom Mattson 4020 Galaxy Series spektrofotometra. Proton ('H) nuklearna magnetska rezonancija (NMR) spektar mjeren je General Electronic GN-Omega 300 (300 Mhz) spektrometrom isto s Me4Si (δ 0.00) ili rezidualnim protoniziranim otapalom (CHCl3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) kao standardom. NMR spektar ugljika (13C) mjeren je s General Elektronic GN-Omega 300 (75 MHz) spektrometrom a otapalo je (CDCl3 δ 77.0; MeOD-d3 δ 49.0; DMSO-d6 δ 39.5) kao standardom. Niska rezolucija masenog spektra (MS) i visika rezolucija masenog spektra (HRMS) postići će se kao eletronski udar (EI) masenog spektra ili kao brzo bombardiranje (FAB) masenog spektra. Elektronski udar masenog spektra (EI-MS) dobije se s Hewlett Packard 5989 A masenim spektrometrom koji je opremljen s Vacumetric Desorption Chemical lonization Probe za uvođenje uzoraka. Izvor iona odražava se na 250°C. Elektronski udar ionizacije postiže se s energojim od 70 eV i električnom zamkom od 300 μA. Tekući-cezijev maseni spektar iona (FAB-MS), u ažurnoj verziji brzo baombardirajučih atoma postiže se Kratos Concept 1-H spekrometrom. Kemijski ionizirani maseni spektar (C1-MS) postiže se upotrebom Hewelett Packard MS Engine (5989A) s plinovima metanom ili amonijakom kao reagensima (1x104 torr do 2.54 torr). Direktno umetanje desorpcije kemijske ionizacije (DCI) sondom (Vaccumetrics, Inc.) uvedeno od 0-0.15 amp u 10 sec. i održavala se na 10amp sve dok tragovi uzorka nisu nestali (~1-2 min). Spektar je skeniran s 50-800 amu na 2 sec per scan. HPLC - elektrosprej maseni spektar (HPLC ES-MS) dobili smo upotrebom Hewlett-Pacard 1100 HPLC opremljenim s kvarternarnom pumpom, detektorom varijabilne valne dužine, C-18 kolonom, i Finnigan LCQ ion trap masenim spektrometrom s elektro sprej ionizatorom. Spektar je skeniran od 120-800 amu upotrebom varijabilnog vremena iona koje je u skladu s brojem iona u rezultatu. Plinska koromatografija -selektivni maseni spektar (GC-MS) dobili smo s Hewlett Packard 5890 plinskom kromatografijom s HP-1 kolonom s metil silikonom (0.33 mM coating: 25 m x 0.2 mm) i Hewlett Packard detektor selektivnih masa (energija ionizacije 70 eV). Osnovne analize provedene su po Robertson Microlit Labs, Madison NJ. Boiling points (mp) are listed uncorrected, and are determined using a Thomas-Hoover boiling point apparatus, or a Mettler FP66 automatic boiling point apparatus. Quadruple transform infrared spectra are achieved using a Mattson 4020 Galaxy Series spectrophotometer. Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electronic GN-Omega 300 (300 Mhz) spectrometer with Me4Si (δ 0.00) or residual protonated solvent (CHCl3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. The NMR spectrum of carbon (13C) was measured with a General Electronic GN-Omega 300 (75 MHz) spectrometer and the solvent (CDCl3 δ 77.0; MeOD-d3 δ 49.0; DMSO-d6 δ 39.5) as a standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) will be achieved as electron impact (EI) mass spectra or as fast bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989 A mass spectrometer equipped with a Vacumetric Desorption Chemical Ionization Probe for sample introduction. The ion source is reflected at 250°C. Electron impact ionization is achieved with an energy of 70 eV and an electric trap of 300 μA. Liquid cesium ion mass spectrometry (FAB-MS), in the updated version of fast bombarding atoms, is achieved with the Kratos Concept 1-H spectrometer. Chemical ionization mass spectrum (C1-MS) is achieved using a Hewelett Packard MS Engine (5989A) with methane or ammonia gases as reagents (1x104 torr to 2.54 torr). Direct insertion of a desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) introduced from 0-0.15 amp in 10 sec. and maintained at 10 amps until the sample traces disappeared (~1-2 min). The spectrum was scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectrum (HPLC ES-MS) was obtained using a Hewlett-Pacard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with an electrospray ionizer. The spectrum was scanned from 120-800 amu using a variable ion time consistent with the number of ions in the result. Gas chromatography-selective mass spectrum (GC-MS) was obtained with a Hewlett Packard 5890 gas chromatography with an HP-1 column with methyl silicone (0.33 mM coating: 25 m x 0.2 mm) and a Hewlett Packard selective mass detector (ionization energy 70 eV). Basic analyzes were performed by Robertson Microlit Labs, Madison NJ.

Sve supstancije otkrivene NMR spektrom, LRMS i drugim osnovnim analizama ili HRMS su u skladu s određenom strukturama. All substances detected by NMR spectra, LRMS and other fundamental analyzes or HRMS conform to specific structures.

Popis kratica i akronima: List of abbreviations and acronyms:

AcOH octena kiselina AcOH acetic acid

anh bezvodni anh anhydrous

atm atmosfera atm atmosphere

BOG tert-butoksikarbonil BOG tert-butoxycarbonyl

CDI 1,1'-karbonil diimidazol CDI 1,1'-carbonyl diimidazole

conc koncentriran conc concentrated

d dan(a) d day(s)

dec d ekompozicija dec d ecomposition

DMAC N,N-dimetilacetamid DMAC N,N-dimethylacetamide

DMPU 1,3-dimetil-3,4,5,6,-tetrahidro-2(2(IH)-pirimidinon DMPU 1,3-dimethyl-3,4,5,6,-tetrahydro-2(2(1H)-pyrimidinone

DMF N,N-dimetilformamid DMF N,N-dimethylformamide

DMSO dimetilsulfoksid DMSO dimethylsulfoxide

DPPA difenilfosforil azid DPPA diphenylphosphoryl azide

EDCI 1-(3-dimetilaminopropil)-3-etilkarbodiimid EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EtOAc etil acetat EtOAc ethyl acetate

EtOH etanol (100%) EtOH ethanol (100%)

Et2O dietil eter Et2O diethyl ether

Et3N trietilamin Et3N triethylamine

h sat (i) h hour (s)

HOBT 1-hidroksibenzotriazol COPD 1-Hydroxybenzotriazole

m-CPBA β-kloroperoperoksibenzoeva kiselina m-CPBA β-chloroperoperoxybenzoic acid

MeOH metanol MeOH methanol

pet.eter petroleter (granice vrenja 30-60°C) pet ether petroleum ether (boiling range 30-60°C)

temp temperatura temp temperature

THF tetrahidrofuran THF tetrahydrofuran

TFA trifluoro AcOH TFA trifluoro AcOH

Tf trifluorometansulfonil Tf trifluoromethanesulfonyl

A. Opće metode za sintezu supstituiranih anilina A. General methods for the synthesis of substituted anilines

A1. Opće metode za oblikovanje aril amina preko formiranja etera slijedeći saponifikaciju estera, Curtius preuređenje, i arbamatnu deprotekciju. Sinteza 2-amino-3-metoksinaftalena. A1. General methods for the formation of aryl amines via ether formation following ester saponification, Curtius rearrangement, and arbamate deprotection. Synthesis of 2-amino-3-methoxynaphthalene.

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Korak 1. Metil-3-metoksi-2-naftoat Step 1. Methyl-3-methoxy-2-naphthoate

Gustu otopinu metil 3-hidroksi-2-naftoata (10.1 g, 50.1 mmol) i K2CO3 (7.96 g, 57.6 mmol) u DMF (200 mL) miješa se na sobnoj temperaturi 15 min., zatim se tretira s jodmetanom (3.43 mL, 55.1 mmol). Smjesa se ostavi preko noći miješati na sobnoj temperaturi, zatim se tretira s vodom (200 mL). Dobivena smjesa ekstrahira se s EtOAc (2x200 mL). Nastali organski sloj ispere se sa zasićenom otopinom NaCl (100 mL), osuši (MgSO4) koncentrira se pod smanjenim tlakom (približno 0.4 mmHg preko noći) i dobije se 3-metoksi-2-naftoat kao jantarno ulje(10.30 g): 1H-NMR (DMSO-d6) δ 2.70 (s, 3H), 2.85 (s, 3H) 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H). A thick solution of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2CO3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temperature for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture is left to stir overnight at room temperature, then treated with water (200 mL). The resulting mixture was extracted with EtOAc (2x200 mL). The resulting organic layer was washed with saturated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced pressure (approximately 0.4 mmHg overnight) and 3-methoxy-2-naphthoate was obtained as an amber oil (10.30 g): 1H- NMR (DMSO-d6) δ 2.70 (s, 3H), 2.85 (s, 3H) 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

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Korak 2. 3-metoksi-naftoična kiselina Step 2. 3-methoxy-naphthoic acid

Otopinu metil 3-metoksi-2-naftoata (6.28 g, 29.10 mmol) i vodu (10 mL) u MeOH (100 mL) na sobnoj temperaturi tretira se s 1 N otopinom NaOH (33.4 mL, 33.4 mmol). Smjesa se zagrije na temperaturu refluksa kroz 3 sata, ohladi na sobnu temperaturu i zakiseli 10% otopinom citronske kiseline. Dobivenu otopinu ekstrahiramo s EtOAc (2x100 mL). Nastali organski sloj ispere se sa zasićenom otopinom NaCl (100 mL), osuši (MgSO4) koncentrira se pod smanjenim tlakom. Ostaci se usitne s heksanom, zatim isperu nekokiko puta s heksanom i dobije se 3-metoksi-2-naftoićna kiselina kao bijela krutina (5.40 g, 92%): 1H-NMR (DMSO-d6) δ 3.88 (s, 3H), 7.34-7.41 (m,2H), 7.49-7.54 (m, 1H), 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J-8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H). A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temperature was treated with 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture is heated to reflux temperature for 3 hours, cooled to room temperature and acidified with a 10% solution of citric acid. The resulting solution was extracted with EtOAc (2x100 mL). The resulting organic layer is washed with saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residues were triturated with hexane, then washed several times with hexane and 3-methoxy-2-naphthoic acid was obtained as a white solid (5.40 g, 92%): 1H-NMR (DMSO-d6) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J-8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (No. 1H).

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Korak 3. 2-(N-(karbobenziloksi)amino-3-metoksinaftalen Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene).

Otopinu 3-metoksi-2-naftoićne kiseline (3.36 g, 16.6 ntmol) i Et3N (2.59 mL, 18.6 mmol) u bezvodnom toluenu (70 mL) miješa se na sobnoj temperaturi 15 min., zatim se tretira s pipetom dodanom otopinom DPPA (5.12 mL, 18.6 mmol) u toluenu (10 mL). Dobivenu otopinu zagrijevamo na 80°C kroz 2 sata. Nakon hlađenja smjese na sobnu temperaturu, štrcaljkom dodamo benzilni alkohol (2.06 mL, 20 mmol). Smjesu držimo zagrijanom na 80°C tjekom noći. Dobivenu smjesu ohladimo na sobnu temperaturu, ohladimo s 10% otopinom citronske kiseline, i ekstrahiramo s EtOAc (2x100 mL). Nastali organski sloj ispere se sa zasićenom otopinom NaCl (100 mL), osušimo (MgSO4) koncentrira se pod smanjenim tlakom. Ostaci se pročiste s kolonslom kromatografijom (14% EtOAc/86% heksan) i dobije se 2-(N-(karbobenziloksi)amino-3-metoksinaftalen kao svjetlo žuto ulje (5.1 g, 100%): 1H-NMR (DMSO-d6) δ 3.89 (s, 3H), 5.17 (s, 2H) 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H). A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 ntmol) and Et3N (2.59 mL, 18.6 mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min., then treated with a pipette added DPPA solution ( 5.12 mL, 18.6 mmol) in toluene (10 mL). The resulting solution is heated to 80°C for 2 hours. After cooling the mixture to room temperature, add benzyl alcohol (2.06 mL, 20 mmol) using a syringe. We keep the mixture heated to 80°C during the night. The resulting mixture was cooled to room temperature, cooled with 10% citric acid solution, and extracted with EtOAc (2x100 mL). The resulting organic layer is washed with saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene) as a light yellow oil (5.1 g, 100%): 1H-NMR (DMSO-d6 ) δ 3.89 (s, 3H), 5.17 (s, 2H) 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

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Korak 4. 2-amino-3-metoksinaftalen Step 4. 2-amino-3-methoxynaphthalene

Gustu otopinu 2-(N-(karbobenziloksi)amino-3-metoksiaftalena (5.0 g, 16.3 mmol) i 10% Pd/C (0.5 g) u EtOAc (70 mL) održava se ispod atmosfere H2 (balon) na sobnoj temperaturi tijekom noći. Dobivena smjesa filtrira se preko Celite® i koncentrira pod smanjenim tlakom te se dobije 2-amino-3-metoksinaftalen svijetlo narančasti prašak (2.40 g, 85%): 1H-NMR (DMSO-d6) δ 3.86 (s, 3H), 6.86 (s, 2H) 7.04-7.16 (m,2H), 7.43 (d, J=8.0 Hz, 1H), 7.56 (d, <J=8.09 Hz, 1H), EI-MS m/z 173 (M+). A thick solution 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 maintained under an atmosphere of H2 (balloon) at room temperature for The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a bright orange powder (2.40 g, 85%): 1H-NMR (DMSO-d6) δ 3.86 (s, 3H) , 6.86 (s, 2H) 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.56 (d, <J=8.09 Hz, 1H), EI-MS m/z 173 (M+ ).

A2. Sinteza ω-karbamil anilina preko formiranja karbamilpiridina slijedeći nukleofilično spajanje s aril aminom. A2. Synthesis of ω-carbamyl aniline via the formation of carbamylpyridine following nucleophilic coupling with an aryl amine.

Sinteza 4-(2-N-metilkarbamil-4-piridiloksi) anilin Synthesis of 4-(2-N-methylcarbamyl-4-pyridyloxy) aniline

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Korak 1a. Sinteza 4-kloro-N-metil-2-piridinkarboksamid putem Menisci-jeve reakcije Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci reaction

Upozorenje: ovo je veoma opasna reakcija, potencijalno eksplozivna. Uz miješanje otopine 4-kloropiridina (10,0 mL) u N-metilformamidu (250 mL) na sobnoj temperaturi dodaje se H2SO4 (3.55 mL) koja generira vanjsku temperaturu. Ovoj smjesi se doda H2O2 (30% wt u H2O, 17 mL) nakon FeSO4 · 7H2O (0.56 g) generira dalje visoku temperaturu. Dobivena smjesa miješa se 1 sat u mraku na sobnoj temperaturi, zatim se polako zagrijava kroz 4 sata do 45°C. Kada se prestanu mjehurići dizati, reakcija je zagrijana na 60°C kroz 16 h. Dobije se tamna neprozirna smeđa otopina koju se razrijedi s H2O (700 mL) zatim s 10% otopinom NaOH (250 mL). Dobivena smjesa se ekstrahira s EtOAc (3x500 mL). Organska faza posebno se ispere sa zasićenom otopinom NaCl (3x150 mL), potom se kombinira sušenje(MgSO4) preko sloja silika gela uz dodatak EtOAc. Nastalo smeđe ulje purificira se kolonskom kromatografijom (gradient od 50% EtOAc/50% heksana do 80% EtOAc/20% heksana). Dobiveno žuto ulje kristalizira se na 0°C kroz 72 h i dobije se 4-klor-N-metil-2-piridinkarboksamid (0.61 g, 5.3%): TLC (50% EtOAc/50% heksan) Rf 0.50; 1H-NMR (CDCl3) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J=5. 1 Hz, 1H), C1-MS m/z 171 ((M+H)+). Warning: this is a very dangerous reaction, potentially explosive. While stirring a solution of 4-chloropyridine (10.0 mL) in N-methylformamide (250 mL) at room temperature, H2SO4 (3.55 mL) is added, which generates an external temperature. To this mixture was added H2O2 (30% wt in H2O, 17 mL) after FeSO4 · 7H2O (0.56 g) generated a further high temperature. The resulting mixture is stirred for 1 hour in the dark at room temperature, then it is slowly heated over 4 hours to 45°C. When the bubbles stop rising, the reaction is heated to 60°C for 16 h. A dark opaque brown solution is obtained which is diluted with H2O (700 mL) then with 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3x500 mL). The organic phase is washed separately with a saturated NaCl solution (3x150 mL), then combined with drying (MgSO4) over a layer of silica gel with the addition of EtOAc. The resulting brown oil is purified by column chromatography (gradient from 50% EtOAc/50% hexanes to 80% EtOAc/20% hexanes). The resulting yellow oil was crystallized at 0°C for 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; 1H-NMR (CDCl3) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 ( d, J=5.1 Hz, 1H), C1-MS m/z 171 ((M+H)+).

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Korak 1b. Sinteza 4-kloropiridin-2-karbonil klorida soli HCl preko pikolinske kiselina Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt via picolinic acid

Bezvodni DMF (6.0 mL) polako se doda u SOCL2 (180 mL) između 40° i 50°C. Otopina se miješa na toj temperaturi 10 min. zatim se doda pikolinićna kiselina (60.0 g, 487 mmol), dodaje se u obrocima preko 30 min. Dobivena otopina zagrije se na 72°C (jako razvijanje 802) kroz 16 h nastane žuti kruti precipitat. Dobivena smjesa ohladi se na sobnu temperaturu, razrijedi se toluenom (500 mL) i koncentrira na 200 mL. Postupak dodavanje/koncentracija toluenom ponovi se dva puta. Nastali skoro suhi ostaci filtriraju se a krutina se ispere s toluenom (2x200 mL) i osuši pod visokim vakuumom kroz 4 sata, dobije se 4-klorpiridin-2-karbonil klorid soli HCl kao žuto-narančasta krutina (92.0 g, 89%). Anhydrous DMF (6.0 mL) was slowly added to SOCL2 (180 mL) between 40° and 50°C. The solution is stirred at this temperature for 10 min. then picolinic acid (60.0 g, 487 mmol) is added, it is added in portions over 30 min. The resulting solution is heated to 72°C (strong development 802) and a yellow solid precipitate forms over 16 h. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The addition/concentration with toluene procedure was repeated twice. The resulting almost dry residue is filtered and the solid is washed with toluene (2x200 mL) and dried under high vacuum for 4 hours to give the 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%).

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Korak 2. Sinteza metil-4-klorpiridin-2-karboksilata soli HCl Step 2. Synthesis of methyl-4-chloropyridine-2-carboxylate HCl salt

Bezvodni DMF (10.0 mL) polako se doda u SOCL2 (300 mL) na 40° i 48°C. Otopina se miješa na toj temperaturi 10 min., zatim se doda pikolinićna kiselina (100 g, 812 mmol), dodaje se preko 30 min. Dobivena otopina zagrije se na 72°C (jako razvijanje S02) kroz 16 h nastane žuta krutina. Dobivena smjesa ohladi se na sobnu temperaturu, razrijedi se toluenom (500 mL) i koncentrira na 200 mL. Postupak dodavanje/koncentracija toluenom ponovi se dva puta. Nastali skoro suhi ostaci filtriraju se a krutina se ispere s toluenom (50 mL) i osuši pod visokim vakumom kroz 4 sata dobije se 4-klorpiridin-2-karbonil klorid soli HCl kao bjelkasta krutina (27.2 g, 16%). Ovaj materijal stavi se sa strane. Anhydrous DMF (10.0 mL) was slowly added to SOCL2 (300 mL) at 40° and 48°C. The solution is stirred at this temperature for 10 min., then picolinic acid (100 g, 812 mmol) is added, it is added over 30 min. The resulting solution is heated to 72°C (strong evolution of SO2) and a yellow solid is formed over 16 h. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The addition/concentration with toluene procedure was repeated twice. The resulting almost dry residue is filtered and the solid is washed with toluene (50 mL) and dried under high vacuum for 4 hours to obtain 4-chloropyridine-2-carbonyl chloride HCl salt as a whitish solid (27.2 g, 16%). Put this material aside.

Crveni filtrat doda se MeOH (200mL) u obrocima pazeći da temperatura ne prede 55°C. Sadržaj se miješa na sobnoj temperaturi 45 min., ohladi na 5°C, dodaje se kap po kap Et2O (200 mL). Dobivena krutina filtrira se, ispere s Et2O (200 mL) i osuši pod smanjenim tlakom na 35°C i dobije se metil-4-klorpiridin-2-karboksilat soli HCl kao bijela krutina (110 g, 65%): mp 108-112, 1H-NMR (DMSO-d6) δ 3.88 (s, 3H), 7.82 (d, 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 (br s, 1H), HPLC ES-MS m/z 172 ((M+H)+). The red filtrate is added to MeOH (200 mL) in portions, making sure that the temperature does not exceed 55°C. The contents are stirred at room temperature for 45 min., cooled to 5°C, and Et2O (200 mL) is added dropwise. The resulting solid was filtered, washed with Et2O (200 mL) and dried under reduced pressure at 35°C to give methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 , 1H-NMR (DMSO-d6) δ 3.88 (s, 3H), 7.82 (d, 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 (br s, 1H), HPLC ES-MS m/z 172 ((M+H) + ).

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Korak 3a. Sinteza 4-klor-N-metil-2-piridinkarboksamid iz metil 4-klorpiridin-2-karboksilata Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate

Suspenziji metil 4-kloropiridina-2-karboksilata soli HCl (89.0 g, 428 mmol) u MeOH (75 mL) na 0°C dodaje se u obrocima otopina 0.2 M metilamina u THF (1L) i pazi se na da temperatura ne pređe 5°C. Dobivena smjesa čuva se na 3°C 5 sati, te koncentrira pod umanjenim tlakom. Dobivena krutina suspendira se u EtOAc (1L) i filtrira. Filtrat se ispere s zasićenom otopinom NaCl (500 mL), osuši (Na2SO4) i koncentrira pod smanjenim tlakom, dobije se 4-klor-N-metil-2-piridinkarboksamid kao svjetlo žuti kristali (71.2g, 97%): mp 41-43°C, 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.61 (d, J=5.1, 1H), 8.85 (br s, 1H), C1-MS m/z 171 ((M+H)+). To a suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0°C, a solution of 0.2 M methylamine in THF (1 L) is added in portions and care is taken that the temperature does not exceed 5 °C. The resulting mixture is stored at 3°C for 5 hours and concentrated under reduced pressure. The resulting solid was suspended in EtOAc (1L) and filtered. The filtrate was washed with saturated NaCl solution (500 mL), dried (Na2SO4) and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide as light yellow crystals (71.2g, 97%): mp 41- 43°C, 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.61 (d, J=5.1, 1H), 8.85 (br s, 1H), C1-MS m/z 171 ((M+H)+).

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Korak 3b. Sinteza 4-kloro-N-metil-2-piridinkarboksamid iz 4-klorpiridin-2-karbonil klorida Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride

4-klorpiridin-2-karboksilatu HCl soli (7.0 g, 32.95 mmol) dodaje se u obrocima otopina 0.2 M metilamina u THF (100 mL) i MeOH (20 ML) na 0°C. Dobivena smjesa čuva se na 3°C 4 sata, te koncentrira pod umanjenim tlakom. Dobivena skoro suha krutina suspendira se u EtOAc (100 mL) i filtrira. Filtrat se ispere zasićenom otopinom NaCl (2x100 mL), osuši (Na2SO4) i koncentrira pod smanjenim tlakom, dobije se 4-klor-N-metil-2-piridinkarboksamid kao žuta kristalna krutina (4.95 g, 88%): mp 37-40°C. To 4-chloropyridine-2-carboxylate HCl salt (7.0 g, 32.95 mmol) was added portionwise a solution of 0.2 M methylamine in THF (100 mL) and MeOH (20 mL) at 0°C. The resulting mixture is kept at 3°C for 4 hours and concentrated under reduced pressure. The resulting almost dry solid was suspended in EtOAc (100 mL) and filtered. The filtrate was washed with saturated NaCl solution (2x100 mL), dried (Na2SO4) and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88%): mp 37-40 °C.

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Korak 4. Sinteza-4-2-(N-metilkarbamoil)-4-piridiloksi) anilin Step 4. Synthesis of 4-2-(N-methylcarbamoyl)-4-pyridyloxy) aniline

Otopina 4-aminofenola (9.60 g, 88.0 mmol) i anh. DMF (150 mL) tertira se s kalijevim terfc-butoksidom (10.29 g, 91.7 mmol), i crvenkasto-smeđa smjesa miješa se na sobnoj temperaturi 2 h. Sadržaj se tretira s 4-klor-N-metil-2-piridinkarboksamidom (15.0 g, 87.9 mmol) i K2CO3 (6.50 g, 47.0 mmol) i potom zagrije na 80°C kroz 8 h. Smjesa se ohladi na sobnu temperaturu i odvoji s EtOAc (500 mL) i zasićenom otopinom NaCl (500 mL). Vodena faza ponovo se ekstrahira s EtOAc (300 mL). Spojeni organski sloj ispere se sa zasićenom otopinom NaCL (4x100 mL), osuši (Na2SO4) i koncentrira pod smanjenim tlakom. Dobivena krutina osuši se pod smanjenim tlakom na 35°C kroz 3 sata, i dobije se 4-2-(N-metilkarbamoil)-4-piridiloksi)anilin koji je krutina svjetlo smeđe boje 17.9 g, 84%: 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' guartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H), 7.33 (d, J=2 .5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H), HPLC ES-MS m/z 244 ((M+H)+). A solution of 4-aminophenol (9.60 g, 88.0 mmol) and anh. DMF (150 mL) was triturated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temperature for 2 h. The contents are treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C for 8 h. The mixture was cooled to room temperature and partitioned with EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was re-extracted with EtOAc (300 mL). The combined organic layer was washed with saturated NaCl solution (4x100 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was 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%: 1H-NMR (DMSO -d6) δ 2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' guartet, 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. Opća metoda za sintezu anilina preko nukleofilične aromatske adicije koju slijedi nitroaren redukcija. A3. A general method for the synthesis of anilines via nucleophilic aromatic addition followed by nitroarene reduction.

Sinteza 5-(4-aminofenoksi)izoinđolin-1,3-diona Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

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Korak 1. Sinteza 5-hidroksiizoindolin-1,3-dion Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione

U smjesu amonijeva karbonata (5.28 g, 54.9 mmol) i conc. AcOH (25 mL) polako se doda 4-hidroksiftalićna kiselina (5.0 g, 27.45 mmol). Dobivenu smjesu zagrijemo na 120°C kroz 45 min., zatim bistru, svijetlo žutu smjesu zagrijemo na 160°C kroz 2 sata. Dobivenu mješavinu održavamo na 160°C i koncentriramo na otprilike 15 mL., potom ohladimo na sobnu temperaturu i podesimo na pH 10, s 1N otopinom NaOH. Smjesu ohladimo na 0°C i polako zakiselimo na pH 5 s 1N otopinom NaOH. Rezultirajuči precipitat sakupimo filtracijom i osušimo pod smanjenim tlakom, prinos 5-hidroksiizoindolin-1,3-diona proizvoda kao svijetložutog praška (3.24g, 72%): 1H-NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H). Into a mixture of ammonium carbonate (5.28 g, 54.9 mmol) and conc. 4-Hydroxyphthalic acid (5.0 g, 27.45 mmol) was slowly added to AcOH (25 mL). Heat the resulting mixture to 120°C for 45 minutes, then heat the clear, light yellow mixture to 160°C for 2 hours. The resulting mixture is maintained at 160°C and concentrated to approximately 15 mL, then cooled to room temperature and adjusted to pH 10, with a 1N NaOH solution. Cool the mixture to 0°C and slowly acidify it to pH 5 with a 1N NaOH solution. The resulting precipitate was collected by filtration and dried under reduced pressure, yield of 5-hydroxyisoindoline-1,3-dione product as a light yellow powder (3.24g, 72%): 1H-NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).

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Korak 2. Sinteza 5-(4-nitrofenoksi)izoindolin-1,3-dion Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione

Uz miješanje gustoj otopini NaH (1.1 g, 44.9 mmol) i DMF (40 mL) na 0°C dodamo kap po kap otopinu 5-hidroksiizoindolin-1,3-dion i DMF (40 mL). Svijetlo žuto-zelena smjesa vrati se na sobnu temperaturu i miješa 1 sat, zatim se doda 1-fluoro-4-nitrobenzen (2.67 g, 18.7 mmol) putem štrcaljke na 3-4 puta. Dobivenu smjesu zagrijemo preko noći na 70°C, zatim ohladimo na sobnu temperaturu i razrijedimo polako dodavajući vodu (150 mL), i ekstrahiramo s EtOAc (2x100mL). Nastali organski sloj osušimo (MgSO4) i kocentriramo pod smanjenim tlakom i dobijemo 5-(4-nitrofenoksi)izoindolin-1,3-dion kao žutu krutinu (3.3 g, 62%): TLC (30% EtOAc/70% heksan) Rf 0.28; 1H-NMR (DMSO-d6) δ 7.23 (d, J=12 Hz, 2H), 7.52-7.57 (m, H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, 1H), CI-MS m/z 285 ((M+H)+), 100%) While stirring, a solution of 5-hydroxyisoindoline-1,3-dione and DMF (40 mL) was added dropwise to a thick solution of NaH (1.1 g, 44.9 mmol) and DMF (40 mL) at 0°C. The light yellow-green mixture was returned to room temperature and stirred for 1 hour, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated overnight at 70°C, then cooled to room temperature and diluted by slowly adding water (150 mL), and extracted with EtOAc (2x100 mL). The resulting organic layer was dried (MgSO4) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) Rf 0.28; 1H-NMR (DMSO-d6) δ 7.23 (d, J=12 Hz, 2H), 7.52-7.57 (m, H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz , 2H), 11.43 (br s, 1H), CI-MS m/z 285 ((M+H)+), 100%)

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Korak 3. Sinteza 5-(4-aminofenoksi)izoindolin-1,3-dion Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

Otopinu 5-(4-nitrofenoksi)izoindolin-1,3-dion (0.6 g, 211 mmol) u conc. AcOH (12 mL) i vode (0.1 mL) miješamo u struji argona dok željezni prah (0.59 g, 55.9 mmol) dodamo polako. Nastalu smjesu miješamo na sobnoj temperaturi 72 sata, zatim razrijedimo vodom (25 mL) i ekstrahiramo s EtOAc (3x50 mL). Nastali organski talog osušimo (MgSO4) i kocentriramo pod smanjenim tlakom i dobijemo 5-(4-aminofenoksi)izoindolin-1,3-dion kao smeđkastu krutinu (0.4 g, 75%): TLC (50% EtOAc/50% heksana) Rf 0.27; 1H-NMR (DMSO-d6) δ 5.14 (br s, 1H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J-=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4 Hz, 1H), 11.02 (s, 1H), HPLC ES-MS m/z 255 ((M+H)+, 100%). A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 211 mmol) in conc. AcOH (12 mL) and water (0.1 mL) were mixed under an argon stream while iron powder (0.59 g, 55.9 mmol) was added slowly. The resulting mixture was stirred at room temperature for 72 hours, then diluted with water (25 mL) and extracted with EtOAc (3x50 mL). The resulting organic precipitate was dried (MgSO4) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) Rf 0.27; 1H-NMR (DMSO-d6) δ 5.14 (br s, 1H), 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. Opća metoda za sintezu pirolilanilina. Sinteza 5-tert-butil-2-(2,5-dimetilpirolil)anilina A4. General method for the synthesis of pyrrolylaniline. Synthesis of 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline

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Korakl. Sinteza 1-(4-tert-butil-2-nitrofenil)-2,5-dimetilpirol) Coracle. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole)

Uz miješanje otopine 2-nitro-4-tert-butilanilina (0.5 g, 2.57 mmol) i cikloheksana (10 mL) doda se štrcaljkom AcOH (0.1 mL) i acetonilaceton (0.299 g, 2.63 mmol). Reakcijska smjesa zagrije se na 120°C za 72 sat s azeotropnim odstanjivanjem hlapijivog dijela. Reakcijska smjesa se ohladi na sobnu temperaturu, razrijedi s CH2Cl2 (10 ml) i uzastopno ispere s 1N otopinom HCl-a (15 mL), 1N otopinom NaOH (15 mL) i zasićenom otopinom NaCl (15 mL), osuši se (MgSO4) i koncentrira pod smanjenim tlakom. Dobivena narančasto-smeđa krutina purificira se kolumnom kromatografijom (60g SiO2: gradient od 6% EtOAc/94% heksan do 25% EtOAc/75% heksan) i dobijemo 1-(4-tert-butil-2-nitrofenil)-2,5 dimetilpirol) kao naranćasto-žutu krutinu (0.34 g, 49%): TLC (15% EtOAc/85% heksana) Rf 0.67; 1H-NMR (CDCl3)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, ,7=2.4 Hz, 1H), C1-MS m/z 273 ((M+H)+), 50%). While mixing the solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) and cyclohexane (10 mL), AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) were added with a syringe. The reaction mixture is heated to 120°C for 72 hours with azeotropic removal of the volatile part. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (10 mL) and washed successively with 1N HCl solution (15 mL), 1N NaOH solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO4) and concentrates under reduced pressure. The obtained orange-brown solid is purified by column chromatography (60g SiO2: gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to obtain 1-(4-tert-butyl-2-nitrophenyl)-2,5 dimethylpyrrole) as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexanes) Rf 0.67; 1H-NMR (CDCl3)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, ,7 =2.4 Hz, 1H), C1-MS m/z 273 ((M+H)+), 50%).

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Korak 2. Sinteza 5-tert-butil-2-(2,5-dimetilpirolil) anilina Step 2. Synthesis of 5-tert-butyl-2-(2,5-dimethylpyrrolyl) aniline

Gustu otopinu 1-(4-tert-butil-2-nitrifenil)-2,5-dimetilpirola (0.341 g, 1.25 mmol)10%Pd/C (0.056 g) i EtOAc (50 mL) pod atmosferom H2 (balon) miješa se 72 sata zatim filtrira kroz sloj Celite® -a. Filtrat se koncentrira pod reduciranim tlakom i dobije se 5-tert-butil-2-(2,5-dimetilpirolil)anilin kao žuta krutina (0.30 g, 99%): TLC (10% EtOAc/90% heksana) Rf 0.43; 1H-NMR (CDCl3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28(br s, 1H). A thick solution of 1-(4-tert-butyl-2-nitriphenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol) in 10%Pd/C (0.056 g) and EtOAc (50 mL) was stirred under an atmosphere of H2 (balloon) is then filtered through a layer of Celite® for 72 hours. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline as a yellow solid (0.30 g, 99%): TLC (10% EtOAc/90% hexanes) Rf 0.43; 1H-NMR (CDCl3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).

A5. Opća metoda za sintezu anilina iz anilina nastalih nukleofiličnom aromatičnom substi-tucijom. Sinteza 4-(2-(N-metilkarbamoil)-4-piridil oksi)-2-metilanilin sol HCl A5. General method for the synthesis of aniline from aniline formed by nucleophilic aromatic substitution. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl salt

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Otopina 4-amino-3-metilfenola (5.45 g, 44.25 mmol) u suhom dimetilacetamidu (75 mL) tretira se s kalijevim tert-butoksidom (10.86 g, 96.77 mmol), i ta crna smjesa miješa se na sobnoj temperaturi sve dok boca ne dosegne sobnu temperaturu. Sadržaj potom tretiramo s 4-klor-N-metil-2-piridinkarboksamid (Metoda A2, Korak 3b; 7.52 g, 44.2 mmol) i zagrije na 110°C kroz 8 sati. Smjesu se ohladi na sobnu temperaturu i razrijedi s vodom (75 mL). Organski sloj ekstrahira se s EtOAc (5x100 mL). Nastali organski sloj ispere se s zasićenom otopinom NaCl (200 mL), osuši s (MgSO4) i koncentrira pod smanjenim tlakom. Ostatak crnog ulja obradi se s Et2O (50 mL) i ultrazvučnoj kupelji. Otopina se tretira s HCl (1 M u Et2O; 100 mL) i miješa na sobnoj temperaturi 5 min. Dobivena krutina tamno ružičaste boje (7.04 g, 24.1 mmol), odvoji se filtracijom od otopine i čuva se do upotrebe pod anaerobnim uvjetima na 0°C. 1H-NMR (DMSO-d6) δ 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (d,d, 47=8.5, 2.6 Hz, 1H), 7.23 (d,d, 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, i7=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H). A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol), and the black mixture was stirred at room temperature until the flask reach room temperature. The contents are then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated to 110°C for 8 hours. Cool the mixture to room temperature and dilute with water (75 mL). The organic layer was extracted with EtOAc (5x100 mL). The resulting organic layer was washed with saturated NaCl solution (200 mL), dried with (MgSO4) and concentrated under reduced pressure. The black oil residue was treated with Et2O (50 mL) and an ultrasonic bath. The solution was treated with HCl (1 M in Et2O; 100 mL) and stirred at room temperature for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) is separated from the solution by filtration and stored under anaerobic conditions at 0°C until use. 1H-NMR (DMSO-d6) δ 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (d,d, 47=8.5, 2.6 Hz, 1H ), 7.23 (d,d, 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, i7=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).

A6. Opća metoda za sintezu anilina iz hiđroksianilina N-protekcijon, nukleofiličnom aromatskom supstitucijom i deprotekcijom. Sinteza 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloranilina A6. General method for the synthesis of aniline from hydroxyaniline by N-protection, nucleophilic aromatic substitution and deprotection. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

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Korak 1: Sinteza 3-klor-4-(2,2,2-trifluoracetilamino) fenola Step 1: Synthesis of 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol

Željezu (3.24 g, 58.00 mino l) uz miješanje doda se TFA (200 mL). Toj gustoj smjesi doda se 2-klor-4-nitrofenol (10.0 g, 58 mmol) i trifluorocteni anhidrid (20 mL). Ta siva gusta smjesa miješa se na sobnoj temperaturi 6 dana. Željezo se odfiltrira iz otopine i dobiveni materijal se koncentrira pod smanjenim tlakom. Preostala siva krutina se disolvira u vodi (20 mL). Nastaloj žutoj otopini doda se zasićena otopina NaHCO3 (50 mL). Krutina koja je precipitirala u otopini odstrani se. Filtrat se polako hladi s otopinom natrijeva bikarbonata sve dok s produkt jasno ne odvoji od otopine (određuje se upotrebom cjevčica koje se podižu). Slabo tamno žuta otopina ekstrahira se s EtOAc (3X125 M1). Dobiveni organski sloj ispere se zasićenom otopinom NaCl (125 M1), osuši s (MgSO4) i koncentrira pod smanjenim tlakom. 1H-NMR (DMSO-d6) indicira u omjer 1 : 1 nitrofenola početnog materijala i željenog produkta 3-klor-4-(2,2,2-trifluoracetilamino) fenola. Nepročišćeni materijal dobije se u slijedećem koraku daljnjom purifikacijom. TFA (200 mL) was added to iron (3.24 g, 58.00 min L) with stirring. To this thick mixture was added 2-chloro-4-nitrophenol (10.0 g, 58 mmol) and trifluoroacetic anhydride (20 mL). This gray thick mixture is stirred at room temperature for 6 days. The iron is filtered off from the solution and the resulting material is concentrated under reduced pressure. The remaining gray solid is dissolved in water (20 mL). A saturated solution of NaHCO3 (50 mL) is added to the resulting yellow solution. The solid that precipitated in the solution was removed. The filtrate is slowly cooled with sodium bicarbonate solution until the product clearly separates from the solution (determined by the use of riser tubes). The slightly dark yellow solution was extracted with EtOAc (3X125 M1). The obtained organic layer is washed with saturated NaCl solution (125 M1), dried with (MgSO4) and concentrated under reduced pressure. 1H-NMR (DMSO-d6) indicates a 1:1 ratio of nitrophenol starting material and the desired product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. Unpurified material is obtained in the next step by further purification.

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Korak 2: Sinteza 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-klorofenil (222-trifluor)acetamid Step 2: Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide

Otopina nepročišćenog 3-klor-4-(2,2,2-trifluoroacetilamino) fenola (5.62 g, 23.46 mmol) u bezvodnom dimetilacetamidu (50 mL) tretira se kalijevim tert-butoksidom (5.16 g, 45.98 mmol) te smeđe crnu smjesu miješa se na sobnoj temperaturi sve dok se bočica ne ohladi na sobnu temperaturu. Dobivenu smjesu tretira se s 4-kloro-N-metil-2-piridinkarboksamidom (metoda A2, Korak 3b; 1.99 g, 11.7 mmol) i zagrije na 100°C pod argonom kroz 4 d. Crna reakciona smjesa ohladi se na sobnu temperaturu i onda se pretoči u hladnu vodu (100 mL). Smjesa se ekstrahira s EtOAc (3x75 mL) i dobiveni organski sloj koncentrira se pod smanjenim tlakom. Ostatno smeđe ulje purificira se kolonskom kromatografijom (gradient od 20% EtOAc/pet. eter do 40% EtOAc/ pet. eter) i dobijemo 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-klorfenil(222-trifluor) acet-amid kao žutu krutinu (8.59 g, 23,0 mmol). A solution of unpurified 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in anhydrous dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brown-black mixture was stirred at room temperature until the vial cools 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 to 100°C under argon for 4 d. The black reaction mixture was cooled to room temperature and then pour into cold water (100 mL). The mixture was extracted with EtOAc (3x75 mL) and the resulting organic layer was concentrated under reduced pressure. The remaining brown oil is purified by column chromatography (gradient from 20% EtOAc/pet ether to 40% EtOAc/pet ether) to obtain 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl(222- trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

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Korak 3: Sinteza 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloroanilin Step 3: Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

Otopina nepročišćenog 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-klorfenil(222-trifluor)acetamida (8.59 g, 23.0 mmol) u bezvodnom dioksinu (20 mL) tretira se 1N otopinom NaOH (20mL). Smeđu otopinu ostavi se uz mućkanje 8 sati. Toj otopini doda se EtOAc (40 mL). Dobiveni zeleni organski sloj ekstrahira se s EtOAc (3x40 mL) i otapalo koncentrira na prinos 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloroanilin, smeđe ulje dok se ne zgusne i zatim stoji (2.86 g, 10.30 mmol): 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, c7=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). A solution of crude 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl(222-trifluoro)acetamide (8.59 g, 23.0 mmol) in anhydrous dioxin (20 mL) was treated with 1N NaOH solution (20 mL). Leave the brown solution with shaking for 8 hours. To this solution was added EtOAc (40 mL). The resulting green organic layer was extracted with EtOAc (3x40 mL) and the solvent concentrated to yield 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, a brown oil until it thickened and then stood (2.86 g, 10.30 mmol): 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, c7=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. Opća metoda za deprotekciju acetliranog anilina. Sinteza 4-klor-2-metoksi-5-(trifluormetil)anilina A7. General method for deprotection of acetylated aniline. Synthesis of 4-chloro-2-methoxy-5-(trifluoromethyl)aniline

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Suspenziju 3-klor-6-(N-acetil)-4-(trifluorometil)anisola (4.00 g, 14.95 mmol) u 6M otopini HCl (24 mL) zagrije se do temperature refluksa za 1 h. Dobivena otopina ostavi se hladiti na sobnoj temperaturi, kroz to vrijeme će se slabo zgusnuti. Nastalu smjesu razrijediti ćemo s vodom (20 mL) a potom tretirati kombinirano NaOH i zasićenom otopinom NaHCO3 sve dok otopina ne postane bazičan. Organski sloj ekstrahiramo s CH2Cl2 (3x50 mL). Nastalu organsku masu osuši se s (MgSO4) i koncentrira pod smanjenim tlakom, dobijemo 4-klor-2-metoksi-5-(trifluormetil)anilina kao smeđeg ulja (3.20 g, 14.2 mmol): 1H-NMR (DMSO-d6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H). A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in 6M HCl solution (24 mL) was heated to reflux for 1 h. The resulting solution is left to cool at room temperature, during which time it will slightly thicken. The resulting mixture will be diluted with water (20 mL) and then treated with combined NaOH and saturated NaHCO3 solution until the solution becomes basic. The organic layer is extracted with CH2Cl2 (3x50 mL). The resulting organic mass was dried with (MgSO4) and concentrated under reduced pressure to obtain 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 1H-NMR (DMSO-d6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. Opća metoda sinteze ω-alkoksi-CG-karboksifenil anilina. Sinteza 4-(3-(N-metilkarbamoil)-4-metoksifenoksi) anilina A8. General method of synthesis of ω-Alkoxy-CG-carboxyphenyl aniline. Synthesis of 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy) aniline

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Korak 1. 4-(3-me toksikarbonil-4-metoksifenoksi)-1-nitrobenzen: Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:

U otopinu 4-(3-karboksi-4-hidroksifenoksi)-1-nitrobenzena (pripremljenu od 2,5-dihidroksibenzoićne kiseline na način kako je opisano u Metodi A13, Korak 1, 12 mmol) i acetona (50 mL) kojem je dodan K2CO3 (5 g) i dimetil sulfat (3.7 mL). Nastala smjesa se zagrije do temperature refluksa preko noći, ohladi se na sobnu temperaturu i filtrira preko sloja Celite®. Dobivenu smjesu koncentrira se pod umanjenim tlakom, absorbira na SiO2, i purificira kolonskom kromatografijom (50% EtOAc/50% EtOAc), i dobije se 4-(3-metoksikarbonil-4-metoksifenoksi)-1-nitrobenzen kao žuti prašak (3 g): mp 115-118°C. To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid as described in Method A13, Step 1, 12 mmol) and acetone (50 mL) to which was added K2CO3 (5 g) and dimethyl sulfate (3.7 mL). The resulting mixture is heated to reflux temperature overnight, cooled to room temperature and filtered through a pad of Celite®. The resulting mixture was concentrated under reduced pressure, absorbed on SiO2, and purified by column chromatography (50% EtOAc/50% EtOAc) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g ): mp 115-118°C.

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Korak 2. 4-(3-karboksi-4-metoksifenoksi)-1-nitrobenzen: Step 2. 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene:

Smjesu 4-(3-metoksikarbonil-4-metoksifenoksi)-1-nitrobenzena (1.2 g), KOH (0.33 g) i vode (5 mL) u MeOH (45 mL) miješa se na sobnoj temperaturi tijekom noći i potom zagrije na temperaturu refluksa kroz 4 h. Dobivenu smjesu ohladimo na sobnu temperaturu i koncentriramo pod smanjenim tlakom. Ostatke radstopimo u vodi (50 mL), i vodenu smjesu zakiselimo s 1N otopinom HCl. Dobivenu smjesu ekstrahiramo s EtOAc (50 mL). Organski sloj osušimo s (MgSO4) i koncentriramo pod smanjenim tlakom i dobijemo 4-(3-karboksi-4-metoksifenoksi)-1-nitrobenzen (1.04 g). 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 warmed to temp. of reflux for 4 h. Cool the resulting mixture to room temperature and concentrate under reduced pressure. The residues are dissolved in water (50 mL), and the aqueous mixture is acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried with (MgSO4) and concentrated under reduced pressure to obtain 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).

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Korak 3 . 4-(3-(N-metilkarbamoil)-4-metoksif enoksi)-1-nitrobenzen: Step 3. 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene:

U otopinu 4-(3-karboksi-4-metoksifenoksi)-1-nitrobenzena (0.50 g, 1.75 rnmol) u CH2Cl2 (12 mL) doda se SOCl2 (0.64 mL, 8.77 mmol) u obrocima. Nastala smjesa se zagrije do temperature refluksa kroz 18 h, ohladi na sobnu temperaturu i koncentrira se pod umanjenim tlakom. Dobivena žuta krutina rastopi se u CH2Cl2 (3 mL), potom nastala otopina tretira s otopinom metilamina (2.0 M u THF, 3.5 mL, 7.02 mmol) u obrocima (PAŽNJA: razvija se plin), i miješa na sobnoj temperaturi 4 sata. Dobivena smjesa tretira se s 1N otopinom NaOH, potom ekstrahira s CH2Cl2 (25 mL). Organski sloj se osuši (Na2SO4) i koncentrira pod smanjenim tlakom, a dobije se 4-(3-(N-metilkarbamoil)-4-metoksifenoksi)-1-nitrobenzen kao žuta krutina (0.50 g, 95%): To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 rnmol) in CH 2 Cl 2 (12 mL) was added SOCl 2 (0.64 mL, 8.77 mmol) in portions. The resulting mixture is heated to the reflux temperature for 18 h, cooled to room temperature and concentrated under reduced pressure. The obtained yellow solid is dissolved in CH2Cl2 (3 mL), then the resulting solution is treated with a solution of methylamine (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas is evolved), and stirred at room temperature for 4 hours. The resulting mixture is treated with 1N NaOH solution, then extracted with CH2Cl2 (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%):

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Korak 4. 4-(3-(N-metilkarbamoil)-4-metoksifenoksi) anilin Step 4. 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy) aniline

Gustu smjesu 4-(3-(N-metilkarbamoil-4-metoksifenoksi)-1-nitrobenzena (0.78 g, 2.60 mmol) i 10% Pd/C (0.20 g) u EtOH (55 mL) miješa se pod 1 atm H2 (balon) kroz 2.5 d, a zatim se filtrira kroz sloj Celite®. Nastalu otopinu koncentrira se pod smanjenim tlakom, pa se dobije 4-(3-(AT-metilkarbamoil)-4-metoksifenoksi) anilin ne potpuno bijela krutina (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) Rf 0.36. A thick mixture 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) was stirred under 1 atm H2 ( balloon) for 2.5 d and then filtered through a layer of Celite®. The resulting solution was concentrated under reduced pressure to give 4-(3-(AT-methylcarbamoyl)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) Rf 0.36.

A9. Opća metoda za pripremu ω-alkilftalimid-sadržavajućih anilina. Sinteza 5-(4-aminofenoksi)-2-metilizoindolin -1,3-diona. A9. General method for the preparation of ω-alkylphthalimide-containing anilines. Synthesis of 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione.

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Korak 1. Sinteza 5-(4-nitrofenoksi)-2-metilizoindolin-1,3-dion Step 1. Synthesis of 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione

Gustu smjesu 5-(4-nitrofenoksi)izoindolin-1,3-dion (A3 Korak 2; 1.0 g, 3.54 mmol) i NaH (0.13g, 5.27 mmol) u DMF (15 mL) miješa se na sobnoj temperaturi 1 h, zatim tretira s metil jodidom (0.3 mL, 4.57 mmol). Dobivenu smjesu miješa se na sobnoj temperaturi tjekom noći, zatim ohaldi na °C i tretira vodom (10 mL). Nastalu krutinu sakupi se i osuši pod smanjenim tlakom i dobije se 5-(4-nitrofenoksi)-2-metilizoindolin-1,3-dion svjetlo žuta krutina (0.87 g, 83%): TLC (35% EtOAc /65% heksan) Rf 0.61. A thick mixture of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.54 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temperature for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture is stirred at room temperature overnight, then cooled to °C and treated with water (10 mL). The resulting solid was collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a light yellow solid (0.87 g, 83%): TLC (35% EtOAc /65% hexane) Rf 0.61.

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Korak 2. Sinteza 5-(4-aminofenoksi)-2-metilizoindolin-1,3-diona Step 2. Synthesis of 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione

Gustu smjesu nitrofenoksi)-2-metilizoindolin-1,3-dion (O . 87 g, 2.78 mmol) i 10% Pd/C (0.10 g) u MeOH miješa se pod 1 atm H2 (balon) preko noći. Dobivenu smjesu se filtrira kroz sloj Celite® i koncentrira se pod smanjenim tlakom. Dobivenu žutu krutinu rastopi se u EtOAc (3 mL) i filtrira preko čepa od SiO2 (60% ETOAc/40% heksan), a dobije se 5-(4-aminofenoksi)-2-metilizoindolin-1,3-dion kao žuta krutina (0.67 g, 86%): TLC (40% EtOAc /60%heksan) Rf 0.27. A thick mixture of nitrophenoxy)-2-methylisoindoline-1,3-dione (O.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm H2 (balloon) overnight. The resulting mixture is filtered through a layer of Celite® and concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3 mL) and filtered through a plug of SiO2 (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) Rf 0.27.

A10. Opća metoda za sintezu ω-karbamoilaril anilina preko reakcije ω-alkoksikarbonilaril prekursora s aminima. Sinteza 4-(2-(N-(2-morfolin-4-iletil)karbamoilpiridil-oksi anilin A10. General method for the synthesis of ω-carbamoylaryl anilines via the reaction of ω-alkoxycarbonylaryl precursors with amines. Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl)carbamoylpyridyl-oxy aniline)

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Korak 1. Sinteza 4-klor-2-(N-(2-morfolin-4-iletil) karbamoil)piridina Step 1. Synthesis of 4-chloro-2-(N-(2-morpholin-4-ylethyl) carbamoyl)pyridine

Otopini metil 4-klorpiridin-2-karboksilata soli HCl ( Metoda A2, Korak 2; 1.01 g, 4.86 mmol) u THF (20 mL) doda se kap po kap 4-(2-aminoetil) morfolin (2.55 mL, 19.4 mmol), a nastala otopina zagrije se do temperature refluksa kroz 20 sati, ohladi na sobnu temperaturu i tretira s vodom (50 mL). Dobivenu smjesu ekstrahiramo s EtOAc (50 mL). Organski talog osušimo (MgSO4), koncentriramo pod smanjenim tlakom da dobijemo 4-klor-2-(N-(2-morfolin-4-iletil)karbamoil)piridin kao žuto ulje (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf 0.50. To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added dropwise 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) , and the resulting solution is heated to reflux temperature for 20 hours, cooled to room temperature and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic residue was dried (MgSO4), concentrated under reduced pressure to give 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH /90% EtOAc) Rf 0.50.

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Korak 2. Sinteza 4-(2-(N-(2-morfolin-4-iletil)karbamoil) piridiloksi)anilina Step 2. Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline

Otopinu 4-aminofenola (0.49 g. 4.52 mmol) i kalijevog tert-butoksida (0.53 g, 4.75 mol) u DMF (8 mL) miješa se 2 h na sobnoj temperaturi, zatim uzastopno tretira s 4-klor-2-(N-(2-morfolin-4-ileti)karbamoil)piridinom (1.22 g, 4.52 mmol) i K2CO3 (0.31 g, 2.26 mmol). Dobivenu smjesu zagrijemo na 75°C preko noći, ohladimo na sobnu temperaturu i odvojimo između EtOAc (25 mL) i zasićenom otopinom NaCl (25 mL). Vodeni sloj ponovo ekstrahiramo s EtOAc (25 mL). Dobiveni organski sloj isperemo zasićenom otopinom NaCl (3x25 mL) i koncentriramo pod smanjenim tlakom. Nastalu smeđu krutinu purificiramo kolonskom kromatografijom (58 g; gradient od 100% EtOAc do 25% MeOH/75% EtOAc) i dobijemo 4-(2-(N-(2-morfolin-4-iletil)karbamoil)piridil oksi)anilin (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf 0.32. 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 for 2 h at room temperature, then successively treated with 4-chloro-2-(N- (2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated to 75°C overnight, cooled to room temperature and separated between EtOAc (25 mL) and saturated NaCl solution (25 mL). The aqueous layer was extracted again with EtOAc (25 mL). The obtained organic layer is washed with saturated NaCl solution (3x25 mL) and concentrated under reduced pressure. The resulting brown solid was purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to obtain 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline ( 1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf 0.32.

A11: Opća metoda za redukciju nitroarena u arilamine. Sinteza 4-(3-karboksifenoksi)anilina A11: General method for the reduction of nitroarenes to arylamines. Synthesis of 4-(3-carboxyphenoxy)aniline

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Gusta otopina 4-(3-karboksifenoksi)-1-nitrobenzena (5.38 g, 20.7 mmol) i 10% Pd/C (0.50 g) u MeOH (120 mL) miješa se pod H2 atmosferom (balon) 2 d. Nastalu smjesu filtriramo preko sloja Celi te® i koncentrira se pod smanjenim tlakom da dobijemo 4-(3- karboksifenoksi)anilin kao smeđu krutinu (2.26 g, 48%): TLC (10% MeOH/90% CH2Cl2) Rf 0.44 (neujednačen). A thick solution 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 H2 atmosphere (balloon) for 2 d. The resulting mixture was filtered over a pad of Celite® and concentrated under reduced pressure to give 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH2Cl2) Rf 0.44 (uneven).

A12. Opća metoda za sintezu izoindolinon-sadržavajuće anilina. Sinteza 4-(1-oksoizoindolin-5-iloksi) anilina. A12. General method for the synthesis of isoindolinone-containing anilines. Synthesis of 4-(1-oxoisoindolin-5-yloxy) aniline.

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Korak 1. Sinteza 5-hidroksiizoindolin-1-on Step 1. Synthesis of 5-hydroxyisoindolin-1-one

Otopini 5-hidroksiftalimida (19.8 g, 121 mmol) u AcOH (500 mL) polako se dodaje cinkov prah (47.6 g, 729 mmol) u obrocima, potom se smjesu zagrije do temperature refluksa kroz 40 min., zagrijano filtrira i koncentrira pod smanjenim tlakom. Reakciju se ponovi na isti način, a ostatke nastalog ulja purificira kolonskom kromatografijom (1.1 kg SiO2: gradienti od 60%EtOAc/60%heksana do 25% MeOH/75% EtOAc) i dobije se 5-hidroksiizoindolin-1-on (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m/z 150((M+H)+). Zinc powder (47.6 g, 729 mmol) was slowly added to a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) in portions, then the mixture was heated to reflux temperature for 40 min., filtered while heated and concentrated under reduced pressure. The reaction is repeated in the same way, and the residues of the resulting oil are purified by column chromatography (1.1 kg SiO2: gradients from 60%EtOAc/60%hexane to 25% MeOH/75% EtOAc) and 5-hydroxyisoindolin-1-one (3.77 g) is obtained ): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m/z 150((M+H)+).

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Korak 2. Sinteza 4-(1-izoindolinon-5-iloksi)-1-nitrobenzen Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene

Gustoj smjesi od NaH (0.39 g, 16.1 mmol) u DMF na 0°C doda se 5-hidroksiizoindolin-1-on (2.0 g, 13.4 mmol) u obrocima. Dobivena gusta smjesa ostavi se na toplom na sobnoj temperaturi, i miješa 45 min., potom se doda 4-fluoro-1-nitrobenzen i smjesa se zagrije na 70°C kroz 3 sata. Smjesa se ohladi na 0°C i tretira dodavanjem kap po kap vode sve dok se ne formira precipitat. Nastalu krutinu sakupimo i dobijemo 4-(1-izoindolinin-5-iloksi)-1-nitrobenzen kao tamno žutu krutinu (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35. To a thick mixture of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting thick mixture is left warm at room temperature and stirred for 45 min., then 4-fluoro-1-nitrobenzene is added and the mixture is heated to 70°C for 3 hours. The mixture is cooled to 0°C and treated by adding water drop by drop until a precipitate forms. The resulting solid was collected to give 4-(1-isoindolin-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.

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Korak 3. Sinteza 4-(1-oksoizoinđolin-5-iloksi)anilina Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline

Gustu smjesu od 4-(1-izoindolin-5-iloksi)-1-nitrobenzena (2.12 g, 7.8 mmol) i 10% Pd/C (0.20 g) i EtOH (50 mL) miješa se pod H2 atmosferom (balon) 4 sata, potom filtrira kroz sloj Celite®. Filtrat se koncentrira pod smanjenim tlakom i dobije 4-(1-oksoizoindolin-5-iloksi)anilin kao tamno žuta krutina: TLC (100% EtOAc) Rf 0.15. A thick mixture of 4-(1-isoindolin-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) and EtOH (50 mL) was stirred under H2 atmosphere (balloon) 4 hour, then filtered through a layer of Celite®. The filtrate was concentrated under reduced pressure to give 4-(1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) Rf 0.15.

A13. Opća metoda za sintezu ω-karbamoil anilina preko EDCI-posrednika amid formacije koja slijedi nitroaren redukciju. Sinteza 4-(3-N-metilkarbamoil£enoksi)anilina A13. General method for the synthesis of ω-carbamoyl anilines via EDCI-mediated amide formation following nitroarene reduction. Synthesis of 4-(3-N-methylcarbamoyl£enoxy)aniline

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Korak 1. Sinteza 4-(3-etoksikarbonilfenoksi)-1-nitro benzena Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene

Smjesu od 4-fluor-1-nitrobenzena (16 mL, 150 mmol), etil 3-hidroksibenzoata (25 g, 150 mmol) i K2CO3 (41 g, 300 mmol) u DMF (125 mL) zagrije se preko noći do temperature refluksa, ohladi na sobnoj temperaturi i tretira s vodom (250 mL). Dobivena smjesa ekstarhira se s EtOAc (3x150 mL). Nastala organska faza se uzastopno ispere s vodom (3x100 mL) i zasićenom otopinom NaCl (2x100 mL), osuši (Na2SO4) i koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (10% EtOAc/90% heksan) i dobije se 4-(3-etoksikarbonilfenoksi)-1-nitrobenzen u obliku ulja (38 g). A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated to reflux overnight. , cooled to room temperature and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3x150 mL). The resulting organic phase is successively washed with water (3x100 mL) and saturated NaCl solution (2x100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to give 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).

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Korak 2. Sinteza 4-(3-karbonilfenoksi)-1-nitrobenzena Step 2. Synthesis of 4-(3-carbonylphenoxy)-1-nitrobenzene

Uz jako miješanje smjesi 4-(3-etoksikarbonilfenoksi)-1-nitrobenzena (5.14 g, 17.9 mmol) u otopini 3:1 THF/voda (75 mL) : doda se otopina LiOH · H2O (1.50 g, 35.8 mmol) u vodi (36 mL). Nastala smjesa zagrije se na 50°C preko noći, zatim ohladi na sobnu temperaturu, koncentrira pod smanjenim tlakom, i podesi na pH 2 s 1 M otopinom HCl. Nastane svijetlo žuta krutina koja se odstrani filtracijom i ispiranjem s heksanom, i dobije se 4-(3-karbonilfenoksi)-1-nitrobenzen (4.40 g, 95%). With vigorous stirring to a 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 was added (36 mL). The resulting mixture was heated to 50°C overnight, then cooled to room temperature, concentrated under reduced pressure, and adjusted to pH 2 with 1 M HCl solution. A light yellow solid formed which was removed by filtration and washing with hexane to give 4-(3-carbonylphenoxy)-1-nitrobenzene (4.40 g, 95%).

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Korak 3. Sinteza 4-(3-(N-metilkarbamoil)fenoksi)-1-nitro benzena Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene

Smjesa od 4-(3-karboksilfenoksi)-1-nitrobenzena (3.72 g, 14.4 mmol), EDCI · HCl (3.63 g, 18.6 mmol), N-metilmorfolina (1.6 g, 14.5 mmol) i metilamina (2.0 M u THF; 8 mL, 16 mmol) u CH2Cl2 (45 mL) miješa se na sobnoj temperaturi tri dana, koncentrira se pod smanjenim tlakom. Ostaci se rastope u EtOAc (50 mL) i nastala smjesa ekstrahira se s 1M otopinom HCl (50 mL). Vodeni sloj se ponovo ekstrahira s EtOAc (2x50 mL). Dobivena organska faza ispere se s zasićenom otopinom NaCl (50 mL), osuši (Na2SO4), i koncentrira pod smanjenim tlakom, te se dobije 4-(3-(N-metilkarbamoil) fenoksi)-1-nitrobenzen kao ulje (1.89 g). A mixture of 4-(3-carboxylphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI · HCl (3.63 g, 18.6 mmol), N -methylmorpholine (1.6 g, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temperature for three days, concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with 1M HCl solution (50 mL). The aqueous layer was re-extracted with EtOAc (2x50 mL). The resulting organic phase was washed with saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g). .

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Korak 4. Sinteza 4-(3-(N-metilkarbamoil)fenoksi)anilina Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline

Gusta smjesa 4-(3-(N-metilkarbamoil)fenoksi)-1-nitrobenzena (1.89 g, 6.95 mmol) i 5% Pd/C (0.24 g) u EtOAc (20 mL) miješa se pod H2 atmosferom (balon) preko noći. Nastala smjesa filtrira se kroz sloj Celite® i koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (5% MeOH/95% CH2Cl2) c Dobiveno ulje zgušnjava se pod vakuumom preko noći, a dobiven 4-(3-(N-metilkarbamoil)fenoksi)anilin je žuta krutina (0.95 g, 56%). A thick mixture 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 H2 atmosphere (balloon) over night. The resulting mixture is filtered through a layer of Celite® and concentrated under reduced pressure. The residues are purified by column chromatography (5% MeOH/95% CH2Cl2) c The obtained oil is concentrated under vacuum overnight, and the obtained 4-(3-(N-methylcarbamoyl)phenoxy)aniline is a yellow solid (0.95 g, 56%).

A14. Opća metoda za sintezu ω-karbamoil anilina preko EDCI posrednika amid formacije koja slijedi nitroaren redukciju. Sinteza 4-3-(5-metil karbamoil)piridiloksi) anilina. A14. General method for the synthesis of ω-carbamoyl anilines via EDCI-mediated amide formation following nitroarene reduction. Synthesis of 4-3-(5-methylcarbamoyl)pyridyloxy)aniline.

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Korak 1. Sinteza 4-(3-(5-metoksikarbonil) piridiloksi)-1-nitrobenzena Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene

Gustoj smjesi (NaH (0.63 g, 26.1 mmol) u DMF (20 mL) doda se otopina od metil 5-hidroksinikotinata (2.0 g, 13.1 mmol) u DMF (10 mL). Dobivena smjesa se doda u otopinu 4-fluoronitrobenzena (1.4 mL, 13.1 mmol) u DMF (10 mL), a nastala smjesa zagrije se preko noći na 70°C, ohladi na sobnu temperaturu, i tretira s MeOH (5 mL) nakon vode (50 mL). Nastalu smjesu ekstrahira se s EtOAc (100 mL). Organski fazu koncentrira se pod smanjenim tlakom. Ostaci se purificiraju kolonskom kromatografijom (30% EtOAc/70% heksan), te dobijemo 4-(3-(5-metoksikarbonil)piridiloksi)-1-nitrobenzen (0.60 g). To a thick mixture (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 to 70 °C overnight, cooled to room temperature, and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g) .

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Korak 2. Sinteza 4-3-(5-metoksikarbonil)piridiloksi) anilina Step 2. Synthesis of 4-3-(5-methoxycarbonyl)pyridyloxy)aniline

Gusta otopina 4-(3-(5-metoksikarbonil)piridiloksi)-1-nitrobenzena (0.60 g, 2.20 iranol) i 10% Pd/C u MeOH/EtOAc miješa se pod H2 atmosfetom (balon) 72 sata. Nastala smjesa filtrira se, a filtrat i koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (gradient od 30% EtOAc/70% heksan do 50% EtOAc/50% heksan) pa se dobije 4-3-(5-metoksikarbonil) piridiloksi)anilin (0.28 g, 60%): 1H-NMR (CDCl3) 6 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (,1H), 8.51 (d, 1H), 8.87 (d, 1H). A thick solution of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 iranol) and 10% Pd/C in MeOH/EtOAc was stirred under H2 atmosphere (balloon) for 72 hours. The resulting mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to give 4-3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 1H-NMR (CDCl 3 ) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

A15. Sinteza anilina preko elekrofilićne nitracije koja slijedi redukciju. Sinteza 4-(3-metilsulfamoil fenoksi)anilina A15. Synthesis of aniline via electrophilic nitration followed by reduction. Synthesis of 4-(3-methylsulfamoylphenoxy)aniline

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Korak 1. Sinteza N-metil-3-brombenzensulfonamida Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

Otopini 3-brombenzensulfonil klorida (2.5 g, 11.2 mmol) u THF (15 mL) na 0°C doda se metilamin (2.0 M u THF; 28 mL, 56 mmol). Nastalu otopinu ostavimo da se zagrije na sobnu temperaturu i miješamo preko noći na sobnoj temperaturi. Dobivena smjesa se odvoji između EtOAc (25 mL) i l M otopine HC1 (25 mL). Vodena faza se ponovo ekstrahira s EtOAc (2x25 mL). Nastala organska faza uzastopno se ispere vodom (2X25 mL) i zasićenom otopinom NaCl (25 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom da bi se dobio N-metil-3-brombenzensulfonamid kao bijela krutina (2.8 g, 99%). To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0°C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). Let the resulting solution warm to room temperature and stir overnight at room temperature. The resulting mixture was partitioned between EtOAc (25 mL) and 1 M HCl solution (25 mL). The aqueous phase was re-extracted with EtOAc (2x25 mL). The resulting organic phase was washed sequentially with water (2X25 mL) and saturated NaCl solution (25 mL), dried (MgSO4) and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%) .

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Korak 2. Sinteza 4-(3-(N-metilsulfamoil)feniloksi) benzena Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene

Gustoj otopini fenola (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), i Cul (4 g, 20 mmol) u DMF (25 mL) doda se N-metil-3-brombenzensulfonamid (2.5 g, 10 mmol), a dobivena smjesa se miješa na temperaturi refluksa preko noći, ohladi na sobnu temperaturu, i odvoji između EtoAc (50 mL) i 1N otopine HCl (50 mL). Vodeni sloj se ponovo ekstrahira s EtOAc (2x50 mL). Nastala organska faza se uzastopno ispere s vodom (2x50 mL) i zasićenom otopinom NaCl (50 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom. Ostaci ulja purificiraju se kolonskom kromatografijom (30% EtOAc/70% heksan) da bi se dobio 4-(3-(AT-metilsulfamoil) feniloksi) benzen (0.30 g). To a thick solution of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), and Cu (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol ), and the resulting mixture was stirred at reflux temperature overnight, cooled to room temperature, and separated between EtoAc (50 mL) and 1N HCl solution (50 mL). The aqueous layer was re-extracted with EtOAc (2x50 mL). The resulting organic phase is successively washed with water (2x50 mL) and saturated NaCl solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(AT-methylsulfamoyl)phenyloxy)benzene (0.30 g).

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Korak 3. Sinteza 4-(3-(N-metilsulfamoil)fenoksi)-1-nitro benzena Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene

Otopini 4-(3-(N-metilsulfamoil) feniloksi) benzena (0.30 g, 1.14 mmol) u TFA (6 mL) na -10°C doda se NaNO2 (0.097 g, 1.14 mmol) u obrocima kroz 5 minuta. Dobivena smjesa miješa se na -10°C 1 sat, zatim se ostavi da se zagrije na sobnu temperaturu, i koncentrira pod reduciranim tlakom. Ostaci se odvoje između EtOAc (10 mL) i vode (10 mL). Organska faza se uzastopno ispire vodom (10 mL) i zasićenom otopinom NaCl (10 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom da bi se dobio 4-(3-(N-metilsulfamoil) feniloksi)-1-nitrobenzen. Ovaj materijal prenese se u slijedeći korak bez daljnje purifikacije. To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaNO2 (0.097 g, 1.14 mmol) in portions over 5 minutes. The resulting mixture was stirred at -10°C for 1 hour, then allowed to warm to room temperature, and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed sequentially with water (10 mL) and saturated NaCl solution (10 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene. This material is transferred to the next step without further purification.

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Korak 4. Sinteza 4-(3-(N-metilsulfamoil) feniloksi) anilina Step 4. Synthesis of 4-(3-(N-methylsulfamoyl) phenyloxy) aniline

Gusta otopina 4-(3-(N-metilsulfamoil)feniloksi)-1-nitrobenzena (0.30 g) i 10% Pd/C (0.030 g) u EtOAc (20 mL) miješa se pod H2 atmosfetom (balon) preko noći. Nastala smjesa filtrira se preko sloja Celite®. Filtrat se koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (30% EtOAc/70% heksan) pa dobijemo 4-(3-(N-metilsulfamoil)feniloksi)anilina (0.070 g). A thick solution 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 H2 atmosphere (balloon) overnight. The resulting mixture is filtered through a layer of Celite®. The filtrate is concentrated under reduced pressure. The residues are purified by column chromatography (30% EtOAc/70% hexane) to obtain 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modifikacija ω-ketona. Sinteza HCl soli 4-(4-(1-(N-metoksi)iminoetil)fenoksianilina A16. Modification of ω-ketone. Synthesis of the HCl salt of 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline

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U gustu otopinu HCl soli 4-(4-acetilfenoksi)anilina (pripremljene na analogan način s Metodom A13, Korak 4; 1.0 g, 3.89 mmol) u smjesi EtOH (10 mL) i piridina (1.0 mL) doda se HC1 sol O-metilhidroksilamina (0.65 g, 7.78 mmol, 2.0 equiv.). Dobivena otopina zagrije se na temperaturu rafluksa kroz 30 min., ohladi na sobnu temperaturu i koncentrira pod reduciranim tlakom. Nastala krutina triturira se s vodom (10 mL) i ispere vodom da bi se dobila HCl sol 4-(4-(1-(N-metoksi) iminoetil)fenoksianilina kao žuta krutina (0.85 g): TLC (50% EtOAc/50% petr.eter), Rf 0.78; 1H-NMR (DMSO-d6) δ 3.90(8, 3H), 5.70 (d, 3H), HPLC-MS m/z 257 ((M+H)+). To a thick solution of the HCl salt of 4-(4-acetylphenoxy)aniline (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) is added the HCl salt O- methylhydroxylamine (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution is heated to reflux temperature for 30 min., cooled to room temperature and concentrated under reduced pressure. The resulting solid was triturated with water (10 mL) and washed with water to give the HCl salt of 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline as a yellow solid (0.85 g): TLC (50% EtOAc/50 % petr.ether), Rf 0.78; 1H-NMR (DMSO-d6) δ 3.90(8, 3H), 5.70 (d, 3H), HPLC-MS m/z 257 ((M+H)+).

A17. Sinteza N-(ω-sililoksialkil)amida. A17. Synthesis of N-(ω-silyloxyalkyl)amide.

Sinteza 4-(4-(2-(N-(2-triizo-propilsililoksi)etilkarbamoil)piridiloksi anilina. Synthesis of 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxy aniline).

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Korak 1. 4-klor-N-(2-triizopropilsililoksi)etilpiridin-2-karboksamid Step 1. 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide

Otopini 4-klor-N-(2-hidroksietil)piridin-2-karboksamida (pripremljenoj na analogan način s Metodom A2, Korak 3b; 1.5 g, 7.4 mmol) u anh DMF (7 mL) doda se triizopropilsilil klorid (1.59 g, 8.2 mmol, 1.1 equiv.) i imidazol (1.12 g, 16.4 mmol, 2.2 equiv.). Dobivena žuta otopina miješa se 3 h na sobnoj temperaturi, potom se koncentrira pod reduciranim tlakom. Ostaci se odvoje između vode (10 mL) i EtOAc (10 mL). Vodeni sloj ekstrahira se s EtOAc (3x10 mL). Nastalu organsku fazu se osuši (MgSO4) i koncentrira pod reduciranim tlakom da bi se dobio 4-klor-(N-(2-triizopropilsilil oksi)etil)piridinkarboksamid kao narančasto ulje (2.32 g, 88%). Ovaj materijal koristi se za slijedeći korak bez purifikacije. 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 anhydrous DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution is stirred for 3 h at room temperature, then concentrated under reduced pressure. The residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The resulting organic phase was dried (MgSO4) and concentrated under reduced pressure to give 4-chloro-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material is used for the next step without purification.

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Korak 2. 4-(4-(2-(N-(2-triizopropilsililoksi)etilkarba moil) piridiloksianilin Step 2. 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline

U otopinu 4-hidroksianilina (0.70 g, 6.0 mmol) i anh.DMF (8 mL) doda se kalijev tert-butoksid (0.67 g, 6.0 mmol, 1.0 eguiv.) odjedamput, jer se oslobađa toplina. Kada se ova smjesa ohladi na sobnu temperaturu doda se otopina 4-klor-2-(N-(2-triizopropilsililoksi)etil) piridinkarboksamid (2.32 g, 6 mmol, l eguiv.) u DMF (4 mL) nakon K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). Nastala smjesa miješa se i zagrije preko noći na 80°C. Dodatnu količinu kalijevog tert-butoksida (0.34 g, 3 mmol, 0.5 ekviv.) i miješa na 80°C još 4 sata. Smjesa se ohladi na 0°C u kupelji led/voda , potom se dodaje voda (približno 1 mL) polako kap po kap. Organski sloj se ekstrahira s EtOAc (3x10 mL). Dobiveni organski sloj ispere se zasićenom otopinom NaCl (20 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom. Smeđi uljni ostaci purificiraju se kolonskomom kromatografijom (SiO2; 30% EtOAc/70% pet.eter) i dobije se bistro svijetlo smeđe ulje (0.99 g, 38%). To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) and anh.DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 eguiv.) at once, as heat was released. When this mixture was cooled to room temperature, a solution of 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, l eguiv.) in DMF (4 mL) was added after K2CO3 (0.42 g , 3.0 mmol, 0.50 equiv.). The resulting mixture is stirred and heated overnight at 80°C. Additional amount of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) and stirred at 80°C for another 4 hours. The mixture is cooled to 0°C in an ice/water bath, then water (approximately 1 mL) is slowly added drop by drop. The organic layer was extracted with EtOAc (3x10 mL). The obtained organic layer was washed with saturated NaCl solution (20 mL), dried (MgSO4) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO2; 30% EtOAc/70% pet ether) to give a clear light brown oil (0.99 g, 38%).

A18. Sinteza 2-piridinkarboksilat estera preko oksidacije 2-metilpiridina. Sinteza 4-(5-(2-metoksikarbonil) piridiloksi)anilina. A18. Synthesis of 2-pyridinecarboxylate ester via oxidation of 2-methylpyridine. Synthesis of 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.

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Korak 1. 4-(5-(2-metil)piridiloksi)-1-netrobenzena. Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.

Smjesa 5-hidroksi-2-metilpiridina (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzena (9.8 mL, 91.6 mmol, 1.0 equiv.), K2CO3 (25 g, 183 mmol, 2.0 equiv.) u DMF (100 mL) zagrije se preko noći na temperaturu refluksa. Dobivena smjesa ohladi se na sobnu temperaturu, tretira vodom (200 mL), i ekstrahira s EtOAc (3x100 mL). Nastali organski sloj uzastopno se ispire vodom (2x100 mL) i zasićenom otopinom NaCl (100 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom da bi se dobio 4-(5-(2-metil)piridiloksi)-1-netrobenzen kao smeđa krutina (12.3 g). 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.), K2CO3 (25 g, 183 mmol, 2.0 equiv.) in DMF ( 100 mL) is heated to reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3x100 mL). The resulting organic layer was washed sequentially with water (2x100 mL) and saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as brown solid (12.3 g).

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Korak 2. Sinteza 4-(5-(2-metoksikarbonil)piridiloksi)-1-nitrobenzena Step 2. Synthesis of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene

Smjesu 4-(5-(2-metil)piridiloksi)-1-nitrobenzena (1.70 g, 7.39 mmol) i selen dioksida (2.50 g, 22.2 mmol, 3.0 eguiv.) u piridinu (20 mL) zagrije se na temperaturu refluksa kroz 5 h, potom ohladi na sobnu temperaturu. Dobivenu gustu smjesu filtrira se, zatim koncentrira pod reduciranim tlakom. Ostatke se rastopi u MeOH (100 mL). Otopinu se tretira s otopinom koncentrirane HCl (7mL), potom zagrije kroz 3 h na temperaturu refluksa, ohladi na sobnu temperaturu i koncentrira pod reduciranim tlakom. Ostaci se odvoje između EtOAc (50 mL) i 1N otopine NaOH (50 mL). Nastali organski sloj se uzastopno ispere vodom (2x50 mL) i zasićenom otopinom NaCl (50 ML), osuši (MgSO4) i koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (SiO2; 50% EtOAc/50% pet.eter) da bi se dobio 4-(5-(2-metoksikarbonil)piridiloksi)-1-nitrobenzen (0.70 g). 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 eguiv.) in pyridine (20 mL) was heated to reflux through 5 h, then cool to room temperature. The resulting thick mixture is filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution is treated with a solution of concentrated HCl (7 mL), then heated to reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 1N NaOH solution (50 mL). The resulting organic layer is successively washed with water (2x50 mL) and saturated NaCl solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; 50% EtOAc/50% pet ether) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.70 g).

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Korak 3. Sinteza 4-(5-(2-metoksikarbonil)piridiloksi)anilin Step 3. Synthesis of 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline

Gustu otopinu 4-(5-(2-metoksikarbonil)piridiloksi)-1-nitrobenzen (0.50 g) i 10% Pd/C (0.050 g) u smjesi EtOAc (20 mL) i MeOH (5 mL) se ostavi pod H2 atmosferom (balon) preko noći. Nastala smjesa filtrira se preko sloja Celite® a filtrat se koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (SiO2; 70% EtOAc/30% heksana) da bi se dobio 4-(5-(2-metoksikarbonil)piridil oksi)anilin (0.40 g). A thick solution 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 left under H2 atmosphere (balloon) overnight. The resulting mixture is filtered through a layer of Celite® and the filtrate is concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; 70% EtOAc/30% hexanes) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A19. Sinteza ω-sulfonilfenil anilina. Sinteza 4-(4-metilsulfonilfenioksi)anilina. A19. Synthesis of ω-sulfonylphenyl aniline. Synthesis of 4-(4-methylsulfonylphenoxy)aniline.

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Korak 1. 4-(-4-metilsulfonilfenoksi)-1-nitrobenzena: Step 1. 4-(-4-methylsulfonylphenoxy)-1-nitrobenzene:

Otopini 4-(4-metiltiofenoksi)-1-nitrobenzena (2.0 g, 7.7 nunol) u CH2Cl2 (75 mL) na 0°C polako se dodaje m-CPBA (57-86%, 4.0 g), i onda se reakcijska smjesa miješa na sobnoj temperaturi 5 h. Reakcijska smjesa se tretira s 1N otopinom NaOH (25 mL). Organski sloj se uzastopno ispire s 1N otopinom NaOH (25 mL), vodom (25 mL) i zasićenom otopinom NaCl (25 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom da bi se dobio 4-(4-metilsulfonilfenoksi)-1-nitrobenzen kao krutina (2.1 g). To a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH 2 Cl 2 (75 mL) at 0 °C was slowly added m-CPBA (57-86%, 4.0 g), and then the reaction mixture stir at room temperature for 5 h. The reaction mixture is treated with 1N NaOH solution (25 mL). The organic layer was washed sequentially with 1N NaOH solution (25 mL), water (25 mL) and saturated NaCl solution (25 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-1 -nitrobenzene as a solid (2.1 g).

Korak 2. 4-(4-metilsulfonilfenoksi)-1-anilin Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline

4-(4-metilsulfonilfenoksi)-1-nitrobenzen reducira se na anilin analognim postupkom kao što je opisano u Metodi A18, Korak 3. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene is reduced to aniline by an analogous procedure as described in Method A18, Step 3.

B. Sinteza urea prekursora B. Synthesis of urea precursors

B1. Opća metoda sinteze izocianata od anilina upotrebom CDI. B1. General method of synthesis of isocyanates from aniline using CDI.

Sinteza 4-bromo-3-(trifluorometil)fenil izocianata. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate.

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Korak 1. Sinteza HCl soli 4-bromo-3-(trifluormetil) anilina Step 1. Synthesis of the HCl salt of 4-bromo-3-(trifluoromethyl) aniline

Otopini 4-brom-3-(trifluormetil)anilina (64g, 267 iranol) u Et2O (500 mL) doda se kap po kap otopina HCl (IM u Et2O; 300 mL) a nastalu smjesu miješa se 16 sati na sobnoj temperaturi. Dobiveni ružićasto-bijeli precipitat odstarni se filtracijom i ispere s Et2O (50 mL) i dobije se HCl sol 4-brom-3-(trifluormetil)anilina (73 g, 98%) To a solution of 4-bromo-3-(trifluoromethyl)aniline (64g, 267 iranol) in Et2O (500 mL) was added dropwise a solution of HCl (1M in Et2O; 300 mL) and the resulting mixture was stirred for 16 hours at room temperature. The resulting pinkish-white precipitate was removed by filtration and washed with Et2O (50 mL) to give the HCl salt of 4-bromo-3-(trifluoromethyl)aniline (73 g, 98%)

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Korak 2. Sinteza 4-brom-3-(trifluormetil)fenil izocianata Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate

Suspenziji od HCl soli 4-bromo-3-(trifluorometil)anilina (36.8 g, 133 rnmol) u toluenu (178 mL) terira se kap po kap s triklormetil klorformatom, a nastalu smjesu zagrije se tijekom 18 sati na temperaturu refluksa. Dobivenu smjesu koncentrira se pod reduciranim tlakom. Ostaci se tretiraju s toluenom (500 mL), i koncentriraju pod reduciranim tlakom. Rezidue se tretiraju s CH2Cl2, potom koncentriraju pod reduciranim tlakom. Po protokolu tretiranje/koncentracija s CH2Cl2 ponavlja se, a dobiveno jantarno ulje čuva se 16 sati na -20°C, da bi dobili 4-brom-3-(trifluormetil)fenil izocianat kao krutinu boje tanina (35.1 g, 86%): GC-MC m/z 256 (M+). A suspension of the HCl salt of 4-bromo-3-(trifluoromethyl)aniline (36.8 g, 133 rnmol) in toluene (178 mL) was treated dropwise with trichloromethyl chloroformate, and the resulting mixture was heated to reflux temperature for 18 hours. The resulting mixture is concentrated under reduced pressure. The residue is treated with toluene (500 mL), and concentrated under reduced pressure. The residues are treated with CH2Cl2, then concentrated under reduced pressure. According to the protocol, the treatment/concentration with CH2Cl2 is repeated, and the obtained amber oil is stored for 16 hours at -20°C, in order to obtain 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tannin-colored solid (35.1 g, 86%): GC-MC m/z 256 (M+).

C. Metode oblikovanja uree C. Methods of forming urea

C1a. Opća metoda za sintezu uree reakcijom izocianata s anilinom. C1a. General method for the synthesis of urea by the reaction of isocyanate with aniline.

Sinteza N-(4-klor-3-(trifluor metil) fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi) fenil) uree Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

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Otopini 4-klor-3-(trifluormetil)fenil izocianata (14.60 g, 65.90 nunol) u CH2Cl2 (35 mL) dodaje se kap po kap suspenzija od 4-(2(N-metilkarbamoil)-4-piridiloksi)anilina (Metoda A2, Korak 4; 16.0 g, 65.77 mino l) u CH2Cl2 (35 mL) na 0°C. Dobivena smjesa se miješa 22 h. na sobnoj temperaturi. Dobivena žuta krutina odstarni se filtracijom, potom ispiranjem s CH2Cl2 (2x30 mL) i sušenjem pod smanjenim tlakom (aproksimativno 1 mm Hg)da bi se dobila N-(4-klor-3-(trifluormetil) fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi) fenil) urea kao gotovo bijela krutina (28.5, 93%): mp 207-209°C; 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2 .5 Hz, 1H), 7.26 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+). To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 nmol) in CH2Cl2 (35 mL) was added dropwise a suspension of 4-(2(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2 , Step 4; 16.0 g, 65.77 min l) in CH2Cl2 (35 mL) at 0°C. The resulting mixture was stirred for 22 h. at room temperature. The resulting yellow solid was purified by filtration, then washed with CH2Cl2 (2x30 mL) and dried under reduced pressure (approximately 1 mm Hg) to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4 -(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as an off-white solid (28.5, 93%): mp 207-209°C; 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.26 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).

C1b. Opća metoda za sintezu uree reakcijom izocianata s anilinom. C1b. General method for the synthesis of urea by the reaction of isocyanate with aniline.

Sinteza N-(4-brom-3-(trifluormetil)fenil)-N'-(4-(2-(N-metil-karbamoil)-4-piridiloksi) fenil) uree. Synthesis of N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methyl-carbamoyl)-4-pyridyloxy)phenyl)urea.

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Otopini 4-brom-3-(trifluormetil)fenil izocianata (Metoda B1, Korak 2; 8.0 g, 30.1 mmol) u CH2Cl2 (80 mL) dodaje se kap po kap otopina 4-(2(N-metilkarbamoil)-4-piridiloksi)anilina (Metoda A2, Korak 4; 7.0 g, 28.8 mmol) u CH2Cl2 (40 mL) na 0°C. Dobivena smjesa se miješa 16 h. na sobnoj temperaturi. Dobivena žuta krutina odstarni se filtracijom, potom ispiranjem s CH2Cl2 (2x50 mL) i sušenjem pod smanjenim tlakom (aproksimativno l mm Hg) na 40°C da bi se dobila N-(4-brom-3-(trif luormetil) fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil) urea kao svijetlo-žuta krutina (13.2, 90%): mp 203-205°C; 1H-NMR (DMSO-d6) δ 2.77 (d, J=4 . 8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)+). To a solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH2Cl2 (80 mL) is added dropwise a solution of 4-(2(N-methylcarbamoyl)-4-pyridyloxy )aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2Cl2 (40 mL) at 0°C. The resulting mixture was stirred for 16 h. at room temperature. The resulting yellow solid was purified by filtration, then washed with CH2Cl2 (2x50 mL) and dried under reduced pressure (approximately 1 mm Hg) at 40°C to give N-(4-bromo-3-(trifluoromethyl)phenyl)- N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a light yellow solid (13.2, 90%): mp 203-205°C; 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)+).

C1c. Opća metoda sinteze uree reakcijom izocianata s anilinom. C1c. General method of urea synthesis by reaction of isocyanate with aniline.

Sinteza N-(4-klor-3-(trifluormetil) fenil)-N'-(2-metil-4-(2-(N-metilkarbamoil) (4-piridiloksi) fenil) uree. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea.

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Otopini 2-metil-4-(2-N-metilkarbamoil)(4-piridiloksi))anilina (Metoda A5; 0.11 g, 0.45 mino l) u CH2Cl2 (1 mL) tretira se sa Et3N (0.16 mL) i otopina 4-klor-3-(trifluormetil)fenil izocianat (0.10 g, 0.45 mmol). Dobivena smeđa otopina se miješa 6 d. na sobnoj temperaturi. Vodeni sloj ponovo se ekstrahira s EtOAc (3x5 mL). Nastali organski talog osuši se s (MgSO4) i koncentrira pod smanjenim tlakom da bi se dobila N-(4-klor-3-(trifluormetil) fenil)-N-(2-metil-4-(2-(N-metil karbamoil)(4-piridiloksi)fenil) urea kao smeđe ulje (0.11 g, 0.22 mmol): 1H-NMR (DMSO-d6) δ 2.77 (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 (app d, J-=2.6 Hz, 2H), 7.84 (d, J-=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H), 8.17 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.87 (q, c7=5.2 Hz, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+). A solution of 2-methyl-4-(2-N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 min l) in CH2Cl2 (1 mL) was treated with Et3N (0.16 mL) and a solution of 4- chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred for 6 days at room temperature. The aqueous layer was re-extracted with EtOAc (3x5 mL). The resulting organic precipitate was dried with (MgSO4) and concentrated under reduced pressure to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(2-methyl-4-(2-(N-methyl)carbamoyl )(4-pyridyloxy)phenyl)urea as a brown oil (0.11 g, 0.22 mmol): 1H-NMR (DMSO-d6) δ 2.77 (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 (app d, J-=2.6 Hz, 2H), 7.84 (d, J-=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H), 8.17 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.87 (q, c7=5.2 Hz, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H) + ).

C1d. Opća metoda sinteze uree reakcijom izocianata s anilinom. C1d. General method of urea synthesis by reaction of isocyanate with aniline.

Sinteza N-(4-klor-3-(trifluormetil) fenil)-N'-(4-aminofenil) uree. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea.

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Otopini 4-klor-3-(trifluormetil)fenil izocianata (2.27 g, 10.3 mmol) u CH2Cl2 (308 mL) doda se p-fenilendiamina (3.32 g, 30.7 mmol) odjedamput. Nastalu smjesu miješa se l h na sobnoj temperaturi, treira s CH2Cl2 (100 mL), i koncentrira po reduciranim tlakom. Nastala ružičasta krutina razrijedi se u smjesi EtOAc (110 mL) i MeOH (15 mL) te bistru otopinu isperemo s =.05 N otopinom HCl. Organski sloj koncentriramo pod reduciranim tlakom, da bi dobili onečišćenu N-(4-klor-3-(trifluormetil)fenil)-N'-4-aminof enil) ureu (3.3 g) : TLC (100 %) To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2Cl2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one portion. The resulting mixture was stirred for 1 h at room temperature, treated with CH2Cl2 (100 mL), and concentrated under reduced pressure. The resulting pink solid is diluted in a mixture of EtOAc (110 mL) and MeOH (15 mL) and the clear solution is washed with =.05 N HCl solution. The organic layer was concentrated under reduced pressure to obtain contaminated N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-4-aminophenyl)urea (3.3 g): TLC (100%)

C1e. Opća metoda sinteze urea reakcijom izocianata s anilinima. Sinteza N-(4-klor-3-(triflormetil)fenil)-N'-(4-etoksikarbonilfenil)uree C1e. General method of urea synthesis by reaction of isocyanates with anilines. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea

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Otopini etil 4-izocianatbenzoata (3.14 g, 16.4 mmol) u CH2Cl2 (30 mL) doda se 4-klor-3-(trifluormetil)anilin (3.12 g, 16.4 mmol), i otopina se miješa na sobnoj temperaturi preko noći. Nastala gusta smjesa razrijedi se s CH2Cl2 (50 mL) i filtrira da se dobije N-(4-klor-3-(triflormetil)fenil)-N'-(4-etoksikarbonilfenil)urea kao bijela krutina (5.93 g, 97%): TLC (40% EtOAc/60% heksan) Rf 0.44. To a solution of ethyl 4-isocyanatebenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.12 g, 16.4 mmol), and the solution was stirred at room temperature overnight. The resulting thick mixture was diluted with CH2Cl2 (50 mL) and filtered to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea as a white solid (5.93 g, 97%) : TLC (40% EtOAc/60% hexane) Rf 0.44.

C1f. Opća metoda sinteze urea reakcijom izocianata s anilinima. Sinteza N-(4-klor-3-(triflormetil)fenil)-N'-(S-karboksilfenil)uree C1f. General method of urea synthesis by reaction of isocyanates with anilines. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(S-carboxylphenyl)urea

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Otopini 4-klor-3-(triflormetil)fenil izocianata(l.21 g, 5.46 mmol) u CH2Cl2 (8 mL) doda se 4-(3-karboksifenoksi) anilin (Metoda A11; 0.81 g, 5.76 mmol), i nastalu smjesu miješa se na sobnoj temperaturi preko noći, i potom tretira s MeOH (8 mL), i miješa još 2 sata. Nastala smeđa krutina otopi se s 1:1 EtOAc/heksan otopinom da se dobije N-(4-klor-3-(triflormetil) fenil)-N'-(3-karboksifenil)urea kao bijela krutina (1.21 g, 76%). To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21 g, 5.46 mmol) in CH2Cl2 (8 mL) was added 4-(3-carboxyphenoxy) aniline (Method A11; 0.81 g, 5.76 mmol), and the resulting the mixture was stirred at room temperature overnight, and then treated with MeOH (8 mL), and stirred for an additional 2 hours. The resulting brown solid was dissolved with 1:1 EtOAc/hexane solution to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl)urea as a white solid (1.21 g, 76%) .

C2a. Opća metoda sinteze uree rakcijom anilina s N,N'-karbonil diimidazol koja slijedi adiciju sekundarnog anilina. C2a. General method of urea synthesis by reaction of aniline with N,N'-carbonyl diimidazole followed by addition of secondary aniline.

Sinteza N-(2-metoksi-5-(trif luorometil)fenil)-N'-(4-(-(N-metilkarbamoil)-4-piridiloksi)fenil) uree Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

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Otopini 2-metoksi-5-(trifluormetil)anilina (0.15 g) i anh. CH2Cl2 (15 mL) na 0°C doda se CDI (0.13 g). Nastala otopina ostavi da se zagrije na sobnu temperaturu preko 1 sat, miješa se na sobnoj temperaturi 16 h., zatim se tretira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilinom (0.18 g). Nastala žuta otopina miješa se 72 sata na sobnoj temperaturi, potom tretira s H2O (125 ml). Dobivena vodena smjesa ekstrahira se s EtOAc (2x150 mL). Nastali organski sloj ispere se s zasićenom otopinom NaCl (100 mL), osuši se (MgSO4), koncentrira pod reduciranim tlakom. Ostaci se usitne (90% EtOAC/10% heksan). Dobivena bijela krutina sakupi se filtracijom i ispere s EtOAc. Filtrat se koncentrira pod reduciranim tlakom i potom rezidualno ulje purificira kolonskom kromatografijom (gradient od 33% EtOAc/67% heksan do 50% EtOAc/50% heksan) i dobije se N-(2-metoksi-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil) uree slabo svijetlo smeđa krutina (0.098g, 30%): TLC (100% EtOAc) Rf 0.62; 1H-NMR (DMSO-d6) δ 2.76 (d, ,7=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)+). Solutions of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) and anh. CDI (0.13 g) was added to CH2Cl2 (15 mL) at 0°C. 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 for 72 hours at room temperature, then treated with H2O (125 ml). The resulting aqueous mixture was extracted with EtOAc (2x150 mL). The resulting organic layer is washed with saturated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced pressure. The residues were triturated (90% EtOAC/10% hexane). The resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and then the residual oil was purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)- N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea light brown solid (0.098g, 30%): TLC (100% EtOAc) Rf 0.62; 1H-NMR (DMSO-d6) δ 2.76 (d, ,7=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. Opća metoda sinteze uree rakcijom anilina s N,N'-karbonil diimidazol koja slijedi adiciju sekundarnog anilina. Simetrični nuzprodukti uree od reakcijske procedure N,N'-karbonil diimidazola. Sinteza bis(4-(2-(N-metoksikarbamoil)-4-piridiloksi)fenil) uree. C2b. General method of urea synthesis by reaction of aniline with N,N'-carbonyl diimidazole followed by addition of secondary aniline. Symmetric urea by-products from the N,N'-carbonyl diimidazole reaction procedure. Synthesis of bis(4-(2-(N-methoxycarbamoyl)-4-pyridyloxy)phenyl)urea.

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Uz miješanje otopine 3-amino-2-metiloksikinolina (0.14 g) i anh. CH2Cl2 (15 mL) na 0°C doda se CDI (0.13 g). Nastala solucija ostavi se na toplom na sobnoj temperaturi preko l sat potom miješa na sobnoj temperaturi 16 sati. Dobivenu smjesu tretira se s 4-(2-(N-metilkarbamoil)-4-piridil oksi)anilinom (0.18 g): Nastalu žutu otopinu miješa se na sobnoj temperaturi 72 sata, potom se tretira vodom (125 mL). Nastala vodena smjesa ekstrahira se s EtOAc (2x150 mL). Dobivenu organsku fazu ispere se sa zasićenom otopinom NaCl (100 mL), osuši se (MgSO4), koncentrira pod reduciranim tlakom. Ostaci se usitne (90% EtOAc/10% heksan). Dobivena bijela krutina sakupi se filtracijom i ispere se s EtOAC da se dobije bis (4-(2-(N-metilkarbamoil)-4-piridiloksi) fenil) urea (0.081 g, 44%): TLC (100% EtOAc) Rf 0.50; 1H-NMR (DMSO-d6) δ 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz, 2H), 8.86 (s, 2H), HPLC ES-MS m/z 513 ((M+H)+). While mixing a solution of 3-amino-2-methyloxyquinoline (0.14 g) and anh. CDI (0.13 g) was added to CH2Cl2 (15 mL) at 0°C. The resulting solution is left warm at room temperature for 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 (2x150 mL). The obtained organic phase is washed with saturated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced pressure. The residues were triturated (90% EtOAc/10% hexane). The resulting white solid was collected by filtration and washed with EtOAC to give bis (4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.081 g, 44%): TLC (100% EtOAc) Rf 0.50 ; 1H-NMR (DMSO-d6) δ 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz , 2H), 8.86 (s, 2H), HPLC ES-MS m/z 513 ((M+H) + ).

C2c. Opća metoda sinteze urea rekcijom izocianata s anilinom. Sinteza N-(2-metoksi-5-(trifluorometi)fenil-N'-(4-(1,3-dioksoizo-indolin-5-iloksi)fenil)uree C2c. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoiso-indolin-5-yloxy)phenyl)urea

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Uz miješanje otopine 2-metoksi-5-(trifluormetil)fenil izocianata (0.10 g, 0.47 mmol) u CH2Cl2 (1.5 mL), doda se odjednom 5-(4-aminofenoksi)izoindolin-1,3-dion (Metoda A3 , Korak 3; 0.12 g, 0.47 mmol). Nastalu smjesu miješamo 12 sati, potom tretiramo s CH2Cl2 (10 mL) i MeOH (5 mL). Dobivenu smjesu naizmjenično ispiremo s 1N otopinom HCl (15 mL) i zasićenom otopinom NaCl (15 mL), osuši se (MgSO4), koncentrira pod reduciranim tlakom da bi se dobila N-(2-metoksi-5-(trifluormetil)fenil-N'-(4-(1,3-dioksoizo-indolin-5-iloksi)fenil)urea kao bijela krutina (0.2 g, 96%): TLC (70% EtOAc/30% heksan) Rf 0.50; 1H-NMR (DMSO-d6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, jr=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS m/z 472 ((M+H)+, 100%). While stirring a solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2Cl2 (1.5 mL), 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 hours, then treated with CH2Cl2 (10 mL) and MeOH (5 mL). The resulting mixture is washed alternately with 1N HCl solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO4), concentrated under reduced pressure to obtain N-(2-methoxy-5-(trifluoromethyl)phenyl-N '-(4-(1,3-dioxoiso-indolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 1H-NMR (DMSO -d6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, jr=8.7 Hz, 1H), 8.53 (br s, 2H ), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS m/z 472 ((M+H)+, 100%).

C2d. Opća metoda sinteze uree reakcijom anilina s N,N'-karbonil diimiđazolom nakon adicije drugog anilina. Sinteza N-(5-(tert-butil)-2-(2,5-dimetilpirolil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil)uree C2d. General method of urea synthesis by reaction of aniline with N,N'-carbonyl diimidazole after addition of another aniline. Synthesis of N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

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Uz miješanje otopine GDI (0.21 g, 1.30 mmol) u CH2Cl2 (2 mL), doda se odjednom 5-(tert-butil)-2-(2,5-dimetilpirolil)anilina (Metoda A4, Korak 2; 0.30 g, 1.24 mmol). Nastalu smjesu miješa se na sobnoj temperaturi 4 h, i zatim se odjednom doda 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilin (0.065 g, 0.261 mmol). Dobivenu smjesu zagrije se na 36°C preko noći, pa ohladi na sobnu temperaturu, razrijedi s EtOAc (5 mL). Nastalu smjesu naizmjence se ispere vodom (15 mL) i 1N otopinom HCl (15 mL), osuši (MgSO4), i filtrira preko sloja silika gela (50 g) da se dobije N-(5-(tert-butil)-2-(2,5-dimetilpirolil)fenil)N'-(4-(2-(N-metilkarbamoil)-4-piridil-oksi)fenil) uree, žućkaste krutine (0.033 g, 24%): TLC (40% EtOAc/70% heksan) Rf 0.24; 1H-NMR (aceton-d6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, .7=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.l Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)+, 100%). While stirring a solution of GDI (0.21 g, 1.30 mmol) in CH2Cl2 (2 mL), 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 h, and then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.261 mmol) was added all at once. The resulting mixture was heated to 36°C overnight, then cooled to room temperature, diluted with EtOAc (5 mL). The resulting mixture was washed alternately with water (15 mL) and 1N HCl solution (15 mL), dried (MgSO4), and filtered over a pad of silica gel (50 g) to give N-(5-(tert-butyl)-2- (2,5-dimethylpyrrolyl)phenyl)N'-(4-(2-(N-methylcarbamoyl)-4-pyridyl-oxy)phenyl)urea, yellow solid (0.033 g, 24%): TLC (40% EtOAc/ 70% hexane) Rf 0.24; 1H-NMR (acetone-d6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, .7=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H ), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.80 (br s, 1H ); HPLC ES-MS 512 ((M+H)+, 100%).

C3. Kombinirana metoda sinteze difenil urea upotrebom trifosgena C3. Combined method of diphenyl urea synthesis using triphosgene

Jedan od anilina koji će biti vezan rastopljen je u diklorometanu (0.10 M). Toj otopini doda se u posudicu od 8 mL (0.5 mL) dikloretan (1.0 mL). U to se doda otopina bis(triklormetil) karbonata (0.12 M u dikloretanu, 0.2 mL, 0.2 equiv.), koju slijedi diisopropiletilamin (0.35 M u dikloroetanu, 0.2 mL, 1.2 equiv.). Posudica se poklopi i zagrije na 80°C kroz 5 sati, ostavi da se ohladi na sobnu temperaturu približno 10 h. Drugi anilin se doda (0.10 M u dikloretanu, 0.5 mL, 1.0 equiv.), kojeg slijedi diizopropiletilamin (0.35 M u dikloroetanu, 0.2 mL, 1.2 equiv.). Nastalu smjesu zagrije se na 80°C kroz 4 sata, ostavi da se ohladi na sobnu temperaturu i tretira s MeOH (0.5 mL). Nastalu smjesu se koncentrira pod reduciranim tlakom a produkt se purificira reverznom fazom HPLC-a. One of the anilines to be bound was dissolved in dichloromethane (0.10 M). Dichloroethane (1.0 mL) is added to this solution in an 8 mL (0.5 mL) beaker. To this is added a solution of bis(trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 mL, 0.2 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The container is covered and heated to 80°C for 5 hours, left to cool to room temperature for approximately 10 hours. A second aniline is added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated to 80°C for 4 hours, allowed to cool to room temperature and treated with MeOH (0.5 mL). The resulting mixture is concentrated under reduced pressure and the product is purified by reverse phase HPLC.

C4. Opća metoda sinteze uree reakcijom anilina s fosgenom nakon adicije drugog anilina. C4. General method of urea synthesis by reaction of aniline with phosgene after addition of another aniline.

Sinteza N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil)uree Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

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Uz miješanje otopini fosgena (1.9 M u toluenu; 2.07 mL 0.21 g, 1.30 iranol) i CH2Cl2 (20 mL) na 0°C doda se bezvodni piridin (0.32 mL) nakon 2-metoksi-5-(trifluormetil)anilina (0.75 g). Žuta otopina ostavi se na toplom na sobnoj temperaturi za vrijeme formiranja precipitata. Žutu smjesu miješa se 1 h, potom koncentrira pod reduciranim tlakom. Nastalu krutinu obradimo s bezvodnim toluenom (20 mL) a potom s 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilinom (priprema je opisana u Metodi A2; 0.30 g) a dobivenu suspenziju zagrijemo na 80°C kroz 20 sati, zatim ostavimo da se ohaldi na sobnoj temperaturi. Nastalu smjesu razrijedimo s vodom (100 mL), potom zasićenom otopinom NaHCO3 učinimo je baznom (2-3 mL). Baznu otopinu ekstrahiramo s EtOAc (2x250 mL). Organski sloj odvoji se ispiranjem sa zasićenom otopinom NaCl, spaja se, osuši (MgSO4), i koncentrira pod reduciranim tlakom. Nastali ružičasto-smeđi ostaci rastope se u MeOH i absorbiraju na SiO2 (100 g). Kolonska kromatogarf i ja (300g SiO2 ; gradient od 1% Et3N/33% EtOAc/66% heksan do 1% Et3N/99% EtOAc do 1% Et3N/20% MeOH/79% EtOAc) slijedi koncentraciju pod smanjenim tlakom na 45°C daje vruću koncentriranu otopinu EtOAc, koja se obradi s heksanom (10 mL) da se polako formiraju kristali N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(N-metil-karbamoil)-4-piridiloksi)fenil)uree (0.44 g): TLC (1% Et3N/99% EtOAc) Rf 0.40. Anhydrous pyridine (0.32 mL) was added to a stirred solution of phosgene (1.9 M in toluene; 2.07 mL 0.21 g, 1.30 iranol) and CH2Cl2 (20 mL) at 0°C after 2-methoxy-5-(trifluoromethyl)aniline (0.75 g) ). The yellow solution is left warm at room temperature during the formation of the precipitate. The yellow mixture is stirred for 1 h, then concentrated under reduced pressure. The resulting solid is treated with anhydrous toluene (20 mL) and then with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (preparation is described in Method A2; 0.30 g) and the resulting suspension is heated to 80°C for 20 hours, then let it cool down at room temperature. Dilute the resulting mixture with water (100 mL), then make it basic with saturated NaHCO3 solution (2-3 mL). The base solution was extracted with EtOAc (2x250 mL). The organic layer is separated by washing with saturated NaCl solution, combined, dried (MgSO4), and concentrated under reduced pressure. The resulting pink-brown residues are dissolved in MeOH and absorbed on SiO2 (100 g). Column chromatography and I (300g SiO2; gradient from 1% Et3N/33% EtOAc/66% hexane to 1% Et3N/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45° C gives a hot concentrated EtOAc solution, which is treated with hexane (10 mL) to slowly form crystals of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methyl- carbamoyl)-4-pyridyloxy)phenyl)urea (0.44 g): TLC (1% Et3N/99% EtOAc) Rf 0.40.

D. Interkonverzija urea D. Interconversion of urea

D1a. Konverzija ω-aminofenil urea u ω-(aroilamino)fenil uree. D1a. Conversion of ω-aminophenyl urea to ω-(aroylamino)phenyl urea.

Sinteza N-(4-kloro-3-((trifluormetil)fenil)-N'-(4-(3-metoksikarbonilfenil)karboksiaminofenil)uree Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea

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Otopini N-(4-klor-3-((trifluormetil)fenil)-N'-(4-aminofenil) uree (Metoda C1d; 0.050 g, 1.52 mmol), mono-metil izoftalata (0.25 g, 1.38 mmol), HOBT · H2O (0.41 g, 3.03 mmol) i izometilmorfolina (0.33 mL, 3.03 mmol) u DMF (8 mL) doda se EDCI · HCl (0.29 g, 1.52 mmol). Nastala smjesa miješa se na sobnoj temperaturi preko noći. razrijedi se s EtOAc (25 mL) i naizmjenično ispire s vodom (25 mL) i zasićenom otopinom NaHCO3 (25 mL). Organski sloj ispere se (Na2SO4) i koncentrira pod reduciranim tlakom. Dobivena krutina usitni se otopinom EtOAc (80% EtOAC/28% heksan) i dobije se N-(4-klor-3-((trifluormetil)fenil)-N-(4-(3-metoksikarbonilfenil)karboksi-aminofenil)urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAC/28% heksan) Rf 0.75. Solutions of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (Method C1d; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT · H2O (0.41 g, 3.03 mmol) and isomethylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added with EDCI · HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temperature overnight. It was diluted with EtOAc (25 mL) and washed alternately with water (25 mL) and saturated NaHCO3 solution (25 mL). The organic layer was washed (Na2SO4) and concentrated under reduced pressure. ) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N-(4-(3-methoxycarbonylphenyl)carboxy-aminophenyl)urea (0.27 g, 43%): mp 121-122; TLC ( 80% EtOAc/28% hexane) Rf 0.75.

D1b. Konverzija ω-karboksifenil urea u ω-(aril karbamoiljfenil uree. D1b. Conversion of ω-carboxyphenyl urea to ω-(aryl carbamoylphenyl urea).

Sinteza N-(4-klor-3-((trifluor metil)fenil)-N'-(4-(3-metilkarbamoilfenil)karbamoilfenil)uree. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea.

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Otopini N-(4-klor-3-((trifluormetil)fenil)-N'-(4-(3-metil karbamoilfenil)karboksiaminofenil) uree (0.14 g, 0.48 mmol), 3-metilkarbamoilanilina (0.080 g, 0.53 mmol), HOBT · H2O (0.14 g, 1.07 mmol) i N-metilmorfolina (0.5 mL, 1.07 mmol) u DMF (3 mL) na 0°C doda se EDCI · HCl (0.10 g, 0.53 mmol). Nastala smjesa ostavi se da se zagrije na sobnoj temperaturi i miješa preko noći. Nastala smjesa obradi se vodom (10 mL), i ekstrahira s EtOAc (25 mL). Organska faza koncentrira se pod reduciranim tlakom. Dobivena žuta krutina otopi se otopinom EtOAc (3.0 ml) potom filtrira preko sloja silika gela (17 g, gradient od 70% EtOAc730% heksan do 10% MeOH/90% EtOAc) i dobije se N-(4-klor-3-((trifluormetil)fenil)-N-(4-(3-metil karbamoilfenil)karbamoilfenil)urea (0.097 g, 41%): mp 225-229; TLC (100% EtOAC) Rf 0.23. Solutions of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methyl carbamoylphenyl)carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol) , HOBT · H2O (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0°C was added EDCI · HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to was warmed to room temperature and stirred overnight. The resulting mixture was treated with water (10 mL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc solution (3.0 mL) then filtered over a layer of silica gel (17 g, gradient from 70% EtOAc730% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N-(4-(3 -methylcarbamoylphenyl)carbamoylphenyl)urea (0.097 g, 41%): mp 225-229; TLC (100% EtOAC) Rf 0.23.

D1c. Povezivanje konverzijom ω-karboksifenil urea u ω(aril karbamoil)fenil urea. D1c. Coupling by conversion of ω-carboxyphenyl urea to ω(aryl carbamoyl)phenyl urea.

Sinteza N-(4-klor-3-((trifluormetil)fenil)-N'-(4-(N-3-(N-(3-piridil) karbamoil)fenil)karbamoil)fenil) uree. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl)urea.

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Smjesa N-(4-klor-3-((trifluormetil)fenil-N'-(3-karboksifenil) uree (Metoda C1f; 0.030 g, 0.067 mmol) i N-cikloheksil-N'-(metilpolistiren)karbodiimida (55 g) u 1,2-dikloretanu (1 mL) obradi se s otopinom 3-aminopiridina u CH2Cl2 (1M; 0.074 mL, 0.074 mmol). (U slučaju netopivosti ili zamućivanja, isto treba dodati malu količinu DMSO). Nastalu smjesu zagrije se preko noći na 36°C. Mutnu reakcijsku smjesu potom obradimo s THF (1 mL) i zagrijavamo kontinuirano kroz 18 sati. Nastalu smjesu obradimo s poli (4-(izocianatmetil)stiren) (0.040 g) i dobivenu smjesu miješa se 72 h na 36°C, zatim ohladi na sobnu temperaturu i filtrira. Nastalu otopinu filtrira se kroz sloj silikagela (1 g). Koncentrira se pod reduciranim tlakom i dobije se N-(4-klor-3-((trifluormetil)fenil)N'-(4-(N-(3-(N-(3-piridil) karbamoil)fenil)karbamoil)fenil) uree (0.024 g, 59%): TLC (70% EtOAc/30% heksan) Rf 0.12. A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl-N'-(3-carboxyphenyl)urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 g) ) in 1,2-dichloroethane (1 mL) is treated with a solution of 3-aminopyridine in CH2Cl2 (1M; 0.074 mL, 0.074 mmol). (In case of insolubility or turbidity, a small amount of DMSO should also be added). The resulting mixture is heated over overnight at 36°C. The cloudy reaction mixture was then treated with THF (1 mL) and heated continuously for 18 hours. The resulting mixture was treated with poly (4-(isocyanatemethyl)styrene) (0.040 g) and the resulting mixture was stirred for 72 h at 36 °C, then cooled to room temperature and filtered. The resulting solution was filtered through a layer of silica gel (1 g). It was concentrated under reduced pressure to give 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) Rf 0.12.

D2. Konverzija ω-karboalkoksiaril urea u ω-karbamoilaril uree. D2. Conversion of ω-carboalkoxyaryl urea to ω-carbamoylaryl urea.

Sinteza N-(4-klor-3-((trifluormetil)fenil)-N'-(4-(3-metilkarbamoilfenil)karboksiaminofenil) uree Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea

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Uzorku N-(4-klor-3-((trifluormetil)fenil)-N'-(4(-3-karbometoksifenil)karboksiaminofenil) uree (0.17 g, 0.34 mmol) doda se (2 M u THF; 1 mL, 1.7 mmol), a dobivena smjesa miješa se preko noći na sobnoj temperaturi, potom koncentrira pod reduciranim tlakom da se dobije N-(4-klor-3-((trifluormetil)fenil)-N'-(4-(3-metilkarbamoilfenil)karboksiaminofenil) ureu kao bijelu krutinu: mp 247; TLC (100%EtOAc) Rf 0.35. To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4(-3-carbomethoxyphenyl)carboxyaminophenyl)urea (0.17 g, 0.34 mmol) was added (2 M in THF; 1 mL, 1.7 mmol), and the resulting mixture is stirred overnight at room temperature, then concentrated under reduced pressure to obtain N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) ) in urea as a white solid: mp 247; TLC (100%EtOAc) Rf 0.35.

D3. Konverzija ω-karboalkoksiaril urea u ω-karboksiaril uree. D3. Conversion of ω-carboalkoxyaryl urea to ω-carboxyaryl urea.

Sinteza N-(4-klor-3-((trifluormetil)fenil)-N'-(4-karboksifenil) uree Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl)urea

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U gustoj otopini N-(4-klor-3-((trifluormetil)fenil)-N'-(4-etoksikarbonilfenil) uree (Metoda Gle; 5.93 g, 15.3 mmol) u MeOH (75 mL) doda se vodena otopina KOH (2.5 N, 10 mL, 23 mmol). Nastalu smjesu zagrije se do temperature refluksa za 12 h, ohladi na sobnu temperaturu, potom koncentrira pod reduciranim tlakom. Ostaci se razrijede se s vodom (50 mL), zatim obrade s 1N otopinom HCl da bi se podesio pH na 2-3. Nastala krutina sakupi se i osuši pod reduciranim tlakom da se dobije N-(4-klor-3-((trifluormetil)fenil)-N'-(4-karboksifenil) ureu kao bijelu krutinu (5.05 g, 92%). To a thick solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea (Method Gle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous solution of KOH ( 2.5 N, 10 mL, 23 mmol). The resulting mixture was heated to reflux temperature for 12 h, cooled to room temperature, then concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with 1N HCl solution to would adjust the pH to 2-3.The resulting solid was collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl)urea as a white solid ( 5.05 g, 92%).

D4. Opća metoda za konverziju ω-alkoksi estera u co-alkil amide. D4. General method for the conversion of ω-Alkoxy esters to co-alkyl amides.

Sinteza N-(4-klor-3-((trifluormetil)fenil)-N'-(4-(3-(5-(2-dimetilaminoetil)karbamoil)piridil)oksifenil) uree Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea

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Korak 1. Sinteza N-(4-klor-3-(trifluormetil)fenil)-N'-((4-(3-(5-karboksipiridil)oksifenil) uree Step 1. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)oxyphenyl) urea)

N-(4-klor-3-(trifluormetil)fenil)-N'-((4-(3-(5-metoksi karbonil piridil)oksifenil) urea sintetizira se iz 4-klor-3-(trifluormetil)fenil izocianata i 4-(3-(5-metoksi karboniIpiridil) oksalina (Metoda A14, Korak 2) na način analogan Metodi C1a. Suspenziju od N-(4-klor-3-(trifluormetil) fenil)-N'-((4-(3-(5-metoksikarbonilpiridil) oksif enil) uree (0.26 g, 0.56 mmol) u MeOH (10 mL) obradi otopinom KOH (0.14 g, 2.5 mmol) u vodi (1mL) i miješa 1 sat. na sobnoj temperaturi. pH nastale smjese korigira se 1 N otopinom HCl na 5. Nastali precipitat odvoji se filtracijom i ispiranjem s vodom. Dobivena krutina rastopi se u EtOAc (10 mL) f a nastala otopina koncentrira se pod reduciranim tlakom. Postupak EtOAc/koncentracija ponovi se dva puta da bi se dobila N-(4-klor-3-(trifluormetil)fenil)-N'-((4-(3-(5-karboksipiridil)oksifenil) urea (0.18 g, 71 %). N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxy carbonyl pyridyl)oxyphenyl) urea is synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxy carbonyl)oxaline (Method A14, Step 2) in a manner analogous to Method C1a. A suspension of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-( 3-(5-Methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and stirred for 1 hour at room temperature. The pH of the resulting the mixture is corrected with 1 N HCl solution to 5. The resulting precipitate is separated by filtration and washed with water. The resulting solid is dissolved in EtOAc (10 mL) f and the resulting solution is concentrated under reduced pressure. The EtOAc/concentration procedure is repeated twice to give obtained N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.18 g, 71 %).

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Korak 2. Sinteza N-(4-klor-3-(trifluormetil) fenil)-N'-((4-(3-(5-(2-dimetil aminoetil)karbamoil) piridil) oksifenil) uree Step 2. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethyl aminoethyl)carbamoyl) pyridyl) oxyphenyl) urea

Smjesu N-(4-klor-3-(trifluormetil)fenil)-.N'-((4-(3-(5-karboksipiridil)oksifenil) uree (0.050 g, 0.011 mmol), N,N-dimetiletilendiamina (0.22 mg, 0.17 mmol),HOBT (0.028 g, 0.17 mmol) N-metilmorfina (0.035 g, 0.28 mmol) i EDCI · HCl (0.032 g, 0.17 mmol) u DMF (2.5 mL) miješa se preko noći na sobnoj temperaturi. Nastalu otopinu odvojimo između EtOAc (50 mL) i vode (50 mL). Organsku fazu ispere se vodom (35 mL), osuši (MgSO4) i koncentrira pod reduciranim tlakom. Ostaci se otope u minimalnoj kolikini CH2Cl2 (oko 2 mL). Nastalu otopinu obradi se kap po kap Et2O i dobijemo N-(4-klor-3-(trifluormetil)fenil)-N'-((4-(3-(5-(2-dimetilaminoetil) karbamoil) piridil)oksifenil) uree kao bijeli precipitat (0.48 g, 84%): 1H-NMR (DMSO-d6) δ 2.10 (s, 6H), 3.26 (s, 6H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H), HPLC ES-MS m/z 522 ((M+H)+). A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-.N'-((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.050 g, 0.011 mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17 mmol),HOBT (0.028 g, 0.17 mmol), N-methylmorphine (0.035 g, 0.28 mmol) and EDCI·HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) were stirred overnight at room temperature. the solution is separated between EtOAc (50 mL) and water (50 mL). The organic phase is washed with water (35 mL), dried (MgSO4) and concentrated under reduced pressure. The residues are dissolved in a minimal amount of CH2Cl2 (about 2 mL). The resulting solution treated drop by drop with Et2O and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl) carbamoyl) pyridyl)oxyphenyl) urea as white precipitate (0.48 g, 84%): 1H-NMR (DMSO-d6) δ 2.10 (s, 6H), 3.26 (s, 6H), 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. Opća metoda deprotekcije N-(ω-sililoksialkil) amida. D5. General method of deprotection of N-(ω-silyloxyalkyl) amides.

Sinteza N-4-klor-3-((trifluormetil) fenil)-N'-(4-(4-(2-(N-(2-hidroksi)etilkarbamoil)piridiloksifenil)uree. Synthesis of N-4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)urea.

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U otopinu N-(4-klor-3-((trifluormetil)fenil)-N'-(4-(4-(2-(N-(2-triizopropilsililoksi)etilkarbamoil)piridiloksifenil) uree (pripremi se na način analogan Metodi C1a; 0.25 g, 0.37 iranol) u anh THF (2 mL) je tetrabutilamonium fluorid (1.0 M u THF; 2 mL). Smjesa se miješa 5 min na sobnoj temperaturi, zatim se tretira vodom (10 mL). Vodena smjesa ekstrahira se sa EtAOc (3x 10 mL). Nastali organski sloj osuši se (MgSO4) i koncentrira pod reduciranim tlakom. Ostaci se purificiraju kolonskom kromatografijom (SiO2; gradient od 100% heksan do 40% EtOAc/60% heksan) da dobijemo N-4-klor-3-((trifluormetil)fenil)-N'-(4-(4-(2-(N-(2-hidroksi)etil karbamoil)piridiloksifenil)uree, bijele krutine (0.019 g, 10%). In a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)urea) (prepared in a manner analogous to Method C1a; 0.25 g, 0.37 iranol) in anh THF (2 mL) is tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture is stirred for 5 min at room temperature, then treated with water (10 mL). The aqueous mixture is extracted with EtAOc (3x 10 mL). The resulting organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; gradient from 100% hexane to 40% EtOAc/60% hexane) to give N-4- chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-hydroxy)ethyl carbamoyl)pyridyloxyphenyl)urea, white solid (0.019 g, 10%).

Dolje navedeni popis je popis supstancija u daljnim tabelama koje su sintetizirane u skladu s detaljnijim postupkom iznesenim gore: The list below is a list of the substances in the following tables that were synthesized according to the more detailed procedure outlined above:

Sinteza supstancija koje služe kao primjeri (vidi tablice označivanja supstancija) Synthesis of substances that serve as examples (see substance labeling tables)

Ulaz 1: 4-(S-AT-metilkarbamoilfenoksi) anilin priprema se u skladu s Metodom A13. U skladu s Metodom C3, 3-tert-butilanilin reagira s bis(triklormetil)karbonatom nakon 4-(3-N-metilkarbamoilfenoksi)anilina, dobije se urea. Entry 1: 4-(S-AT-methylcarbamoylphenoxy) aniline is prepared according to Method A13. According to Method C3, 3-tert-butylaniline reacts with bis(trichloromethyl)carbonate after 4-(3-N-methylcarbamoylphenoxy)aniline, urea is obtained.

Ulaz 2: 4-fluor-1-nitrobenzen i p-hidroksiacetofenon reagira u skladu s Metodom A 13, Korak 1 pa se dobije 4-(4-acetilfenoksi)-1-nitrobenzen. 4-(4-acetilfenoksi)-1-nitro benzen reducira se u skladu s Metodom A13, Korak 4 da se dobije 4-(4-acetilfenoksi)anilin. U skladu s Metodom C3, 3-tert-butilanilin reagira s bis(triklormetil) karbonatom nakon 4(4-acetilfenoksi)anilina, da se dobije urea. Input 2: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to Method A 13, Step 1 to give 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitro benzene is reduced according to Method A13, Step 4 to give 4-(4-acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline is reacted with bis(trichloromethyl)carbonate after 4(4-acetylphenoxy)aniline to give urea.

Ulaz 3: U skladu s Metodom C2d, 3-tert-butilanilin tretira se s CDI , nakon 4 (3-N-metilkarbamoil)-4-metoksifenoksi) anilina, koji će biti pripremljen u skladu s Metodom A8, pa se dobije urea. Entry 3: According to Method C2d, 3-tert-butylaniline is treated with CDI, after 4 (3-N-methylcarbamoyl)-4-methoxyphenoxy) aniline, which will be prepared according to Method A8, and urea is obtained.

Ulaz 4: 5-tert-butil-2-metoksianilin pretvara se u 5-tert-butil-2-metoksifenil izocianat u skladu s Metodom B1. 4(3-N-metilkarbamoilfenoksi)anilin, priprema se u skladu s Metodom A13, nastaje reakcija s izocianatom u skladu s Metodom C1a, da se dobije urea. Entry 4: 5-tert-butyl-2-methoxyaniline is converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method B1. 4(3-N-methylcarbamoylphenoxy)aniline, prepared according to Method A13, is reacted with isocyanate according to Method C1a, to obtain urea.

Ulaz 5: U skladu s Metodom C2d, 5-tert-butil-2-metoksianilin reagira s CDI nakon 4-(3-N-metilkarbamoil)-4-metoksi fenoksi)anilina, koji će biti pripremljeni u skladu s Metodom A8, da se dobije urea. Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI after 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which will be prepared according to Method A8, to urea is obtained.

Ulaz 6: 5-(4-aminofenoksi)izoindolin-1,3-dion priprema se u skladu s Metodom A3. U skladu s Metodom 2d, 5-tert-butil-2-metoksianilin reagira s CDI nakon 5-(4-aminofenoksi) izoindolin-1,3-diona, da se dobije urea. Entry 6: 5-(4-aminophenoxy)isoindoline-1,3-dione is prepared according to Method A3. According to Method 2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI after 5-(4-aminophenoxy)isoindoline-1,3-dione to give urea.

Ulaz 7: 4-(1-oksoizoindolin-5-iloksi)anilin sintetizira se u skladu s Metodom A12. U skladu s Metodom 2d., 5-tert-butil-2-metoksianilin reagira s CDI nakon 4-(1-oksoizoindolin-5-iloksi)anilina, da se dobije uree. Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline is synthesized according to Method A12. According to Method 2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI after 4-(1-oxoisoindolin-5-yloxy)aniline to give the urea.

Ulaz 8: 4-(3-N-metilkarbamoilfenoksi)anilin sintetizira se u skladu s Metodom A13. U skladu s Metodom C2a, 2-metoksi-5-(trifluorometil)anilin reagira s CDI nakon 4-(3-N-metilkarbamoilfenoksi)anilina, da se dobije urea. Entry 8: 4-(3-N-methylcarbamoylphenoxy)aniline is synthesized according to Method A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline is reacted with CDI after 4-(3-N-methylcarbamoylphenoxy)aniline to give urea.

Ulaz 9: 4-hidroksiacetofenon reagira s 2-klor-5-nitropiridinom i dobije se 4-(4-acetilfenoksi)-5-nitropiridin u skladu s Metodom A3, Korak 2. Sukladno metodi A8, Korak 4, 4-(4-acetilfenoksi)-5-nitropiridin reducira se u 4-(4-acetilfenoksi)-5-aminopiridin. 2-metoksi-5-(trifluorometil) anilin pretvara se u 2-metoksi-5-(trifluorometil)fenil izocianat u skladu s Metodom B1. Izocianat reagira s 4-(4-acetilf enoksi)-5-aminopiridinom sukladno Metodi C1a, da se dobije urea. Entry 9: 4-hydroxyacetophenone is reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4- acetylphenoxy)-5-nitropyridine is reduced to 4-(4-acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl) aniline is converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate is reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method C1a to give urea.

Ulaz 10: 4-fluoro-1-nitrobenzen i p-hidroksiacetofenon reagiraju u skladu s Metodom A13, Korak 1 i dobije se 4-(4-acetilfenoksi)-1-nitrobenzen. 4-(4-acetilfenoksi)-1-nitrobenzen reducira se sukladno Metodi A13, Korak 4 dobije se 4- Entry 10: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to Method A13, Step 1 to give 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-acetylphenoxy)-1-nitrobenzene is reduced according to Method A13, Step 4 to obtain 4-

(4-acetilfenoksi) anilin. U skladu s Metodom C3, 5-(trifluormetil)-2-metoksibutilanilin reagira s bis (triklormetil) karbonatom nakon 4-(4-acetilfenoksi)anilin, da se dobije urea. (4-acetylphenoxy) aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline is reacted with bis(trichloromethyl)carbonate after 4-(4-acetylphenoxy)aniline to give urea.

Ulaz 11: 4-klor-N-metil-2-piridinkarboksamid, koji je sintetiziran u skladu s Metodom A2, Korak 3a, ušao je u reakciju s 3-aminofenolom u skladu s Metodom A2, Korak 4 korištenjem DMAC na mjestu DMF-a i daje 3-(-2-(N-metilkarbamoil)-4-piridiloksi)anilin. U skladu s Metodom C4, 2-metoksi-5-(trifluorometil)anilin reagira s fosgenom iza 3-(-2-(N-metilkarbamoil)-4-piridiloksi) anilina, i daje ureu. Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF and gives 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline reacts with phosgene behind 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 12: 4-klorpiridin-2-karbonil klorid sol HCl reagira s amonijakom u skladu s Metodom A2, Korak 3b, u oblik 4-klor-2-piridinkarboksamid. 4-klor-2-piridinkarboksamid reagira s 3-aminofenolom u skladu s Metodom A2, Korak 4 upotrebom DMAC na mjestu DMF-a i daje 3-(2-karbamoil-4-piridiloksi)anilin. U skladu s Metodom C2a 2-metoksi-5-(trifluormetil)anilin reagira s fosgenom iza 3-(2-karbamoil-4-piridiloksi)anilinom da se dobije urea. Entry 12: 4-chloropyridine-2-carbonyl chloride salt HCl reacts with ammonia according to Method A2, Step 3b, to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a 2-methoxy-5-(trifluoromethyl)aniline reacts with phosgene behind 3-(2-carbamoyl-4-pyridyloxy)aniline to give urea.

Ulaz 13: 4-klor-N-metil-2-piridinkarboksamid sintetizira se u skladu s Metodom A2, Korak 3b. 4-klor-A7-metil-2-piridinkarnboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 korištenjem DMAC na mjestu DMF da se dobije 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilin. U skladu s Metodom C2a, 2-metoksi-5-(trifluormetil)anilin reagira s CDI iza 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilinom, da se dobije urea. Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide is synthesized according to Method A2, Step 3b. 4-Chloro-A7-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline is reacted with CDI behind 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 14: 4-klorpiridin-2-karbonil klorid soli HCl reagira s amonijakom u skladu s Metodom A2, Korak 3b u oblik 4-kloro-2-piridinkarboksamid. 4-klor-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2. Korak 4 koristeći DMAC na mjestu DMF da se dobije 4-(2-karbamoil-4-piridiloksi)anilin. U skladu s Metodom C4, 2-metoksi-5-(trifluormetil)anilin reagira s fosgenom iza 4-(2-karbamoil-4-piridiloksi)anilina, da se dobije urea. Entry 14: 4-chloropyridine-2-carbonyl chloride HCl salt reacts with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide reacts with 4-aminophenol according to Method A2. Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline is reacted with phosgene behind 4-(2-carbamoyl-4-pyridyloxy)aniline to give urea.

Ulaz 15: U skladu s Metodom C2d, 5-(trifluormetil)-2-metoksianilin reagira s CDI iza 4-(3-N-metilkarbamoil)-4-metoksifenoksi)anilin, kada je pripremljen u skladu s Metodom A8, pa se dobije urea. Entry 15: According to Method C2d, 5-(trifluoromethyl)-2-methoxyaniline is reacted with CDI behind 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, when prepared according to Method A8, to give urea.

Ulaz 16: 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-metilanilin sintetizira se u skaladu s Metodom A5. 5-(trifluormetil)-2-metoksianilin pretvori se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. Izocianat reagira s 4-(2-(A7-metilkarbamoil)-4-piridiloksi)-2-metilanilin u skladu s Metodom C1c da se dobije urea. Entry 16: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline is synthesized in cascade with Method A5. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. The isocyanate is reacted with 4-(2-(A7-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method C1c to give the urea.

Ulaz 17 : 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloranilin se sintetizira u skladu s Metodom A6. 5-(trifluormetil)-2-metoksianilin pretvori se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluorometil)-2-metoksifenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloranilin u skladu s Metodom C1c, da se dobije urea. Entry 17: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline is synthesized according to Method A6. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method C1c to give urea.

Ulaz 18: U skladu s Metodom A2, Korak 4, 5-amino-2-metilf enol reagira s 4-klor-N-metil-2-piridinkarboksamidom, koji se sintetizira u skladu s Metodom A2, Korak 3b, da se dobije 3-(2-(N-metilkarbamoil)-4-piridiloksi)-4-metilanilin. 5 (tri-fluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 3-(2-(N-metilkarbamoil)-4-piridiloksi)-4-metilanilinom u skladu s Metodom C1a, da se dobije urea. Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to Method A2, Step 3b, to give 3 -(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C1a to give urea.

Ulaz 19: 4-klorpiridin-2-karbonil klorid reagira s etilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-kloro-N-etil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 i dobije se 4-(2-(N-etilkarbamoil)-4-piridiloksi)anilin. 5-(trifluorometil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(2-(N-etilkarbamoil)-4-piridiloksi) anilinom u skladu s Metodom Cla, da se dobije urea. Entry 19: 4-chloropyridine-2-carbonyl chloride is reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy) aniline according to Method Cla to give urea.

Ulaz 20: U skladu s Metodom A2, Korak 4, 4-amino-2-klorfenol reagira s 4-klor-N-metil-2-piridinkarboksamidom, koji će se sintetizirati u skladu s Metodom A2, Korak 3b, da se dobije 4-(2-(N-metilkarbamoil)-4-piridiloksi)-3-kloranilin. 5-(tri fluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluorometil)-2-metoksifenil izocianat reagirat će s 4-(2-(N-metilkarbamoil)-4-piridiloksi)-3-kloranilinom u skladu s Metodom C1a, da se dobije urea. Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which will be synthesized according to Method A2, Step 3b, to give 4 -(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate will react with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method C1a to give urea.

Ulaz 21.: 4-(4-metiltiofenoksi)-1-nitrobenzen će oksidirati u skladu s metodom A19, Korak 1 da se dobije 4-(4-metilsulfonilfenoksi)-1-nitrobenzen. Nitrobenzen će biti reduciran u skladu s Metodom A19, Korak 2, da se dobije 4-(4-metilsulfonilfenoksi)-1-anilin. U skadu s Metodom C1a, 5-(trifluormetil)-2-metoksifenil izocianat će reagirati s 4-(4-metilsulfonilfenoksi)-1-anilin, da se dobije urea. Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene will be oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. Nitrobenzene will be reduced according to Method A19, Step 2, to give 4-(4-methylsulfonylphenoxy)-1-aniline. In accordance with Method C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate will react with 4-(4-methylsulfonylphenoxy)-1-aniline to give urea.

Ulaz 22: 4-(3-karbamoilfenoksi)-1-nitrobenzen se reducira na 4-(3-karbamoilfenoksi)anilin u skladu s Metodom A15, korak 4. U skladu s Metodom C1a, 5-(trifluorometil)-2-metoksifenil izocianat će reagirati s 4-(3-karbamoilfenoksi)anilinom, da bi nastala urea. Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene is reduced to 4-(3-carbamoylphenoxy)aniline according to Method A15, step 4. According to Method C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate will react with 4-(3-carbamoylphenoxy)aniline to form urea.

Ulaz 23: 5-(4-aminofenoksi)izoindolin-1,3-dion sintetizira se u skladu s Metodom A3. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s metodom B1. 5-(triflurometil)-2-metoksianilin reagira s 5-(4-aminofenoksi)izoindolin-1,3-dionom u skladu s Metodom C1a, da bi se dobila urea. Entry 23: 5-(4-aminophenoxy)isoindoline-1,3-dione is synthesized according to Method A3. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(trifluoromethyl)-2-methoxyaniline is reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according to Method C1a to give urea.

Ulaz 24: 4-klorpiridin-2-karbonil klorid reagira s dimetilaminom u skladu s Metodom A2, Korak 3b; Nastali 4-klor-N,N-dimetil-2-piridinkarboksamid reagira s 4-amino fenolom u skladu s Metodom A2, Korak 4, pa se dobije 4-(2-(N,N-dimetilkarbamoil)-4-piridiloksi) anilin. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(2-(N,N-dimetilkarbamoil)-4-piridiloksi)anilinom u skladu s Metodom C1a, da bi se dobila ure. Entry 24: 4-chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to Method A2, Step 3b; The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy) aniline . 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method C1a to give the urea.

Ulaz 25: 4-(1-oksoizoindolin-5-iloksi)anilin sintetizira se u skladu s Metodom A12. 5-(trifluormetil)-2-metoksianilin obradi se s CDI, iza 4-(1-oksoizoindolin-5-iloksi)anilina u skladu s Metodom C2d, da se dobije urea. Entry 25: 4-(1-oxoisoindolin-5-yloxy)aniline is synthesized according to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, after 4-(1-oxoisoindolin-5-yloxy)aniline according to Method C2d, to give the urea.

Ulaz 26: 4-hidroksiacetofenon reagira s 4-fluornitrobenzenom u skladu s Metodom A13, Korak 1 dobije se 4-(4-acetilfenoksi)nitrobenzen. Nitrobenzen će se reducirati u skladu s Metodom A13, Korak 4, dobije se 4-(4-acetilfenoksi)anilin koji se pretvara u 4-(4-(1-(N-metoksi)iminoetil)feniksianilin sol HCl u skladu s Metodom A16. 5-(trifluormetil)-2-metoksianilin se pretvori u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s u 4-(4-(1-(N-metoksi)iminoetil)fenoksianilin sol HCl po Metodi C1a, da se dobije urea. Entry 26: 4-hydroxyacetophenone is reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. Nitrobenzene will be reduced according to Method A13, Step 4, to give 4-(4-acetylphenoxy)aniline which is converted to 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(trifluoromethyl)-2-methoxyphenyl isocyanate reacts with u 4-(4-(1-( N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method C1a, to obtain urea.

Ulaz 27: 4-klor-N-metilpiridinkarboksamid sintetizira se kao što je opisano u Metodi A2, Korak 3b. Klorpiridin reagira s 4-aminotiofenolom u skladu s metodom A2, korak 4 da se dobije 4-(4-(2-(N-metilkarbamoil)feniltio)anilin. 5-(trifluormetil)-2-metoksianilin se pretvori u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(4-(2-(N-metilkarbamoil)feniltio) anilinom u skladu s Metodom C1a, Entry 27: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in Method A2, Step 3b. Chloropyridine is reacted with 4-aminothiophenol according to method A2, step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl )-2-methoxyphenyl isocyanate in accordance with Method B1. 5-(trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(4-(2-(N-methylcarbamoyl)phenylthio) aniline in accordance with Method C1a,

da se dobije urea. to get urea.

Ulaz 28: 5-(4-aminofenoksi)-2-metilizoindolin-1,3-dion sintetizira se u skladu s Metodom A9. 5-(trifluormetil)-2-metoksianilin se pretvori u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 5-(4-aminofenoksi)-2-metilizoindilin-1,3-dionom u skladu s Metodom C1a, da se dobije urea. Entry 28: 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 5-(4-aminophenoxy)-2-methylisoindiline-1,3-dione according to Method C1a to give urea.

Ulaz 29: 4-klor-N-metilpiridinkarboksamid sintetizira se kao što je opisano u Metodi A2, Korak 3b. Klorpiridin reagira s 3-aminotiofenolom u skladu s Metodom A2, Korak 4 da se dobije 3-(4-(2-(N-metilkarbamoil)feniltio)anilin. 5-(trifluormetil)-2-metoksianilin se pretvori u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 3-(4-(2-(N-metilkarbamoil)feniltio)anilinom u skladu s Metodom C1a, da se dobije urea. Entry 29: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in Method A2, Step 3b. Chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl )-2-methoxyphenyl isocyanate according to Method B1 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method C1a to give urea .

Ulaz 30: 4-klorpiridin-2-karbonil klorid reagira s izopropilaminom u skladu s Metodom A2, Korak 3.b. Nastali 4-klor-N-izopropil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 i dobije se 4-(2-(N-izopropilkarbamoil)-4-piridiloksi)anilin. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1, 5-(trif luormetil)-2-metoksifenil izocianat reagira s 4-(2-(N-izopropilkarbamoil)-4-piridiloksi)anilinom u skladu s Metodom C1a, da se dobije urea. Entry 30: 4-chloropyridine-2-carbonyl chloride is reacted with isopropylamine according to Method A2, Step 3.b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(2-(N-isopropylcarbamoyl) )-4-pyridyloxy)aniline according to Method C1a, to obtain urea.

Ulaz 31: 4-(3-(5-metoksikarbonil)piridiloksi)anilin sintetizira se u skladu s Metodom A14. 5-(trifluormetil)-2-metoksianilin se pretvara u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(3-(5-metoksi karbonil)piridiloksi) anilinom u skadu s Metodom C1a da se dobije urea. N-(5-(trifluormetil)-N'-(4-(3-(5-metoksi karbonil piridil)oksi)fenil urea saponificira se u skladu s Metodom D4, Korak 1, i odgovarajuća kiselina veže se s 4-(2-aminoetil)morfolinom u skladu s metodom D4, Korak 2, da se dobije amid. Entry 31: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline is synthesized according to Method A14. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy) aniline in accordance with Method C1a to give urea. N-(5-(trifluoromethyl)-N'-(4-(3-(5-methoxy carbonyl pyridyl)oxy)phenyl urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with 4-(2 -aminoethyl)morpholine according to Method D4, Step 2, to give the amide.

Ulaz 32: 4-(3-(5-metoksikarbonil)piridiloksi)anilin sintetizira se u skladu s Metodom A14. 5-(trifluormetil)-2-metoksianilin se pretvara u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(3-(5-metoksi karbonil)piridiloksi) anilinom u skladu s Metodom C1a da se dobije urea. N-(5-(trifluorometil)-N'-(4-(3-(5-metoksi karbonilpiridil)oksi)fenil urea saponificira se u skladu s Metodom D4, Korak 1, i odgovarajuća kiselina veže se s metilaminom s Metodom D4, Korak 2, da se dobije amid. Entry 32: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline is synthesized according to Method A14. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy) aniline according to Method C1a to give urea. N-(5-(trifluoromethyl)-N'-(4-(3-(5-methoxy carbonylpyridyl)oxy)phenyl urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with methylamine according to Method D4, Step 2, to get the amide.

Ulaz 33: 4-(3-(5-metoksikarbonil)piridiloksi)anilin sintetizira se u skladu s Metodom A14. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 5-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(3-(5-metoksikarbonil)piridiloksi) anilinom u skladu s Metodom C1a da se dobije urea. N-(5-(trifluorometil)-2-metoksifenil)-N'-(4-(3-(5-metoksikarbonilpiridil)oksi)fenil urea saponificira se u skladu s Metodom D4, Korak 1, i odgovarajuća kiselina veže se s N(4-dimetiletilendiaminom u skladu s Metodom D4, Korak 2, da se dobije amid. Entry 33: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline is synthesized according to Method A14. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy) aniline according to Method C1a to give urea. N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with N (4-dimethylethylenediamine according to Method D4, Step 2, to give the amide.

Ulaz 34: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluormetil)-2-metoksifenil izocianatom u skladu s Metodom C1f da se dobije N-(5-(trifluormetil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s 3-aminopiridinom u skladu s metodom D1c. Entry 34: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which binds with 3-aminopyridine according to method D1c.

Ulaz 35: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluormetil)-2-metoksianilin se pretvara u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluorometil)-2-metoksifenil izocianatom u skladu s Metodom C1f da se dobije N-(5-(trifluorometil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s N-(4-fluorfenil)piperazinom u skladu s Metodom D1c. Entry 35: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which is coupled with N-(4-fluorophenyl)piperazine according to Method D1c.

Ulaz 36: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluorometil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluormetil)-2-metoksifenil izocianatom u skladu s Metodom C1f da se dobije N-(5-(trifluormetil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s 4-fluoroanilinom u skladu s Metodom D1c. Entry 36: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which binds with 4-fluoroaniline according to Method D1c.

Ulaz 37: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluormetil)-2-metoksifenil izocianatom u skladu s Metodom C1f, da se dobije N-(5-(trifluormetil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s 4-(dimetilamino)anilinom u skladu s Metodom D1c. Entry 37: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f, to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) ) urea, which binds with 4-(dimethylamino)aniline according to Method D1c.

Ulaz 38: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluormetil)-2-metoksianilin se pretvara u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluormetil)-2-metoksifenil izocianatom u skladu s Metodom C1f, da se dobije N-(5-(trifluormetil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s 5-amino-2-metoksipiridinom u skladu s Metodom D1c. Entry 38: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f, to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) ) urea, which binds with 5-amino-2-methoxypyridine according to Method D1c.

Ulaz 39: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluormetil)-2-metoksianilin pretvara se u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluormetil)-2-metoksifenil izocianatom u skladu s Metodom C1f da se dobije N-(5-(trifluormetil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s 4-morfolinanilinom u skladu s Metodom D1c. Entry 39: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which binds with 4-morpholinaniline according to Method D1c.

Ulaz 40: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 5-(trifluormetil)-2-metoksianilin se pretvara u 5-(trifluormetil)-2-metoksifenil izocianat u skladu s Metodom B1. 4-(3-karboksifenoksi)anilin reagira s 5-(trifluormetil)-2-metoksifenil izocianatom u skladu s Metodom C1f da se dobije N-(5-(trifluormetil)-2-metoksifenil)-N'-(3-karboksifenil) urea, koja se veže s N-(2-piridil)piperazinom u skladu s Metodom D1c. Entry 40: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to give N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which is coupled with N-(2-pyridyl)piperazine according to Method D1c.

Ulaz 41: 4-(3-(N-metilkarbamoil)fenoksi)anilin sintetizira se u skladu s Metodom A13 . U skladu s Metodom C3, 4-kloro-3-(fluormetil)anilin pretvara se u izocianat, potom reagira s 4-(3-(N-metilkarbamoil)fenoksi)anilinom, da se dobije urea. Entry 41: 4-(3-(N-methylcarbamoyl)phenoxy)aniline is synthesized according to Method A13. According to Method C3, 4-chloro-3-(fluoromethyl)aniline is converted to isocyanate, then reacted with 4-(3-(N-methylcarbamoyl)phenoxy)aniline to give urea.

Ulaz 42 : 4-(2-N-metilkarbamil-4-piridiloksi)anilin sintetizira se u skladu s Metodom A2 . 4-kloro-3-(trifluormetil)fenil izicianat reagira s 4-(2-N-metilkarbamil-4-piridiloksi)anilinom u skladu s Metodom C1a da se dobije urea. Entry 42: 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline is synthesized according to Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method C1a to give urea.

Ulaz 43: 4-klorpiridin-2-karbonil klorid sol HCl reagira s amonijakom u skladu s Metodom A2, Korak 3b da bi se formirao 4-klor-2-piridinkarbokasmid. 4-klor-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4, da bi nastao 4-(2-karbamoil-4-piridiloksi)anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(2-karbamoil-4-piridiloksi)anilinom, da se dobije urea. Entry 43: 4-chloropyridine-2-carbonyl chloride salt HCl is reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to give urea.

Ulaz 44: 4-klorpiridin-2-karbonil klorid sol HCl reagira s amonijakom u skladu s Metodom A2, Korak 3b da bi se formirao 4-klor-2-piridinkarboksamid. 4-klor-2-piridinkarboksamid reagira s 3-aminofenolom u skladu s Metodom A2, Korak 4 da bi nastao 4-(2-karbamoil-4-piridiloksi)anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 3-(2-karbamoil-4-piridiloksi)anilinom da se dobije urea. Entry 44: 4-chloropyridine-2-carbonyl chloride salt HCl is reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to give urea.

Ulaz 45: 4-klor-A7-metil-2-piridinkarboksamid sintetizira se u skladu s Metodom A2, Korak 3a, reagira s 3-aminofenilom u skladu s Metodom A2, Korak 4, u oblik 3-(2-(N-metilkarbamoil)-4-piridiloksi)anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 3-(2-(N-metilkarbamoil)-4-piridiloksi) anilinom, da se dobje urea. Entry 45: 4-Chloro-A7-methyl-2-pyridinecarboxamide is synthesized according to Method A2, Step 3a, reacted with 3-aminophenyl according to Method A2, Step 4, to form 3-(2-(N-methylcarbamoyl) )-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline to give urea.

Ulaz 46: 5-(4-aminofenoksi)izoindolin-1,3-dion sintetizira se u skladu s Metodom A3 . U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 5-(4-aminofenoksi)izoindolin-1,3-dionom, da se dobije urea. Entry 46: 5-(4-aminophenoxy)isoindoline-1,3-dione is synthesized according to Method A3. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to give urea.

Ulaz 47: 4-(2-(AT-metilkarbamoil)-4-piridiloksi)-2-metilanilin sintetizira se u skladu s Metodom A5. U skladu s Metodm C1c, 4-klor-3-(trifluormetil)fenil izocianat reagira s 5-(4-aminofenoksi)izoindolin-1, 3-dionom, da se dobije urea. Entry 47: 4-(2-(AT-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. According to Method C1c, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to give urea.

Ulaz 48: 4-(B-N-metilsulfamoil)feniloksi)anilin sintetizira se u skladu s Metodom A15. U skladu s Metodom C1a 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-N-metilsulfamoil)feniloksi)anilinom, da se dobije urea. Entry 48: 4-(B-N-methylsulfamoyl)phenyloxy)aniline is synthesized according to Method A15. In accordance with Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to obtain urea.

Ulaz 49: 4-(3-N-metilsulfamoil)-4-piridiloksi)-2-kloranilin sintetizira se u skladu s Metodom A6. U skladu s Metodom C1a 4-klor-3-(trifluormetil) fenil izocianat reagira s 4-(2-N-metilkarbamoil)-4-piridiloksi)-2-kloranilinom, da se dobije urea. Entry 49: 4-(3-N-methylsulfamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to give urea.

Ulaz 50: U skladu s Metodom A2, Korak 4, 5-amino-2-metilfenol reagira s 4-klor-N-metil-2-piridinkarboksamidom, koji je sintetiziran u skladu s Metodom A2, Korak 3b, dobije se 3-(2-(N-metilkarbamoil)-4-piridiloksi)-4-metilanilin. U skladu s Metodom C1a; 4-klor-3-(trifluorometil)fenil izocianat reagira s 3-(2-(N-metilkarbamoil)-4-piridiloksi)-4-metilanilinom, da se dobije urea. Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3b, to give 3-( 2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. In accordance with Method C1a; 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to give urea.

Ulaz 51: 4-klorpiridin-2-karbonil klorid reagira s etilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-kloro-N-etil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 i dobije se 4-(2-(N-etilkarbamoil)-4-piridiloksi)anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat koji reagira s 4-(2-(N-etilkarbamoil)-4-piridiloksi) anilinom, da se dobije urea. Entry 51: 4-chloropyridine-2-carbonyl chloride is reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy) aniline to give urea.

Ulaz 52: U skladu s Metodom A2, Korak 4, 4-amino-2-klorfenol reagira s 4-klor-A7-metil-2-piridinkarboksamidom, koji je sintetiziran u skladu s Metodom A2, Korak 3b, dobije se 4-(2-(N-metilkarbamoil)-4-piridiloksi)-4-kloranilin. U skladu s Metodom C1a; 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)-4-kloranilinom, da se dobije urea. Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-A7-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3b, to give 4-( 2-(N-methylcarbamoyl)-4-pyridyloxy)-4-chloroaniline. In accordance with Method C1a; 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-chloroaniline to give urea.

Ulaz 53: 4-(4-metiltiofenoksi)-1-nitrobenzen oksidira u skladu s Metodom A19, Korak 1 i dobije se 4-(4-metilsulfonilfenoksi)-1-nitrobenzen. Nitrobenzen se reducira u skladu s Metodom A19, Korak 2, da se dobije 4-(4-metilsulfonilfenoksi)-1-anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(4-metilsulfonilfenoksi)-1-anilinom, da se dobije urea. Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene is oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. Nitrobenzene is reduced according to Method A19, Step 2, to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to give urea.

Ulaz 54: 4-brombenzensulfonil klorid reagira s metilaminom u skladu s Metodom A15, Korak 1 da se dobije N-metil-4-brombenzensulfonamid. N-metil-4-brombenzensulfonamid se veže s fenolom u skladu s Metodom A15, Korak 2, da se dobije 4-(4-(N-metilsulfamoil)fenoksi)benzen. 4-(4-(N-metilsulfamoil)fenoksi) benzen se pretvara u 4-(4-(N-metil sulfamoil)fenoksi)-1-nitrobenzen u skladu s Metodom A15, Korak 3 . 4-(4-(N-metilsulfamoil)fenoksi)-1-nitrobenzen se reducira u 4-(4-(N-metilsulfamoil) fenoksi) anilin u skladu s Metodom A15, Korak 4. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-N-metilsulfamoil)fenoksi)anilinom, da se dobije urea. Entry 54: 4-Bromobenzenesulfonyl chloride is reacted with methylamine according to Method A15, Step 1 to give N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide is coupled with phenol according to Method A15, Step 2, to give 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-methylsulfamoyl)phenoxy)benzene is converted to 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(4-(N-methylsulfamoyl)phenoxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro -3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-N-methylsulfamoyl)phenoxy)aniline to give urea.

Ulaz 55: 5-hidroksi-2-metilpiridin se veže s 1-fluoro-4-nitrobenzenom u skladu s Metodom A18, Korak 1 pa se dobije 4-(5-(2-metil)piridiloksi)-1-nitrobenzen. Metilpiridin oksidira u skladu karboksilnom kiselinom, zatim esterificira u skladu s Metodom A18, Korak 2 da se dobije 4-(5-(2-metoksikarbonil)piridiloksi)-1-nitrobenzen. Nastali nitro-benzen se reducira u skladu s Metodom A18, Korak 3, da se dobije 4-(5-(2-metoksikarbonil)piridiloksi)anilin. Anilin reagira s 4-klor-3-(trifluorometil)fenil izocianatom u skladu s Metodom C1a, da se dobije urea. Entry 55: 5-hydroxy-2-methylpyridine is coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene. Methylpyridine is oxidized according to carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The resulting nitro-benzene is reduced according to Method A18, Step 3, to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. Aniline is reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1a to give urea.

Ulaz 56: 5-hidroksi-2-metilpiridin se veže s 1-fluor-4-nitrobenzenom u skladu s Metodom A18, Korak 1, pa se dobije 4-(5-(2-metil)piridiloksi)-1-nitrobenzen. Metilpiridin oksidira se u skladu karboksilnom kiselinom, zatim esterificira u skladu s Metodom A18, Korak 2, da se dobije 4-(5-(2-metoksikarbonil)piridiloksi)-1-nitrobenzen. Nastali nitrobenzen se reducira u skladu s Metodom A18, Korak 3, da se dobije 4-(5-(2-metoksikarbonil)piridiloksi)anilin. Anilin reagira s 4-klor-3-(trifluormetil)fenil izocianatom u skladu s Metodom C1a, da se dobije N-(4-klor-3-(trifluormetil)fenil)-N'-(4-(2-(metoksikarbonil)-5-piridiloksi)fenil) urea. Metil ester reagira s metilaminom u skladu s Metodom D2, da se dobije N-(4-klor-3-(trifluormetil)fenil)-N'-(4-(2-(metoksikarbamoil)-5-piridiloksi)fenil) urea. Entry 56: 5-hydroxy-2-methylpyridine is coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1, to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene. Methylpyridine is oxidized according to carboxylic acid, then esterified according to Method A18, Step 2, to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The resulting nitrobenzene is reduced according to Method A18, Step 3, to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. Aniline is reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1a, to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl) -5-pyridyloxy)phenyl)urea. The methyl ester is reacted with methylamine according to Method D2 to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbamoyl)-5-pyridyloxy)phenyl)urea.

Ulaz 57: N-(4-klor-3-(trif luormetil) fenil)-N'-(4-aminofenil) urea pripremi se u skladu s Metodom C1d. N-(4-klor-3-(trifluormetil)fenil)-N'-(4-aminofenil) urea veže se s mono-metilizoftalatom u skladu s Metodom D1a, da se dobije urea. Entry 57: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea was prepared according to Method C1d. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea is coupled with monomethylisophthalate according to Method D1a to give urea.

Ulaz 58: N-(4-klor-3-(trifluormetil)fenil)-N'-(4-aminofenil) urea pripremi se u skladu s Metodom C1d. AT-(4-klor-3-(trifluormetil)fenil)-N'-(4-aminof enil) urea veže se s mono-metilizoftalatom u skladu s Metodom D1a da se dobije N-(4-klor-3-(trifluorometil)fenil)-N'-(4-(3-metoksikarbonilfenil) karboksiaminofenil) urea. U skladu s Metodom D2, N-(4-klor-3-(trifluormetil) fenil)-N'-(4-(3-metoksikarbonilf enil) karboksi aminofenil) urea reagira s metilaminom, da se dobije odgovarajući metil amid. Entry 58: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea was prepared according to Method C1d. AT-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea is coupled with mono-methylisophthalate according to Method D1a to give N-(4-chloro-3-(trifluoromethyl) )phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea. According to Method D2, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea is reacted with methylamine to give the corresponding methyl amide.

Ulaz 59: 4-klorpiridin-2-karbonil klorid reagira s dimetilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-klor-N,N-dimetil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 i dobije se 4-(2-N,N-dimetilkarbamoil)-4-piridiloksi) anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N,N-dimetilkarbamoil)-4-piridiloksi) anilinom, da se dobije urea. Entry 59: 4-chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-N,N-dimethylcarbamoyl)-4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy) aniline to give urea.

Ulaz 60: 4-hidroksiacetofenon regira s 4-fluornitrobenzenom u skladu s Metodom A13, Korak 1, pa se dobije 4-(4-acetilfenoksi)nitrobenzen. Nitrobenzen reducira se u skladu s Metodom 13, Korak 4, pa se dobije 4-(4-acetilfenoksi)anilin, koji se pretvori u 4-(4-(1-(AT-metoksi) iminoetil) fenoksianilin sol HCl u skladu s Metodom A16. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat se reducira s 4-(4-acetilfenoksi)anilinom, da se dobije urea. Entry 60: 4-hydroxyacetophenone is reacted with 4-fluoronitrobenzene according to Method A13, Step 1, to give 4-(4-acetylphenoxy)nitrobenzene. Nitrobenzene is reduced according to Method 13, Step 4, to give 4-(4-acetylphenoxy)aniline, which is converted to 4-(4-(1-(AT-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16 According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reduced with 4-(4-acetylphenoxy)aniline to give urea.

Ulaz 61: 4-(3-karboksifenoksi)-1-nitrobenzen sintetizita se u skladu s Metodom A13, Korak 2. 4-(3-karboksifenoksi)-1-nitrobenzen veže se s 4-(2-aminofenil)morfolin u skladu s Metodom A13, Korak 3 da se dobije 4-(3-(N-(2-morfoliniletil)karbamoil)feniksi)-1-nitrobenzen. U skladu s Metodom A13, Korak 4, 4-(3-(N-(2-morfoliniletil) karbamoil)feniksi)-1-nitrobenzen se reducira u 4-(3-(N-(2-morfoliniletil)karbamoil)feniksi)anilin. U skladu s Metodom C1a 4-klor-3-(trifluormetil)fenil izocianat se reducira s 4-(3-(N-(2-morfoliniletil)karbamoil)feniksi)anilinom, da se dobije urea. Entry 61: 4-(3-carboxyphenoxy)-1-nitrobenzene is synthesized according to Method A13, Step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene is coupled with 4-(2-aminophenyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13, Step 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy) aniline. According to Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reduced with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to give urea.

Ulaz 62: 4-(3-karboksifenoksi)-1-nitrobenzen sintetizira se u skladu s Metodom A13, Korak 2. 4-(3-karboksifenoksi)-1-nitrobenzen veže se s 1-(2-aminoetil)piridinom u skladu s Metodom A13, Korak 3, da se 4-(3-(N-(2-piperidiletil)karbamoil)fenoksi)-1-nitrobenzen. U skladu s Metodom A13, Korak 4, 4-(3-(N-(2-piperidiletil) karbamoil)fenoksi)-1-nitrobenzen se reducira u 4-(3-(N-(2-piperidiletil)karbamoil)fenoksi)anilin. U skladu s Metodom C1a, 4-klor-3-(trifluorometil)fenil izocianat reagira s 4-(4-acetilfenoksi)anilinom, da se dobije urea. Entry 62: 4-(3-carboxyphenoxy)-1-nitrobenzene is synthesized according to Method A13, Step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene is coupled with 1-(2-aminoethyl)pyridine according to By Method A13, Step 3, that 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13, Step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy) aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(4-acetylphenoxy)aniline to give urea.

Ulaz 63. 4-(3-karboksifenoksi)-1-nitrobenzen sintetizira se u skladu s Metodom A13, Korak 2. 4-(3-karboksif enoksi)-1-nitrobenzen veže se s tetrahidrofurfurilaminom u skladu s Metodom A13, Korak 3 da se dobije 4-(3-(N-(tetrahidrofurilmetil)karbamoil)fenoksi)-1-nitrobenzen. U skladu s Metodom A13, Korak 4, 4-(3-(N-(tetrahidrofurilmetil)karbamoil)fenoksi)-1-nitrobenzen se reducira u 4-(3-(N-(tetrahidrofurilmetil)karbamoil) fenoksi)anilin. U skladu s Metodom C1a , 4-klor-3-(trif luormetil) fenil izocianat reagira s 4-(3-(N-(tetrahidrofurilmetil)karbamoil)fenoksi)anilinom, da se dobije urea. Entry 63. 4-(3-Carboxyphenoxy)-1-nitrobenzene is synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene is coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene is obtained. According to Method A13, Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline to give urea.

Ulaz 64: 4-(3-karboksifenoksi)-1-nitrobenzen sintetizira se u skladu s Metodom A13, Korak 2. 4-(3-karboksifenoksi)-1-nitrobenzen veže se s 2-aminometil-1-etilpirolidinom u skladu s Metodom A13, Korak 3 da se dobije 4-(3-(N-((1-metilpirolidinil) metil) karbamoil)fenoksi)-1-nitrobenzen. U skladu s Metodom A13, Korak 4, 4-(3-(N-((1-metilpirolidinil)metil)karbamoil)fenoksi)-1-nitrobenzen se reducira u 4-(3-(N-((1-metilpirolidinil)metil)karbamoil)fenoksi)anilin. U skaladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat regira s 4-(3-(N-((1-metilpirolidinil) metil)karbamoil)fenoksi)anilinom, da se dobije urea. Entry 64: 4-(3-carboxyphenoxy)-1-nitrobenzene is synthesized according to Method A13, Step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene is coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((1-methylpyrrolidinyl) methyl) carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13, Step 4, 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-((1-methylpyrrolidinyl) methyl)carbamoyl)phenoxy)aniline. In a cascade with Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to give the urea.

Ulaz 65: 4-klor-N-metilpiridinkarboksamid sintetizira se kao što je opisano u Metodi A2, Korak 3b. Klorpiridin reagira s 4-aminotiofenolom u skladu s Metodom A2, Korak 4, da se dobije 4-(4-(2-(N-metilkarbamoil)feniltio)anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-(N-((1-metilpirolidinil) metil)karbamoil)fenoksi)anilinom, da se dobije urea. Entry 65: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in Method A2, Step 3b. Chloropyridine is reacted with 4-aminothiophenol according to Method A2, Step 4, to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl) phenyl isocyanate reacts with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to give urea.

Ulaz 66: 4-klorpiridin-2-karbonil klorid reagira s izopropilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-klor-N-izopropil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 da se dobije 4-(2-(N-izopropilkarbamoil)-4-piridiloksi) anilin. U skladu s Metodom C1a, 4-kloro-3-(trifluorometil)fenil izocianat reagira s 4-(2-(N-izopropilkarbamoil)-4-piridiloksi) anilinon, da se dobije urea. Entry 66: 4-chloropyridine-2-carbonyl chloride is reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy) anilinone to give urea.

Ulaz 67: 4-klor-3-(trifluormetil)fenil-N'-(4-etoksikarbonil fenil) urea se sintetizira u skladu s Metodom C1e, 4-klor-3-(trifluormetil) fenil-N'-(4-etoksikarbonilfenil) urea sapinificira se u skladu s Metodom D3, i dobije se N-(4-klor-3-(trifluormetil)fenil-N'-(4-karboksifenil) urea. N-(4-klor-3-(trifluormetil)fenil-N'-(4-karboksifenil) urea se veže s 3-metilkarbamoilanilinom u skladu s Metodom D1b, da se dobije 4-klor-3-(trifluormetil)fenil-N'-(4-(-metil karbonilfenilfenil)karbamoilfenil) urea. Entry 67: 4-chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl)urea is synthesized according to Method C1e, 4-chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) ) urea is sapinified according to Method D3, and N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea is obtained. N-(4-chloro-3-(trifluoromethyl)phenyl) -N'-(4-carboxyphenyl)urea is coupled with 3-methylcarbamoylaniline according to Method D1b to give 4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(-methylcarbonylphenylphenyl)carbamoylphenyl)urea .

Ulaz 68: 5-(4-aminofenoksi)-2-metilizoindolin-1,3-dion sintetizira se u skladu s Metodom A9. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 5-(4-aminofenoksi)-2-metilizoindolin-1,3-dionom, da se dobije urea. Entry 68: 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to give urea.

Ulaz 69: 4-klor-N-metilpiridinkarboksamid sintetizira se kako je opisano u Metodi A2, Korak 3b. Klorpiridin reagira s 3-aminotiofenolom u skladu s metodom A2, Korak 4, da se dobije 3-(4-(2-(N-metilkarbamoil) feniltio) anilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 3-(4-(2-(N-metilkarbamoil)feniltio) anilin da se dobije urea. Entry 69: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in Method A2, Step 3b. Chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4, to give 3-(4-(2-(N-methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl) phenyl isocyanate reacts with 3-(4-(2-(N-methylcarbamoyl)phenylthio) aniline to give urea.

Ulaz 70: 4-(2-(N-(2-morfolin-4-iletil)karbamoil)piridil oksi)anilin sintetizira se u skladu s Metodom A10. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N-(2-morfolin-4-iletil)karbamoil)piridil oksi)anilinom,da se dobije urea. Entry 70: 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to give urea.

Ulaz 71: 4-(3-(5-metoksikarbonil)piridiloksi)anilin sintetizira se u skladu s Metodom A14. 4-klor-3-(trifluormetil)-2-metoksifenil izocianat reagira s 4-(3-(5-metoksikarbonil)piridiloksi)anilinom u skladu s Metodom C1a da se dobije urea. N-(4-klor-3-(trifluormetil)-2-metoksifenil-N'-4-(3-(5-metoksikarbonilpiridil) oksi)fenil urea se saponificira u skladu s Metodom D4, Korak 1, i veže se s odgovarajućom kiselinom s 4-(2-aminoetil)morfolinom, da se dobije amid. Entry 71: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline is synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to give urea. N-(4-chloro-3-(trifluoromethyl)-2-methoxyphenyl-N'-4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl urea is saponified according to Method D4, Step 1, and coupled with the appropriate acid with 4-(2-aminoethyl)morpholine to give the amide.

Ulaz 72: 4-(3-(5-metoksikarbonil)piridiloksi)anilin sintetizira se u skladu s Metodom A14. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-(5-metoksikarbonil) piridiloksi)anilinom u skladu s Metodom C1a, da se dobije urea. N-(5-(trifluormetil)-2-metoksifenil-N'-4-(3-(5-metoksi karbonilpiridil)oksi)fenil) urea se saponificira u skladu s Metodom D4, Korak 1, i odgovarajuća kiselina veže se s metilaminom u skladu s Metodom D4, Korak 2, da se dobije amid. Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to give urea. N-(5-(trifluoromethyl)-2-methoxyphenyl-N'-4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with methylamine according to Method D4, Step 2, to give the amide.

Ulaz 73 : 4-(3-(5-metoksikarbonil)piridiloksi)anilin sintetizira se u skladu s Metodom A14. 4-klor-3-(trifluorometil)fenil izocianat reagira s 4-(3-(5-metoksikarbonil) piridiloksi) anilinom u skladu s Metodom C1a, da se dobije urea. N-(5-(trifluorometil)-2-metoksifenil-N'-4-(3-(5-metoksikarbonilpiridil)oksi)fenil) urea se saponificira u skladu s Metodom D4, Korak 1, i veže se s odgovarajućom kiselinom s N,N-dimetiletilendiaminom u skladu s Metodom D4, Korak 2 da se dobije amid. Entry 73 : 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline is synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to give urea. N-(5-(trifluoromethyl)-2-methoxyphenyl-N'-4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to Method D4, Step 1, and coupled with the appropriate acid with N ,N-dimethylethylenediamine according to Method D4, Step 2 to give the amide.

Ulaz 74: 4-klorpiridin-2-karbonil klorid sol HCl reagira s 2-hidroksietilaminom u skladu s Metodom A2, Korak 3b u oblik 4-klor-N-(2-triziopropilsiloksi)etilpiridin-2-karbo-ksamid. 4-klor-N-(2-triziopropilsililoksi)etilpiridin-2-karbo-ksamid reagira s triizopropilsilil kloridom nakon s 4-aminofenol u skladu s Metodom A17 u oblik 4-(4-(2-(N-(2-triizopropilsililoksi)etilkarbamoil)piridiloksianilin. U skladu s Metodom C1a, 4-klor-3-(trifluorometil)fenil izocianat reagira s 4-(4-(2-(N-(2-triizopropilsililoksi)etilkarbamoil)piridiloksianilin da se dobije N-(4-klor-3-((trifluormetil) fenil)-N-(4-(4-(2-(N-(2-etilkarbamoil) piridiloksifenil) urea. Entry 74: 4-chloropyridine-2-carbonyl chloride salt HCl is reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-trisiopropylsiloxy)ethylpyridine-2-carboxamide. 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide reacts with triisopropylsilyl chloride followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyaniline According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-(4- chloro-3-((trifluoromethyl)phenyl)-N-(4-(4-(2-(N-(2-ethylcarbamoyl)pyridyloxyphenyl)urea).

Ulaz 75: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-(5-metoksikarbonil) piridil-oksi)anilin u skladu s Metodom C1f, pa se dobije urea, koja se veže s 3-aminopiridinom u skladu s Metodom D1c. Entry 75: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyl-oxy)aniline according to Method C1f, resulting in urea, which binds with 3-aminopyridine according to Method D1c.

Ulaz 76: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-karboksimetoksi)anilinom u skladu s Metodom C1f, pa se dobije urea, koja se veže s N-(4-acetilfenil)piperazinom u skladu s Metodom D1c. Entry 76: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxymethoxy)aniline in accordance with Method C1f, and urea is obtained, which binds with N-(4-acetylphenyl)piperazine in accordance with Method D1c.

Ulaz 77: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-karboksifenoksi)anilinom u skladu s Metodom C1f, pa se dobije urea, koja se veže s 4-fluoranilinom u skladu s Metodom D1c. Entry 77: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to Method C1f, resulting in urea, which binds with 4-fluoroaniline according to Method D1c.

Ulaz 78: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-(5-karboksifenolsi)anilinom u skladu s Metodom C1f pa se dobije urea, koja se veže s 4-(dimetilamino)anilinom u skladu s Metodom D1c. Entry 78: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(5-carboxyphenolsi)aniline according to Method C1f and urea is obtained, which binds with 4-(dimethylamino)aniline according to Method D1c.

Ulaz 79: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-(5-karboksifenolsi)anilinom u skladu s Metodom C1f pa se dobije urea, koja se veže s N-feniletilendiaminom u skladu s Metodom D1c. Entry 79: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(5-carboxyphenolsi)aniline in accordance with Method C1f and urea is obtained, which binds with N-phenylethylenediamine in accordance with Method D1c.

Ulaz 80: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-karboksifenolsi)anilinom u skladu s Metodom C1f, pa se dobije urea, koja se veže s 2-metoksietilaminom u skladu s Metodom D1c. Entry 80: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenolsi)aniline according to Method C1f, resulting in urea, which is bound with 2-methoxyethylamine according to Method D1c.

Ulaz 81: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(3-(5-karboksifenolsi)anilinom u skladu s Metodom C1f pa se dobije urea, koja se veže s 5-amino-2-metoksipiridinom u skladu s Metodom D1 Entry 81: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(5-carboxyphenolsi)aniline in accordance with Method C1f and urea is obtained, which binds with 5-amino-2-methoxypyridine in accordance with Method D1

c. c.

Ulaz 82: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira 4-(3-karboksifenolsi)anilinom u skladu s Metodom C1f pa se dobije urea, koja se veže s 4-morfolinanilinom u skladu s Metodom D1c. Entry 82: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenolsi)aniline according to Method C1f and urea is obtained, which binds with 4-morpholinaniline according to Method D1c.

Ulaz 83: 4-(3-karboksifenoksi)anilin sintetizira se u skladu s Metodom A11. 4-klor-3-(trifluormetil)fenil izocianat reagira 4-(3-karboksifenolsi)anilinom u skladu s Metodom C1f, pa se dobije urea, koja se veže s N-(2-piridil)piperazinom u skladu s Metodom D1c. Entry 83: 4-(3-carboxyphenoxy)aniline is synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenolsi)aniline in accordance with Method C1f, and urea is obtained, which binds with N-(2-pyridyl)piperazine in accordance with Method D1c.

Ulaz 84: 4-klorpiridin-2-karbonil klorid sol HCl regaira s 2-hidroksietilaminom u skladu s Metodom A2, Korak 3b u oblik 4-klor-N-(2-triizopropil sililoksi) etilpiridin-2-karboksamid. 4-klor-N-(2-triizopropil sililoksi)etilpiridin-2-karboksamid reagira s triizopropilsilil kloridom, nakon 4-aminofenola u skladu s Metodom A17 u oblik 4-(4-(2-(N-(2-triizopropilsililoksi)etilkarbamoil)piridil oksianilin. U skladu s Metodom C1a, 4-klor-3-(trifluormetil)fenil izocianat reagira s 4-(4-(2-(N-(2-triizopropilsililoksi) etilkarbamoil)piridil oksianilinom da se dobije N-(4-klor-3-((trifluormetil)fenil)-N'-4-(4-(2-(N-(2-triizopropilsilil oksi)etilkarbamoil)piridiloksifenil)urea. Urea se deprotek-tira u skladu s Metodom D5 da se dobije N-(4-klor-3-((trifluormetil)fenil)-N-4-(4-(2-(N-(2-hidroksi) etil karbamoil)piridiloksifenil) urea. Entry 84: 4-chloropyridine-2-carbonyl chloride salt HCl reacts with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide reacts with triisopropylsilyl chloride, after 4-aminophenol in accordance with Method A17 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl) )pyridyloxyaniline According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-(4 -chloro-3-((trifluoromethyl)phenyl)-N'-4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)urea. Urea is deprotected according to Method D5 to gives N-(4-chloro-3-((trifluoromethyl)phenyl)-N-4-(4-(2-(N-(2-hydroxy) ethyl carbamoyl) pyridyloxyphenyl) urea.

Ulaz 85: 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilin sintetizira se u skladu s Metodom A2. 4-brom-3-(tri fluormetil)anilin se pretvara u 4-brom-3-(trifluor metil)fenil izocianat u skladu s Metodom BI. U skadu s Metodom C1a, 4-bromo-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilinom, da se dobije urea. Entry 85: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline is synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method BI. In accordance with Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 86: 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloranilin sintetizira se u skladu s Metodom A6. 4-brom-3-(trifluormetil)anilin pretvara se u 4-brom-3-(tri fluor metil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-brom-3-(trifluormetil)fenil izocianat reagira s 4-(2-(AT-metilkarbamoil)-4-piridiloksi)-2-klor anilinom, da se dobije urea. Entry 86: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(AT-methylcarbamoyl)-4-pyridyloxy)-2-chloro aniline to give urea.

Ulaz 87: U slakdu s Metodom A2, Korak 4, 4-amino-2-klorfenol regira s 4-klor-N-metil-2-piridinkarboksamidom , koji je sintetiziran u skladu s Metodom A2, Korak 3b, pa se dobije 4-(2-(N-metilkarbamoil)-4-piridiloksi)-3-kloranilin. 4-brom-3-(trifluormetil)anilin se pretvara u 4-brom-3-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, u 4-brom-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)-3-kloranilinom, da se dobije urea. Entry 87: In accordance with Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3b, to give 4- (2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to give urea.

Ulaz 88: 4-klorpiridin-2-karbonil klorid reagira s etilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-klor-N-etil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4 pa se dobije 4-(2-(N-etilkarbamoil)-4-piridiloksi) anilin. 4-brom-3-(trifluormetil)anilin se pretvara u 4-brom-3-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-brom-3-(trifluormetil) fenil izocianat reagira s 4-(2-(N-etilkarbamoil)-4-piridiloksi)anilinom da se dobije urea. Entry 88: 4-chloropyridine-2-carbonyl chloride is reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol in accordance with Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy) aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 89: 4-klor-N-metil-2-piridinkarboksamid, koji je sintetizitan u skladu s Metodom A2, Korak 3a, reagira s 3-aminofenolom u skladu s Metodom A2, Korak 4 da se dobije oblik 3-(2-(N-metilkarbamoil)-4-piridiloksi) anilin. 4-brom-3-(trifluormetil)anilin pretvara se u 4-brom-3-(trifluor metil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a 4-brom-3-(trifluormetil)fenil izocianat reagira s 3-(2-(N-metilkarbamoil)-4-piridil oksi) anilin, da se dobije urea. Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, is reacted with 3-aminophenol according to Method A2, Step 4 to give the form 3-(2-( N-methylcarbamoyl)-4-pyridyloxy) aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. In accordance with Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 90: U skladu s Metodom A2, Korak 4, 5-amino-2-metilfenol reagira s 4-klor-N-metil-2-piridinkarboksamidom, koji je sintetiziran u skladu s Metodom A2, Korak 3b, pa se dobije 3-(2-(N-metilkarbamoil)-4-piridiloksi)-4-metil anilin. 4-brom-3-(trifluormetil)anilin se pretvara u 4-brom-3-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a 4-brom-3-(trifluormetil)fenil izocianat reagira s 3-(2-(N-metilkarbamoil)-4-piridiloksi) anilinom, da se dobije urea. Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3b, to give 3- (2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methyl aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline to give urea.

Ulaz 91: 4-klorpiridin-2-karbonil klorid reagira s dimetilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-klor-N,N-dimetil-2-piridinkarboksamid reagira s 4-amino fenolom u skladu s Metodom A2, Korak 4 pa se dobije 4-(2-(N,N-dimetilkarbamoil)-4-piridiloksi) anilin. 4-brom-3-(trifluormetil)anilin se pretvara u 4-brom-3-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-brom-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N,N-etilkarbamoil)-4-piridil oksi)anilinom, da se dobije urea. Entry 91: 4-chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol in accordance with Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy) aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N,N-ethylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 92: Sinteza 4-klor-N-metilpiridinkarboksamida opisana je u Metodi A2, Korak 3b. Klorpiridin reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4, pa se dobije 4-(4-(2-(N-metilkarbamoil)feniltio)anilin. 4-brom-3-(tri fluormetil)anilin se pretvara u 4-brom-3-(trifluor metil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-brom-3-(trifluormetil)fenil izocianat reagira s 4-(4-(2-(N-metilkarbamoil)feniltio)anilinom, da se dobije urea. Entry 92: The synthesis of 4-chloro-N-methylpyridinecarboxamide is described in Method A2, Step 3b. Chloropyridine is reacted with 4-aminophenol according to Method A2, Step 4, to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4 -bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1 In accordance with Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(4-(2-(N-methylcarbamoyl)phenylthio )aniline, to obtain urea.

Ulaz 93: Sinteza 4-klor-N-metilpiridinkarboksamida opisana je u Metodi A2, Korak 3b. Klorpiridin reagira s 3-aminofenolom u skladu s Metodom A2, Korak 4, pa se dobije 3-(4-(2-(N-metilkarbamoil) feniltio) anilin. 4-brom-3-(tri fluormetil)anilin se pretvara u 4-brom-3-(trifluor metil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-brom-3-(trifluormetil)fenil izocianat reagira s 3-(4-(2-(N-metilkarbamoil)feniltio)anilinom, da se dobije urea. Entry 93: The synthesis of 4-chloro-N-methylpyridinecarboxamide is described in Method A2, Step 3b. Chloropyridine is reacted with 3-aminophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4 -bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1 In accordance with Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(4-(2-(N-methylcarbamoyl)phenylthio )aniline, to obtain urea.

Ulaz 94: 4-(2-(N-(2-morfolin-4-iletil)karbamoil)piridil oksi)anilin sintetizita se u skladu s Metodom A10. 4-brom-3-(trifluormetil)anilin pretvara se u 4-brom-3-(trifluor metil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-brom-3-(trifluormetil)fenil izocianat reagira s 4-(2-(N-(2-morfolin-4-iletil)karbamoil)piridil oksi)anilinom, da se dobije urea. Entry 94: 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to give urea.

Ulaz 95: 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilin sintetizira se u skladu s Metodom A2. 4-klor-2-metoksi-5-(trifluormetil)anilin sintetizira se u skladu s Metodom A7. 4-klor-2-metoksi-5-(trifluormetil)anilin pretvara se u 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-klor-2-metoksi-5-(trifluorometil) fenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilinom i dobije se urea. Entry 95: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 96: 4-(2-(A7-metilkarbamoil)-4-piridiloksi)-2-klor anilin sintetizira se u skladu s Metodom A6. 4-klor-2-metoksi-5-(trifluormetil)anilin se sintetizira u skladu s Metodom A7 . 4-klor-2-metoksi-5-(trifluormetil)anilin pretvara se u 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-klor-2-metoksi-5-(trifluormetil) fenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)-2-kloranilinom i dobije se urea. Entry 96: 4-(2-(A7-methylcarbamoyl)-4-pyridyloxy)-2-chloro aniline was synthesized according to Method A6. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to give urea.

Ulaz 97: U skladu s Metodom A2, Korak 4, 4-amino-2-klorfenol reagira s 4-klor-N-metil-2-piridinkarboksamidom, koji je sintetiziran u skladu s Metodom A2, Korak 3b; i dobije se 4-(2-(N-metilkarbamoil)-4-piridiloksi)-3-klor anilin. 4-klor-2-metoksi-5-(trifluorometil)anilin sintetizira se u skladu s Metodom A7. 4-klor-2-metoksi-5-(trifluormetil)anilin pretvori se u 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s metodom C1a, 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat reagira s 4-(2-(N-metilkarbamoil)-4-piridiloksi)-3-kloranilinom da se dobije urea. Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3b; and 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloro aniline is obtained. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to give urea.

Ulaz 98: 4-klor-N-metil-2-piridinkarboksamid sintetiziran u skladu s Metodom A2, Korak 3b, reagira s 3-aminofenolom u skladu s Metodom A2, Korak 4, pa se dobije oblik 3-(2-(N-metilkarbamoil)-4-piridiloksi)anilin. 4-klor-2-metoksi-5-(trifluormetil)anilin sintetizira se u skladu s Metodom A7 . 4-klor-2-metoksi-5-(trifluormetil)anilin se pretvara u 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat reagira s 3-(2-(N-metilkarbamoil)-4-piridiloksi)anilinom, da se dobije urea. Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3b, is reacted with 3-aminophenol according to Method A2, Step 4, to form 3-(2-(N- methylcarbamoyl)-4-pyridyloxy)aniline. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate is reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 99: 4-klorpiridin-2-karbonil klorid reagira s etilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-klor-A7-etil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4, pa se dobije 4-(2-(N-etilkarbamoil)-4-piridiloksi)anilin. 4-klor-2-metoksi-5-(trifluormetil)anilin se sintetizira u skladu s Metodom A7. 4-klor-2-metoksi-5-(trifluormetil)anilin pretvara se 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-klor-2-metoksi-5-(trifluormetil) fenil izocianat reagira s 4-(2-(N-etilkarbamoil)-4-piridiloksi)anilinom da se dobije urea. Entry 99: 4-chloropyridine-2-carbonyl chloride is reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-A7-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to Method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Ulaz 100: 4-klorpiridin-2-karbonil klorid reagira s dimetilaminom u skladu s Metodom A2, Korak 3b. Nastali 4-klor-N,N-dimetil-2-piridinkarboksamid reagira s 4-amino fenolom u skladu s Metodom A2, Korak 4, pa se dobije 4-(2-(N,N-dimetilkarbamoil)-4-piridiloksi) anilin. 4-klor-2-metoksi-5-(trifluorometil)anilin sintetizira se u skladu s Metodom A7. 4-klor-2-metoksi-5-(trifluormetil)anilin pretvara se 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat u skladu s Metodom B1. U skladu s Metodom C1a, 4-klor-2-metoksi-5-(trifluormetil)fenil izocianat reagira s 4-(2-(N,N-dimetilkarbamoil)-4-piridiloksi) anilinom da se dobije urea. Entry 100: 4-chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy) aniline . 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to Method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate is reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy) aniline to give urea.

Ulaz 101: 4-klor-(N-metil-2-piridinkarboksamid sintetiziran u skladu s Metodom A2, Korak 3b, reagira s 3-aminofenolom u skladu s Metodom A2, Korak 4, da se dobije oblik 3-(2-(N-metilkarbamoil)-4-piridiloksi)anilin. Sinteza 2-amino-3-metoksinaftalena opisana je u Metodi A1. U skladu s Metodom C3 2-amino-3-metoksinaftalen regira s bis(triklormetil) karbonatom nakon 3-(2-(N-metilkarbamoil)-4-piridiloksi) anilinom u oblik uree. Entry 101: 4-Chloro-(N-methyl-2-pyridinecarboxamide) synthesized according to Method A2, Step 3b, is reacted with 3-aminophenol according to Method A2, Step 4, to give the form 3-(2-(N -methylcarbamoyl)-4-pyridyloxy)aniline. The synthesis of 2-amino-3-methoxynaphthalene is described in Method A1. In accordance with Method C3, 2-amino-3-methoxynaphthalene reacts with bis(trichloromethyl)carbonate after 3-(2-( N-methylcarbamoyl)-4-pyridyloxy) aniline to form urea.

Ulaz 102: 4-(2-(N-metilkarbamoil)-4-piridiloksi)anilin sintetizira se u skladu s Metodom A2 . 5-tert-butil-2-(2,5-dimetilpirolil)anilin sintetizira se u skladu s Metodom A4. 5-tert-butil-2-(2,5-dimetilpirolil)anilin reagira s CDI nakon 4-(2-(N-metilkarbamoil)-4-piridiloksi) anilina u skladu s Metodom C2d, da se dobije urea. Entry 102: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline is synthesized according to Method A2. 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline is synthesized according to Method A4. 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline is reacted with CDI after 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline according to Method C2d to give urea.

Ulaz 103: 4-klor-N-metil-2-piridinkarboksamid sintetiziran je u skladu s Metodom A2, Korak 3b. 4-klor-N-metil-2-piridinkarboksamid reagira s 4-aminofenolom u skladu s Metodom A2, Korak 4, upotrebom DMAC na mjesto DMF i dobije se 4-(2-(N-metilkarbamoil)-4-piridiloksi) anilin. U skladu s Metodom C2b, 3-amino-2-metoksikvinolin s CDI s regira s 4-(2-(N-metilkarbamoil)-4-piridiloksi) anilinom pa se dobije bis (4-(2-(N-metilkarbamoil)-4-piridiloksi) fenil urea. Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline. According to Method C2b, 3-amino-2-methoxyquinoline with CDI is treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline to give bis (4-(2-(N-methylcarbamoyl)- 4-pyridyloxy) phenyl urea.

Nabrojane supstancije u tablicama sintetizirane su u skladu s gore detaljiziranim postupcima. The listed substances in the tables were synthesized according to the procedures detailed above.

Tablice Tables

Supstancije navedene u tablicama 1-6 sintetizirane su u skladu s gore prikazanim općim metodama, a više detalja postupaka koji su navedeni kao primjeri su u popisu gore navedenih ulaza, a karakterizacija je pokazana u tablicama. The substances listed in Tables 1-6 were synthesized according to the general methods shown above, and more details of the procedures are exemplified in the list of inputs above, and the characterization is shown in the tables.

Tablica 1. 3-tert-butilfenil uree Table 1. 3-tert-butylphenyl urea

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Tablica 2. Table 2.

5-tert-butil-2-metoksi£enil uree 5-tert-butyl-2-methoxyphenyl urea

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Tablica 3. 5-(triflormetil)-2-metoksifenil uree Table 3. 5-(trifluoromethyl)-2-methoxyphenyl urea

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Tablica 4. 3-(trifluormetil)-4-klorfenil uree Table 4. 3-(trifluoromethyl)-4-chlorophenyl urea

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Tablica 5. 3-(trifluormetil)-4-bromfenil uree Table 5. 3-(trifluoromethyl)-4-bromophenyl urea

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Tablica 6. 5-(trifluormetil)-4-klor-2-metoksifenil uree Table 6. 5-(trifluoromethyl)-4-chloro-2-methoxyphenyl urea

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Tablica 7. Dodatne uree Table 7. Additional urea

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Prethodni primjeri mogu se ponoviti s istim posljedicama sa supstitucijom generičkih ili specifičnih opisanih reaktanata i/ili uvjeta provođenja ovih patenata za njihovo korištenje u prethodnim primjerima. The previous examples can be repeated with the same consequences with the substitution of generic or specific described reactants and/or conditions of implementation of these patents for their use in the previous examples.

Od gore opisanih, stručnjaci mogu lagano ustanoviti bitne karakteristike ovih pronalazaka i bez odstupanja od smisla i namjere, mogu se učiniti različite izmjene i modifikacije invencije te prilagođivanje za različite upotrebe i uvjete. From those described above, those skilled in the art can readily ascertain the essential characteristics of these inventions and without departing from the spirit and intent, various changes and modifications of the invention can be made and adaptations for different uses and conditions can be made.

Claims (67)

1. Spoj formule I: A - D – B (I) ili njegova farmaceutski prihvatljiva sol, naznačen time, da D je -NH-C(O)-NH- A je supstituirani dio od 40 ugljikovih atoma u formuli -L-(M-L')q, gdje L je 5 i 6 član cikličke strukture vezan direktno na D, L' obuhvaća supstituirani ciklički dio najmanje 5 članova, M je skupina koja povezuje i ima najmanje jedan atom, q je cjelina od 1-3, i svaka ciklička struktura od L i L' sadržava O -4 člana grupe koja sadržava dušik, kisik i sumpor, i B je supstituiran ili nesupstituiran, sve do tricikličog arila s najmanje 6-članom cikličnom strukturom koja direktno vezuje D koji sadržava 0-4 člana grupe koja sadržava dušik, kisik i sumpor, i da je L' supstituiran najmanje jednim supstituentom odabranim iz grupe koja sadržava –SO2Rx i -C(O)Rx i -C(NRy)Rz, Ry vodik ili ugljik koji se osniva na polovici sve do 24 atoma ugljika optimalno sadržava heteroatome odabrane između N, S i O i optimalno halosupstituiranih, do per halo, Rz je vodik ili ugljik koji se osniva na polovici sve do 30 atoma ugljika optimalno supstituiran halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S ili O i optimalno supstituiranih halogenom. Rx je Rz ili NRaRb gdje su Ra i Rb a) samostalni vodik ugljik na osnovi polovice sve do 30 atoma ugljika koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani helogenom, ili -OSi(Rf)3 gdje je Rf vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika koji optimalno sadržavaju heteroatome odabrane od N, S i O i optimalno supstituirane halogenom, vodikom i ugljikom na osnovu supstituenata sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom; ili b) Ra je Rb zajedničkog oblika s 5-7 članova heterocikličke strukture od 1-3 heteroatoma odabranih od N, Si O, ili supstituiranih 5-7 člana heterociklične strukture s 1-3 heteroatoma odabranih od N, S i O suptituiranih halogenom, hidroksi ili ugljikom na osnovu supstituenata sve do 24 ugljikova atoma, koji optimalno sadržavaju heteroatome odabrane od N, S i O i koji su optimalno supstituirani halogenom odabranim između N, S i O i optimalno su supstituirani s halogenom ili C) jedan od Ra ili Rb je -C(O)-, Cl-C5 divalentna alkilna skupina ili supstituirani Cl-C5 divalentna alkilna grupa je veza s polovicom L na oblik ciklične strukture s najmanje 5 članova naznačen time, da je supstituent supstituirane Cl-C5 divalentne alkilne skupine odabran iz skupine koja sadržava halogen, hidroksi i ugljik na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i oni su optimalno supstituirani halogenom; gdje je B supstituiran, L je supstituiran ili je L' dodatno supstituiran, a supstituent je odabran iz skupine koja sadržava halogen, sve do per-halo, i Wn, gdje je n 0-3; pri čemu je svaki W neovisno odabran iz skupine koja sadržava -CN, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7,-NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar i ugljik baziran na polovici sve do 24 atoma ugljika, optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiranih s jednim ili više supstituenata nasumce odabranih iz skupine koja sadržava -CN, -CO2R7, -C (O) R7, -C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, i halogena sve do per-halo, sa svakim R7 nasumce odabranim između H ili ugljika baziranim na osnovu polovice sve do 24 atoma ugljika, optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiranih s halogenom; pri čemu Q je -O-, -S-, -N (R7)-, -(CH2)m-, -C(O)-; -CH(OH)-; -(CH2)nO-, - (CH2)mS-, - (CH2)mN(R7)-, -O(CH2)m-CHXa-, -Cxa2, -S-(CH2)m- i -N(R7) (CH2)m-, gdje je m= 1-3 a Xa je halogen; i Ar je 5- ili 6-član aromatske strukture koji sadržava 0-2 člana odabrana iz skupine koja sadržava, dušik, kisik i sumpor, koji su optimalno supstituirani halogenom, sve do per-halo, i optimalno supstituirani s Zn1, pri čemu ni je 0 do 3 i svaki Z je neovisno odabran iz skupine koja sadržava -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, -SR7, -NR7R7, -NR7 C(O)OR7, NRC(O)R ,i ugljik baziran na osnovu polovice sve do 24 atoma ugljika, optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiranih s jednim ili više supstituenata iz skupine koja sadržava: -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7 i -NR7C(O)OR7, sa R7 kao što je gore definirano,1. Compound of formula I: A - D - B (I) or a pharmaceutically acceptable salt thereof, characterized in that D is -NH-C(O)-NH- A is a substituted part of 40 carbon atoms in the formula -L-(M-L')q, where L is the 5 and 6 member of the cyclic structure attached directly to D, L' comprises a substituted cyclic moiety of at least 5 members, M is a linking group having at least one atom, q is a group of 1-3, and each cyclic structure of L and L' contains O -4 group members which contains nitrogen, oxygen and sulphur, i B is substituted or unsubstituted, up to a tricyclic aryl with at least a 6-membered ring structure directly attached to D containing 0-4 members of a nitrogen, oxygen, and sulfur containing group, and that L' is substituted by at least one substituent selected from the group consisting of –SO2Rx and –C(O)Rx and –C(NRy)Rz, Ry hydrogen or carbon that is based on half of up to 24 carbon atoms optimally contains heteroatoms selected from N, S and O and optimally halosubstituted, up to per halo, Rz is hydrogen or carbon based on half of up to 30 carbon atoms optimally substituted with halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S or O and optimally substituted with halogen. Rx is Rz or NRaRb where Ra and Rb are a) independent hydrogen carbon based half up to 30 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based substituent up to 24 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally are substituted by halogen, or -OSi(Rf)3 where Rf is hydrogen or carbon based on half up to 24 carbon atoms which optimally contain heteroatoms selected from N, S and O and optimally substituted with halogen, hydrogen and carbon based on substituents up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted by halogen; or b) Ra is Rb of the common form with 5-7 members of the heterocyclic structure of 1-3 heteroatoms selected from N, Si O, or substituted 5-7 members of the heterocyclic structure with 1-3 heteroatoms selected from N, S and O substituted with halogen, hydroxy or by carbon based on substituents up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and which are optimally substituted with halogen selected from N, S and O and are optimally substituted with halogen or C) one of Ra or Rb is -C(O)-, a Cl-C5 divalent alkyl group or a substituted Cl-C5 divalent alkyl group is a bond with half of L on the form of a cyclic structure with at least 5 members indicated by the fact that the substituent of the substituted Cl -C5 divalent alkyl group selected from the group containing halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and they are optimally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, and the substituent is selected from the group containing halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7 . -CO2R7, -C(O)R7, -C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, and halogens up to per-halo , with each R7 randomly selected from H or carbon based on half of up to 24 carbon atoms, optimally containing heteroatoms selected from N, S, and O and optimally substituted with halogen; wherein Q is -O-, -S-, -N (R7)-, -(CH2)m-, -C(O)-; -CH(OH)-; -(CH2)nO-, - (CH2)mS-, - (CH2)mN(R7)-, -O(CH2)m-CHXa-, -Cxa2, -S-(CH2)m- and -N(R7 ) (CH2)m-, where m= 1-3 and Xa is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen, and sulfur, which are optimally substituted with halogen, up to per-halo, and optimally substituted with Zn1, where neither is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, -SR7, -NR7R7, -NR7 C(O )OR7, NRC(O)R, and carbon based on half of up to 24 carbon atoms, with an optimal content of heteroatoms selected from N, S, and O and optimally substituted with one or more substituents from the group consisting of: -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7 and -NR7C(O)OR7, with R7 as defined above, 2. Spoj prema zahtjevu 1, naznačen time, da: Ry je vodik, C1-10 alkil, C1-10 alkoksi, C3-10 cikloalkil ima 0-3 heteroatoma, C2-10 alkenil, C1-10alkenoil, C6.12 aril, C3-12 hetaril ima 1-3 heteroatoma odabrana između N, S i O, C7-24 aralkil, C7-24 alkaril, supstituirani C1-10 alkil, supstituirani C1-10alkoksi, supstituirani C3-10 cikloalkil ima 0-3 heteroatoma odabrana između N, S i O, supstituirani C6-14 aril, supstituirani C3-12 hetaril, ima 1-3 heteroatoma odabrana između N, S i O, supstituirani C7-24 aralkil gdje Ry je supstituirana skupina, s halogenom sve do per halo, Rz je vodik, C1-10 alkil, C1-10 alkoksi, C3-10 cikloalkil i ima 0-3 heteroatoma, C2.10 alkenil, C1-10alkenoil, C6-12 aril, C3-C12 hetaril i ima 1-3 heteroatoma odabrana između S, N i O, C7-24 alkar il, C7-24 aralkil, supstituirani C1-10 alkil, supstituirani C1.10 alkoksi, supstituirani C6-C14 aril, C3 -C10 cikloalkil ima 0-3 heteroatoma odabrana između S, N i O, C3-C12 hetaril ima 1-3 heteroatoma odabrana između S, N i O, supstituirani C7-24 alkaril ili supstituirani C7-24 aralkil gdje je Rz supstituirana skupina, ona je supstituirana halogenom do per halo, vodikom, C1-10 alkil, C3-12 cikloalkil ima 0-3 heteroatoma odabrana između O, S i N, C3-C12 hetaril ima 1-3 heteroatoma odabranih između N, S i O, C1-10, alkoksi, C6-12 aril, C1-6 halo supstituirani alkil sve do per halo, C6-12 halo supstituirani aril sve do per halo aril, C3 -C12 halo supstituirani cikloalkil sve do per halo cikloalkil ima 0-3 heteroatoma odabrana između N, S i O, halo supstituirani C3-12 hetaril sve do per halo hetaril ima 1-3 heteroatoma odabrana između O, N i O, halo supstituirani C7 -C24 aralkil sve do per halo aralkil, halo supstituirani C7-C24 alkaril sve do per halo alkaril, i -C(O)Rg. Ra i Rb su a) samostalni vodik ugljik na osnovu odabranog od skupine koja sadržava ci-cio alkil, C1-C10 alkoksi, C3-C10 cikloalkil, C2-C10 alkenil, C1.C10 alkenoil, C6-12 aril, C3-C12 hetaril ima 1-3 heteroatoma odabranih između O, N i S, C3-12 cikloalkil ima 0-3 heteroatom odabrana između N, S i O, C7-24 aralkil, C7-C24 alkaril, supstituirani C1.10 alkil, supatituirani C1-10 alkoksi, C3-10 cikloalkil, ima 0-3 heteroatoma odabrana između N, S i O, supstituirani C6-12 aril, supstituirani C3-12 hetaril ima 1-3 heteroatoma odabranih između N, S i O, supstituirani C7-24 aralkil, gdje su Ra i Rb supstituirajuće skupine, one su supstituirane halogenom sve do per halo, vodik, C1-10 alkil, C3-C12 cikloalkil ima 0-3 heteroatoma odabranih između S, N i O, C3-C12 hetaril ima 1-3 heteroatoma odabranih između O, S, i N, C3-C12 hetaril ima 1-3 heteroatoma odabrana između N, S i O, C1-10 alkoksi, C6-12 arila, C1-6halo supstituirana alkil skupina sve do per halo alkil, C6-C12 halo supstituiran aril sve do per halo aril, C3-C12 halo supstituiran cikloalkil ima 0-3 heteroatoma odabrana između N, S i O, sve do per halo cikloalkil, halo supstituiran C3-C12 hetaril sve do per halo hetaril, halo supstituirani C7-C24 aralkil sve do per halo aralkil, halo supstituirani C7-C24 alkaril sve do per halo alkaril, i -C(O)Rg; ili -OSi(Rf)3 gdje je Rf vodik, C1-10 alkil, C1-10 alkoksi, C3-10 cikloalkil ima 0-3 heteroatoma odabrana između O, S i N, C6-12 aril, C3-C12 hetaril ima 1-3 heteroatoma odabranih između O , S i N, C7-24 aralkil, supstituirani C1-10 alkil, supstituirani C1-10 alkoksi, C3-C12 cikloalkil ima 0-3 heteroatoma odabranih između O, S i N, supstituirani C3-C12 heteraril ima 1-3 heteroatoma odabranih između O, S i N, supstituirani C6-12 aril, i sipstituirani C7-C24 alkaril, gdje je Rf supstituirajuda skupina, ona je supstituirana halogenom sve do per halo, vodik, C1-10 alkil, C3 -C12 cikloalkil ima 0-3 heteroatoma odabranih između O, S i N, C1-10 alkoksi, C6-12 aril, C7-C24 alkaril, C7-C24 aralkil, C1-6 halo supstituirani alkil sve do per halo alkil; C6-12 halo supstituirani aril sve do per halo aril, C3-C12 halo supstituirani cikloalkil ima 0-3 hetroatoma odabranih između N, S i O; sve do per halo cikloalkil, halo supstituirani C3-C12 hetaril sve do per halo hetaril, halo supstituirani C7-C24 aralkil sve do per halo aralkil, halo supstituirani C7-C24 aralkil sve do per halo aralkil, i -C(O)Rg; ili b) Ra je Rb zajedničkog oblika s 5-7 članova heterocikličke strukture od 1-3 heteroatoma odabranih od N, Si O, ili supstituiranih 5-7 člana heterociklične strukture s 1-3 heteroatoma odabranih od N, S i O s supstituentom iz skupine koja sadržava halogen sve do per halo, hidroksi, C1-10 alkil, C3-C12 cikloalkil ima 0-3 heteroatoma odabrana između O, S i N, C3-12 hetaril ima 1-3 heteroatoma odabrana između N, S i O, C1-10 alkoksi, C6-12 aril, C7-24 alkaril, C7-24 aralkil, halo supstituirani C1-6 alkil sve do per halo alkil, halo supstituirani C6-12 aril sve do per halo aril, halo supstituiran C3-C12 cikloalkil ima 0-3 heteroatoma odabranih između N, S i O, sve do per hako cikloalkil, halo supstituirani C3-C12 hetaril sve do per halo hetaril, halo supstituirani C7-C24 aralkil sve do per halo aralkil, halo supstituirani C7-C24 alkaril sve do per halo alkaril, i -C(O)Rg; ili c) jedan od Ra ili Rb je -C(O)-, C1-C5 divalentna alkilen skupina ili supstituirana C1-C5 divalentna alkilen skupina povezana s polovicom L oblika ciklične strukture s najmanje 5 članova pri čemu je supstituent supstituirane C1-C5 divalentne alkilen skupine odabran iz skupine koja sadržava halogen, hidroksi, C1-10 alkil, C3-12 cikloalkil ima 0-3 heteroatoma odabranih između O, S i N, C3-C12 hetaril ima 1-3 heteroatoma odabranih između N, S i O, C1-10 alkoksi, C6-12 aril, C7-24 alkaril, C7-24 aralkil, C1-6 halo supstituirani alkil sve do per halo alkil, C6.12 halo supstituirani aril sve do per halo aril, C3-C12 halo supstituiran cikloalkil ima 0-3 heteroatoma odabranih između N, S i O, sve do per halo cikloalkil, halo supstituirani C3-C12 hetaril sve do per halo hetaril, halo supstituirani C7-C24 aralkil sve do per halo aralkil, halo supstituirani C7-C24 alkaril sve do per halo alkaril, i -C(O)Rg; gdje je Rg C1-10 alkil; -CN, -CO2R7, -ORd, -SRd, -NO2, -C(O)Re, -NRdRe, NRdC(O)ORe, i -NRdC(O)Re i Rd i Re su neovisno odabrani iz skupine koja sadržava vodik, C1-10 alkil, C1-10 alkoksi, C3-C10 cikloalkil koji ima 0-3 atoma odabrana između O, N i S, C6-C12 aril, C3 -C12 hetaril koji ima 1-3 heteroatoma odabranih između O, N i S, C7-24 aralkil, C7-24 arkalil, sve do per halo supstituirani C1.10 alkil, sve do halo supstituiranog C3-C10 cikloalkil ima 0-3 heteroatoma odabranih između O, N i S, C6-C14 aril, sve do per halo supstituirani C3-C12 hetaril koji ima 1-3 heteroatoma odabranih između O, N i S, halo supstituirani C7-C24 alkaril sve do per halo alkaril i sve do per halo supstituirani C7-C24 aralkil, W je neovisno odabran iz skupine koja sadržava -CN, -CO2R7, -C(O)NR7R7, -C (O)-R7, -NO2, -OR7, -SR7,-NR7R7, -NR7C(O)OR7, -NR7C(O)R7, C1-C10 alkil, C1-C10 alkoksi, C2-C10 alkenil, C1-C10 alkenoil, C3-C10 cikloalkil ima 0-3 heteroatoma odabranih između O, S i N, C6-C14 aril, C7 -C24 alkaril, C7 -C24 aralkil, C3-12 heteroaril ima 1-3 heteroatoma odabranih između O, N i S, C4-C23 alkheteroaril ima 1-3 heteroatoma odabranih između O, N i S, supstituirani C1.10 alkil, supstituirani C1-10 alkoksi, supstituirani C2-C10 alkenoil, supstituirani C1-C10 alkenoil, supstituirani C3-C10 cikloalkil koji ima 0-3 heteroatoma odabranih između O, N i S, supstituirani C6-C12 aril, supstituirani C3-C12 hetaril ima 1-3 heteroatoma odabranih između O, N i S, supstituirani C7-C24 aralkil, supstituirani C7-C24 alkaril, C4-C23 alkheteroaril ima 1-3 heteroatoma odabranih između O, N i S, i -Q-Ar; R7 je neovisno odabran iz skupine koja sadržava H, C1-C10 alkil, C1-C10 alkoksi, C2-C10 alkenil, C1-C10 alkenoil, C3-C10 cikloalkil ima 0-3 heteroatoma odabranih između O, S i N, C6-C14 aril, C3-C13 hetaril koji ima 1-3 heteroatoma odabrana između O, N i S, C7-C14 alkaril, C7-C24 aralkil, C4-C23 alkheteroaril ima 1-3 heteroatoma odabranih između O, N i S, sve do per halo supstituiranog C1-C10 alkil, sve do per halo supstituiranog, C3-C10 cikloalkil ima 0-3 heteroatoma odabranih između O, N i S, sve do per halo supstituiranog C6-C14 aril, sve do per halo supstituiranog C3-C13 hetaril, ima 1-3 heteroatoma odabranih između O, N i S, sve do per halo supstituiranog C7-C24 aralkil, sve do per halo supstituiranog C7-C14 alkaril, i sve do per halo supstituiranog C4-C23 alkheteroaril; i svaki Z je neovisno odabaran iz skupine koja sadržava -CN, -CO2R7, -C(O)-R7, -C(O)NR7R7, -NO2, -OR7, -SR7,-NR7R7, -NR7C(O)OR7, -NR7C(O)R7, C1-C10 alkil, C1-C10 alkoksi, C2-C10 alkenil, C1-C10 alkenoil, C3-C10 cikloalkil ima 0-3 heteroatoma odabrana između O, N i S, C6-C14 aril, C3-C13 hetaril ima 1-3 heteroatoma odabrana između O, N i S, C7-C24 aralkil, C4-C23 alkheteroaril ima 1-3 heteroatoma odabranih između O, N i S, supstituirani C1-C10 alkil, supstituirani C1-C10 alkoksi, supstituirani C2-C10 alkenil, supstituirani C1-C10 alkenoil, supstituirani C3-C10 cikloalkil koji ima 0-3 heteroatoma odabranih između O, N i S, supstituirani C6-C12 aril, supstituirani C7-C24 alkaril, supstituirani C7 -C24 aralkil i supstituirani C4-C23 alkheteroaril ima 1-3 heteroatoma odabranih između O, N i S, pri čemu je Z supstituirana grupa, s jedan ili više supstituenata odabranih između -CN, -CO2R , -COR, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)OR7 i -NR7C(O)R7,2. Compound according to claim 1, characterized in that: Ry is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms, C2-10 alkenyl, C1-10alkenoyl, C6.12 aryl, C3-12 hetaryl having 1-3 heteroatoms selected from N , S and O, C7-24 aralkyl, C7-24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C6-14 aryl, substituted C3-12 hetaryl, having 1-3 heteroatoms selected from N, S and O, substituted C7-24 aralkyl where Ry is a substituted group, with halogen up to per halo, Rz is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl and has 0-3 heteroatoms, C2-10 alkenyl, C1-10alkenoyl, C6-12 aryl, C3-C12 hetaryl and has 1-3 heteroatoms selected between S, N and O, C7-24 alkaryl, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C6-C14 aryl, C3-C10 cycloalkyl has 0-3 heteroatoms selected from S, N and O, C3-C12 hetaryl has 1-3 heteroatoms selected from S, N and O, substituted C7-24 alkaryl or substituted C7-24 aralkyl where Rz is a substituted group, it is substituted by halogen to per halo, hydrogen, C1-10 alkyl, C3-12 cycloalkyl has 0-3 heteroatoms selected from O, S and N, C3-C12 hetaryl has 1-3 heteroatoms selected from N, S and O, C1-10, alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo, C6-12 halo substituted aryl up to per halo aryl, C3 -C12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo substituted C3-12 hetaryl until per hello he tharyl has 1-3 heteroatoms selected from O, N and O, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)R 8 . Ra and Rb are a) independent hydrogen carbon based on selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, C2-C10 alkenyl, C1-C10 alkenyl, C6-12 aryl, C3-C12 hetaryl has 1-3 heteroatoms selected from O , N and S, C3-12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, C7-24 aralkyl, C7-C24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, C3-10 cycloalkyl, 0-3 heteroatoms selected from N, S and O, substituted C6-12 aryl, substituted C3-12 hetaryl has 1-3 heteroatoms selected from N, S and O, substituted C7-24 aralkyl, where Ra and Rb are substituting groups, they are halogen substituted up to per halo, hydrogen, C1-10 alkyl, C3-C12 cycloalkyl having 0-3 heteroatoms selected from S, N, and O, C3-C12 hetaryl having 1-3 heteroatoms selected from O, S, and N , C3-C12 hetaryl has 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C1-6halo substituted alkyl group up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl has 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo hetaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)Rg; or -OSi(Rf)3 where Rf is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl has 0-3 heteroatoms selected from O, S and N, C6-12 aryl, C3-C12 hetaryl has 1- 3 heteroatoms selected from O , S and N, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-10 alkoxy, C3-C12 cycloalkyl has 0-3 heteroatoms selected from O, S and N, substituted C3-C12 heteraryl has 1-3 heteroatoms selected from O, S and N, substituted C6-12 aryl, and substituted C7-C24 alkaryl, where Rf is the substituent group, it is substituted with halogen up to per halo, hydrogen, C1-10 alkyl, C3-C12 cycloalkyl has 0-3 heteroatoms selected from O, S and N, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl; C6-12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O; up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo hetaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 aralkyl up to per halo aralkyl, and -C(O)Rg; or b) Ra is Rb of the common form with 5-7 members of the heterocyclic structure of 1-3 heteroatoms selected from N, Si O, or substituted 5-7 members of the heterocyclic structure with 1-3 heteroatoms selected from N, S and O with a substituent from the group containing halogen up to per halo, hydroxy, C1-10 alkyl, C3-C12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1 -10 alkoxy, C6-12 aryl, C7-24 alkaryl, C7-24 aralkyl, halo substituted C1-6 alkyl up to per halo alkyl, halo substituted C6-12 aryl up to per halo aryl, halo substituted C3-C12 cycloalkyl has 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo hetaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)Rg; or c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group connected to half of the L form of a cyclic structure with at least 5 members wherein the substituent of the substituted C1-C5 divalent alkylene group is selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C3-12 cycloalkyl has 0-3 heteroatoms selected from O, S and N, C3-C12 hetaryl has 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-24 alkaryl, C7-24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6.12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo hetaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)Rg; where R 8 is C 1-10 alkyl; -CN, -CO2R7, -ORd, -SRd, -NO2, -C(O)Re, -NRdRe, NRdC(O)ORe, and -NRdC(O)Re and Rd and Re are independently selected from the group consisting of hydrogen , C1-10 alkyl, C1-10 alkoxy, C3-C10 cycloalkyl having 0-3 atoms selected from O, N and S, C6-C12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-24 aralkyl, C7-24 aralkyl, up to per halo substituted C1-10 alkyl, up to halo substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C6-C14 aryl, up to per halo substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N and S, halo substituted C7-C24 alkaryl up to per halo alkaryl and up to per halo substituted C7-C24 aralkyl, W is independently selected from the group consisting of -CN, -CO2R7, -C(O)NR7R7, -C (O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C (O)R7, C1-C10 Alkyl, C1-C10 Alkoxy, C2-C10 Alkenyl, C1-C10 Alkenoyl, C3-C10 Cycloalkyl has 0-3 heteroatoms selected from O, S and N, C6-C14 Aryl, C7-C24 alkaryl, C7 -C24 aralkyl, C3-12 heteroaryl having 1-3 heteroatoms selected from O, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1.10 alkyl, substituted C1- 10 Alkoxy, substituted C2-C10 alkenoyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N and S, substituted C7-C24 aralkyl, substituted C7-C24 alkaryl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and -Q-Ar; R7 is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C3-C13 heteraryl having 1-3 heteroatoms selected from O, N and S, C7-C14 alkaryl, C7-C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per halo substituted C1-C10 alkyl, up to per halo substituted, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per halo substituted C6-C14 aryl, up to per halo substituted C3-C13 hetaryl, has 1-3 heteroatoms selected from O, N and S, up to per halo substituted C7-C24 aralkyl, up to per halo substituted C7-C14 alkaryl, and up to per halo substituted C4-C23 alkheteroaryl; and each Z is independently selected from the group consisting of -CN, -CO2R7, -C(O)-R7, -C(O)NR7R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, - NR7C(O)R7, C1-C10 Alkyl, C1-C10 Alkoxy, C2-C10 Alkenyl, C1-C10 Alkenoyl, C3-C10 Cycloalkyl has 0-3 heteroatoms selected from O, N and S, C6-C14 Aryl, C3- C13 hetaryl has 1-3 heteroatoms selected from O, N and S, C7-C24 aralkyl, C4-C23 alkheteroaryl has 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C7-C24 alkaryl, substituted C7-C24 aralkyl and substituted C4 -C23 alkheteroaryl has 1-3 heteroatoms selected from O, N and S, where Z is a substituted group, with one or more substituents selected from -CN, -CO2R , -COR, -C(O)NR7R7, -OR7, - SR7, -NO2, -NR7R7, -NR7C(O)OR7 and -NR7C(O)R7, 3. Spoj prema zahtjevu 1, naznačen time, da je M jedna ili više skupina koje povezuju, odabranih između skupina koje sadržavaju -O-, -S-, -N(R)-, -(CH2)m-, -C(O)-, CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN (R7)-, -O(CH2)m-CHXa, CXa2, -S-(CH2)m-, i - N(R7)(CH2)m-, gdje je m= 1-3, Xa je halogen, a R7 je definiran kao u zahtjevu 1.3. A compound according to claim 1, characterized in that M is one or more linking groups selected from groups containing -O-, -S-, -N(R)-, -(CH2)m-, -C( O)-, CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN (R7)-, -O(CH2)m-CHXa, CXa2, -S-(CH2 )m-, and - N(R7)(CH2)m-, where m= 1-3, Xa is halogen, and R7 is defined as in claim 1. 4. Spoj prema zahtjevu 1, naznačen time, da ciklična struktura B i L veze direktno do D, nije u orto poziciji s OH supstituirana.4. Compound according to claim 1, indicated by the fact that the cyclic structure of B and L links directly to D, is not substituted with OH in the ortho position. 5. Spoj prema zahtjevu 1, naznačen time, da ciklična struktura B i L veze direktno do D, nije supstituirana u orto poziciji polovicom koja ima ionizirani vodik i pKa 10 ili manje.5. A compound according to claim 1, characterized in that the cyclic structure of B and L links directly to D, is not substituted in the ortho position by a moiety having ionized hydrogen and a pKa of 10 or less. 6. Spoj prema zahtjevu 1, naznačen time, da B u formuli I je supstituirana ili nesupstituirana polovica šest člane hetaril polovice, navedena hetaril polovica ima od 1-4 člana odabrana između skupine hetaril atoma koja sadržava dušik, kisik i sumpor u ravnoteži s ugljikom u hetaril polovici.6. A compound according to claim 1, characterized in that B in formula I is a substituted or unsubstituted half of a six-membered hetaryl moiety, said hetaryl moiety has 1-4 members selected from a group of hetaryl atoms containing nitrogen, oxygen and sulfur in balance with carbon in the hetaryl half. 7. Spoj prema zahtjevu 1, naznačen time, da B u formuli I je nesupstituirana fenilna skupina, nesupstituirana piridil skupina, nesupstituirana pirimidil skupina, a fenilna skupina je supstituirana sa supstituentom odabranim iz skupine koja sadržava halogen i Wn, pri čemu su W i n definirani kao u zahtjevu 1, a pirimidil skupina je supstituirana sa supstituentom odabranim iz skupine koja sadržava halogen i Wn, gdje su W i n definirani kao u zahtjevu 1, ili supstituirana pirimidil skupina koja je supstituirana s supstituentom odabranim iz skupine koja sadržava halogen i Wn, pri čemu su W i n definirani kao u zahtjevu 1.7. Compound according to claim 1, characterized in that B in formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidyl group, and the phenyl group is substituted with a substituent selected from the group containing halogen and Wn, where W and n are defined as in claim 1, and the pyrimidyl group is substituted with a substituent selected from the group containing halogen and Wn, where W and n are defined as in claim 1, or a substituted pyrimidyl group that is substituted with a substituent selected from the group containing halogen and Wn, at where W and n are defined as in claim 1. 8. Spoj prema zahtjevu 6, naznačen time, da je B u formuli I supstituirana fenilna skupina, supstituirana pirimidinil skupina, ili supstituirana piridil skupina supstituirana l do 3 puta s jednim ili više supstituenata odabranih iz skupina koje sadržava -CN, halogen, C1-C10 alkil, C1-C10 alkoksi, -OH, sve do per halo supstituirane alkil, sve do per halo supstituirane C1-C10 alkoksi ili fenil supstituirane s halogenom sve do per halo.8. A compound according to claim 6, characterized in that B in formula I is a substituted phenyl group, a substituted pyrimidinyl group, or a substituted pyridyl group substituted 1 to 3 times with one or more substituents selected from groups containing -CN, halogen, C1- C10 Alkyl, C1-C10 Alkoxy, -OH, up to per halo substituted alkyl, up to per halo substituted C1-C10 Alkoxy or phenyl substituted with halogen up to per halo. 9. Spoj prema zahtjevu 1, naznačen time, da je L, šesti član cikličke strukture, direktno vezan na D, i da je supstituiran ili nesupstituiran 6 člana aril polovice ili supstituiran ili nesupstituiran 6 člana hetaril polovice, pri čemu hetaril polovica ima 1 do 4 člana odabrana iz skupine heteroatoma koja sadržava dušik, kisik i sumpor u ravnoteži s navedenom hetaril polovicom je ugljik, pri čemu je jedan ili više supstituenata odabrano iz skupine koja sadržava halogen i Wn, pri čemu su W i n definirani kao u zahtjevu 1.9. A compound according to claim 1, indicated by the fact that L, the sixth member of the cyclic structure, is directly attached to D, and that 6 members of the aryl half are substituted or unsubstituted or 6 members of the hetaryl half are substituted or unsubstituted, wherein the hetaryl half has 1 to 4 members selected from the group of heteroatoms containing nitrogen, oxygen and sulfur in balance with the said hetaryl moiety is carbon, wherein one or more substituents are selected from the group containing halogen and Wn, where W and n are defined as in claim 1. 10. Spoj prema zahtjevu 8, naznačen time, da je L, 6 člani cikličke strukture direktno vezan na D, i da je supstituiran fenil, nesupstituiran fenil, supstituiran pirimidinil, nesupstituiran pirimidinil, supstituiran piridil, nesupstituirana piridil skupina.10. Compound according to claim 8, characterized in that L, 6 members of the cyclic structure is directly attached to D, and that it is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl, unsubstituted pyridyl group. 11. Spoj prema zahtjevu 1, naznačen time, da supstituirana ciklička polovica L' obuhvaća 5 do 6 član aril polovice ili hetaril polovice, pri čemu hetaril polovica obuhvaća l do 4 člana odabrana iz skupine heteroatoma koja sadržava dušik, kisik i sumpor.11. Compound according to claim 1, characterized in that the substituted cyclic half L' includes 5 to 6 members of the aryl half or hetaryl half, wherein the hetaryl half includes 1 to 4 members selected from the group of heteroatoms containing nitrogen, oxygen and sulfur. 12. Spoj prema zahtjevu 1, naznačen time, da je supstituirana ciklička polovica L' fenil, piridinil ili pirimidinil.12. Compound according to claim 1, characterized in that the substituted cyclic half L' is phenyl, pyridinyl or pyrimidinyl. 13. Spoj prema zahtjevu 3, naznačen time, da je supstituirana ciklička polovica L' fenil, piridinil ili pirimidinil.13. Compound according to claim 3, characterized in that the substituted cyclic half L' is phenyl, pyridinyl or pyrimidinyl. 14. Spoj prema zahtjevu 6, naznačen time, da je supstituirana ciklička polovica L' fenil, piridinil ili pirimidinil.14. Compound according to claim 6, characterized in that the substituted cyclic half L' is phenyl, pyridinyl or pyrimidinyl. 15. Spoj prema zahtjevu 8, naznačen time, da je supstituirana ciklička polovica L' fenil, piridinil ili pirimidinil.15. Compound according to claim 8, characterized in that the substituted cyclic half L' is phenyl, pyridinyl or pyrimidinyl. 16. Spoj prema zahtjevu 9, naznačen time, da je supstituirana ciklička polovica L' fenil, piridinil ili pirimidinil.16. Compound according to claim 9, characterized in that the substituted cyclic half L' is phenyl, pyridinyl or pyrimidinyl. 17. Spoj prema zahtjevu 10, naznačen time, da je supstituirana ciklička polovica L' fenil, piridinil ili pirimidinil.17. Compound according to claim 10, characterized in that the substituted cyclic half L' is phenyl, pyridinyl or pyrimidinyl. 18. Spoj prema zahtjevu 14, naznačen time, da je M jedna ili više skupina koje povezuju odabranih između skupina koje sadržavaju -O-, -S-, - N(R)-, -(CH2)m-, -C (O)-, CH(OH)-, -(CH2)nO-, -(CH2)nS-, -(CH2)mN (R7)-, -O(CH2)n- CHXa, CXa2, -S-(CH2)n-, i - N (R7) (CH2)n-, gdje je m= 1-3, Xa je halogen a R je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom sve do per halo.18. Compound according to claim 14, characterized in that M is one or more linking groups selected from groups containing -O-, -S-, -N(R)-, -(CH2)m-, -C (O )-, CH(OH)-, -(CH2)nO-, -(CH2)nS-, -(CH2)mN (R7)-, -O(CH2)n- CHXa, CXa2, -S-(CH2) n-, i - N (R7) (CH2)n-, where m= 1-3, Xa is halogen and R is hydrogen or carbon based on half up to 24 carbon atoms, optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen up to per halo. 19. Spoj prema zahtjevu 15, naznačen time, da je M jedna ili više skupina koje povezuju odabrana između skupina koje sadržavaju -O-, -S-, -N(R)-, -(CH2)m-, -C(O)-, CH(OH)-, -(CH2)mO-, -(CH2)nS-, -(CH2)mN(R7)-, -O(CH2)n- CHXa, CXa2, -S-(CH2)m-, i - N(R7)(CH2)m-, gdje je m= 1-3, Xa je halogen i R7 je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom sve do per halo.19. Compound according to claim 15, characterized in that M is one or more linking groups selected from groups containing -O-, -S-, -N(R)-, -(CH2)m-, -C(O )-, CH(OH)-, -(CH2)mO-, -(CH2)nS-, -(CH2)mN(R7)-, -O(CH2)n- CHXa, CXa2, -S-(CH2) m-, i - N(R7)(CH2)m-, where m= 1-3, Xa is halogen and R7 is hydrogen or carbon based on half up to 24 carbon atoms, optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen up to per halo. 20. Spoj prema zahtjevu 16, naznačen time, da je M jedna ili više skupina koje povezuju odabranih između skupina koje sadržavaju -O-, -S-, - N(R)-, -(CH2)m-, -C(O)-, CH(OH)-, -(CH2)mO-, -(CH2)nS-, - (CH2)mN(R7)-, -O(CH2)n-CHXa, CXa2, -S-(CH2)m-, i -N (R7) (CH2)n-, gdje je m = 1-3, XA je halogen a R je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom sve do per halo.20. Compound according to claim 16, characterized in that M is one or more connecting groups selected from groups containing -O-, -S-, -N(R)-, -(CH2)m-, -C(O )-, CH(OH)-, -(CH2)mO-, -(CH2)nS-, - (CH2)mN(R7)-, -O(CH2)n-CHXa, CXa2, -S-(CH2) m-, and -N (R7) (CH2)n-, where m = 1-3, XA is halogen and R is hydrogen or carbon based on half up to 24 carbon atoms, optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen up to per halo. 21. Spoj prema zahtjevu 17, naznačen time, da je M jedna ili više skupina koje povezuju odabranih između skupina koje sadržavaju -O-, -S-, -N(R)-, -(CH2)m-, -O(O)-, CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN (R7)-, -O(CH2)n-CHXa, CXa2, -S-(CH2)m-, i -N (R7) (CH2)n-, gdje je m = 1-3, Xa je halogen a R7 je vodik ili ugljik na osnovnu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom sve do per halo.21. Compound according to claim 17, characterized in that M is one or more linking groups selected from groups containing -O-, -S-, -N(R)-, -(CH2)m-, -O(O )-, CH(OH)-, -(CH2)mO-, -(CH2)mS-, -(CH2)mN (R7)-, -O(CH2)n-CHXa, CXa2, -S-(CH2) m-, and -N (R7) (CH2)n-, where m = 1-3, Xa is halogen and R7 is hydrogen or carbon on the basic halves up to 24 carbon atoms, optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen up to per halo. 22. Spoj prema zahtjevu 1, naznačen time, da je L' dodatno supstituiran 1 do 3 puta s jednim ili više supstituentom iz skupine C1-C10 alkil, sve do per halo supstituiranim C1-C10 alkil, -CN, -OH; halogenom, C1-C10 alkoksi i sve do per halo supstituiranim C1-C10 alkoksi.22. The compound according to claim 1, characterized in that L' is additionally substituted 1 to 3 times with one or more substituents from the group C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH; halogen, C1-C10 Alkoxy and up to per halo substituted C1-C10 Alkoxy. 23. Spoj prema zahtjevu 13, naznačen time, da je L' dodatno supstituiran 1 do 3 puta s jednim ili više supstituentom iz skupine C1-C10 alkil, sve do per halo supstituiranim C1-C10 alkil, -CN, -OH; halogenom, C1-C10 alkoksi i sve do per halo supstituiranim C1-C10 alkoksi.23. Compound according to claim 13, characterized in that L' is additionally substituted 1 to 3 times with one or more substituents from the group C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH; halogen, C1-C10 Alkoxy and up to per halo substituted C1-C10 Alkoxy. 24. Spoj prema zahtjevu 18, naznačen time, da je L' dodatno supstituiran 1 do 3 puta s jednim ili više supstituentom iz skupine C1-C10 alkil, sve do per halo supstituiranim C1-C10 alkil, -CN, -OH; halogenom, C1-C10 alkoksi i sve do per halo supstituiranim C1-C10 alkoksi.24. A compound according to claim 18, characterized in that L' is additionally substituted 1 to 3 times with one or more substituents from the group C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH; halogen, C1-C10 Alkoxy and up to per halo substituted C1-C10 Alkoxy. 25. Spoj prema zahtjevu 19, naznačen time, da je L' dodatno supstituiran 1 do 3 puta s jednim ili više supstituentom iz skupine C1-C10 alkil, sve do per halo supstituiranim C1-C10 alkil, -CN, -OH; halogenom, C1-C10 alkoksi i sve do per halo supstituiranim C1-C10 alkoksi.25. Compound according to claim 19, characterized in that L' is additionally substituted 1 to 3 times with one or more substituents from the group C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH; halogen, C1-C10 Alkoxy and up to per halo substituted C1-C10 Alkoxy. 26. Spoj prema zahtjevu 20, naznačen time, da je L' dodatno supstituiran 1 do 3 puta s jednim ili više supstituentom iz skupine C1-C10 alkil, sve do per halo supstituiranim C1-C10 alkil, -CN, -OH; halogenom, C1-C10 alkoksi i sve do per halo supstituiranim C1-C10 alkoksi.26. Compound according to claim 20, characterized in that L' is additionally substituted 1 to 3 times with one or more substituents from the group C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH; halogen, C1-C10 Alkoxy and up to per halo substituted C1-C10 Alkoxy. 27. Spoj prema zahtjevu 21, naznačen time, da je L' dodatno supstituiran 1 do 3 puta s jednim ili više supstituentom iz skupine C1-C10 alkil, sve do per halo supstituiranim C1-C10 alkil, -CN, -OH; halogenom, C1-C10 alkoksi i sve do per halo supstituiranim C1-C10 alkoksi.27. Compound according to claim 21, characterized in that L' is additionally substituted 1 to 3 times with one or more substituents from the group C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH; halogen, C1-C10 Alkoxy and up to per halo substituted C1-C10 Alkoxy. 28. Spoj prema zahtjevu 1, naznačen time, da je L' supstituiran s -C(O)Rx.28. A compound according to claim 1, characterized in that L' is substituted with -C(O)Rx. 29. Spoj prema zahtjevu 1, naznačen time, da je L' supstituiran s -SO2Rx.29. Compound according to claim 1, characterized in that L' is substituted with -SO2Rx. 30. Spoj prema zahtjevu 1, naznačen time, da je L' supstituiran s -C(O)Rx.30. The compound according to claim 1, characterized in that L' is substituted by -C(O)Rx. 31. Spoj prema zahtjevu 1, naznačen time, da je L' supstituiran s -SO2RX.31. Compound according to claim 1, characterized in that L' is substituted with -SO2RX. 32. Spoj prema zahtjevu 1, naznačen time, da je L' supstituiran s -C(O)Rx ili -SO2Rx, pri čemu Rx je NRaRb.32. The compound according to claim 1, characterized in that L' is substituted by -C(O)Rx or -SO2Rx, wherein Rx is NRaRb. 33. Spoj prema zahtjevu 13, naznačen time, da je L' supstituiran s -C(O)Rx ili -SO2Rx, pri čemu Rx je NRARb, a Ra i Rb su a) slobodni vodik ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom, hidroksi i ugljikom na osnovi supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom, ili -Osi(Rf)3 gdje je Rf je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimnalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane s halogenom;. ili b) Ra i Rb zajednički oblik 5-7 članova heterolitičke strukture s 1-3 heteroatoma odabranih između N, S i O, ili supstituirani 5-7 član heterolitičke strukture s 1-3 heteroatoma odabranih između N, S i O supstituiran s halogenom, hidroksi ili ugljikom na osnovu supstituenta od sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom, ili c) jedan od Ra i Rb je -C(O)-, Cl-C5 divalentna alkilen skupina ili supstituirana C1-C5 divalentna alkilen skupina povezana s polovicom L u oblik cikličke strukture s najmanje 5 članova, pri čemu supstituent supstituirane C1-C5 divalentne alkilen skupine je odabran iz skupine koja sadržava halogen, hidroksi i ugljik, na osnovi supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom.33. Compound according to claim 13, characterized in that L' is substituted with -C(O)Rx or -SO2Rx, where Rx is NRARb, and Ra and Rb are a) free hydrogen carbon based on half up to 30 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on substituents up to 24 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally are substituted by halogen, or -Osi(Rf)3 where Rf is hydrogen or carbon based on half up to 24 carbon atoms optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and optimally substituted with halogen;. or b) Ra and Rb common form of 5-7 members of heterolytic structure with 1-3 heteroatoms selected from N, S and O, or substituted 5-7 member of heterolytic structure with 1-3 heteroatoms selected from N, S and O substituted with halogen, hydroxy or carbon-based substituents of up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted with halogen, or c) one of Ra and Rb is -C(O)-, a Cl-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group connected to half of L in the form of a cyclic structure with at least 5 members, wherein the substituent of the substituted C1-C5 divalent the alkylene group is selected from the group containing halogen, hydroxy and carbon, based on the substituent up to 24 carbon atoms, which optimally contains heteroatoms selected from N, S and O and are optimally substituted by halogen. 34. Spoj prema zahtjevu 18, naznačen time, da je L' supstituiran s -C(O)Rx ili -SO2Rx, pri čemu Rx je NRaRb, a Ra i Rb su slobodni vodik ili ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirani halogenom, hidroksi ili ugljikom na osnovi supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom.34. The compound according to claim 18, characterized in that L' is substituted with -C(O)Rx or -SO2Rx, where Rx is NRaRb, and Ra and Rb are free hydrogen or carbon based on half up to 30 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy or carbon based substituents up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen. 35. Spoj prema zahtjevu 19, naznačen time, da je L' supstituiran s -C(O)RX, pri čemu Rx je NRaRb, a Ra i Rb su slobodni vodik ili ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, vodikom ili ugljikom na osnovi supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom.35. The compound according to claim 19, characterized in that L' is substituted with -C(O)RX, where Rx is NRaRb, and Ra and Rb are free hydrogen or carbon based on half up to 30 carbon atoms optimally contain heteroatoms selected between N, S and O and optimally substituted with halogen, hydrogen or carbon on the basis of the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted with halogen. 36. Spoj prema zahtjevu 20, naznačen time, da je L' supstituiran s -C(O)RX ili -SO2RX, pri čemu Rx je NRaRb, a Ra i Rb su slobodni vodik ili ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi ili ugljikom na osnovi supstituenta od sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom.36. The compound according to claim 20, characterized in that L' is substituted with -C(O)RX or -SO2RX, where Rx is NRaRb, and Ra and Rb are free hydrogen or carbon based on half up to 30 carbon atoms optimally contain heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen. 37. Spoj prema zahtjevu 21, naznačen time, da je L' supstituiran s -C(O)RX ili -SO2RKf pri čemu Rx je NRaRb, a Ra i Rb su slobodni vodik ili ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi ili ugljikom na osnovi supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom.37. The compound according to claim 21, characterized in that L' is substituted with -C(O)RX or -SO2RKf, where Rx is NRaRb, and Ra and Rb are free hydrogen or carbon based on half up to 30 carbon atoms optimally contain heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy or carbon based substituent up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen. 38. Spoj formule I A - D – B (I) ili njegova farmaceutski prihvatljiva sol, naznačen time, da D je -NH-C(O)-NH- A je supstituirana polovica sve do 40 atoma ugljika u formuli: -L-(M-L')q, gdje je L 6 člana aril polovica ili 6 člana hetaril polovica povezana direktno na D, L' obuhvaća supstituiranu cikličku polovicu s najmanje 5 članova, M je grupa koja veže, a ima najmanje jedan atom, q je cjelina od 1-3; a svaka ciklička struktura L i L' sadržava 0-4 članova i od grupe koja sadržava dušik, kisik ili sumpor, i B je supstituirana ili nesupstituirana, sve do tricikličke ili heteroaril polovice sve do 30 atoma ugljika s najmanje jednim 6-članom cikličkom strukturom povezana direktno na D koji sadržava 0-4 člana skupine koja sadržava dušik, kisik ili sumpor, pri čemu je L' supstituiran s najmanje jednim supstituentom koji je odabran iz skupine koja sadržava –SO2Rx, -C(O)Rx i -C(NRy)Rz; Ry je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno halosupstituiran, sve do per halo, Rz je vodik ili ugljik na osnovu polovice sve do 30 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno halosupstituiran halogenom, vodikom ili ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom; Rx je R2 ili NRaRb gdje Ra i Rb su a) slobodni vodik ugljik na osnovu polovice sve do 24 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno halosupstituiran halogenom, vodikom ili ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O su optimalno supstituirani halogenom; ili -OSi(Rf)3 gdje Rf je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiran s halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom; ili b) Ra i Rb zajedno imaju oblik 5-7 člane heterocikličke strukture od 1-3 heteroatoma odabranih između N; S i O, ili supstituiranu 5-7 članu heterocikličku strukturu od 1-3 heteroatoma odabrana između N, S i O supstituirana halogenom, hidroksi ili ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom; ili c) jedan od Ra ili Rb je -C(O)-, C1-C5 divalentna alkilen skupina ili supstituirana C1-C5 divalentna alkilen skupina povezuje polovicu L do oblika cikličke strukture s najmanje 5 članova, pri čemu je supstituent supstituirane C1-C5 divalentne alkilne skupine odabran iz skupine koja sadržava halogen, hidroksi i ugljik na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom; gdje je B supstituiran, L je supstituiran ili L' dodatno supstituiran, supstituenti su odabrani iz skupine koja sadržava halogen, sve do per halo, i Wn, gdje n je 0-3; pri čemu je svaki W slobodno odabran iz skupine -CN, -CO2R7, -C(O)NR7R7-, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar i ugljik na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituiranog s jednm ili više supstituenata slobodno odabranih iz skupine koja sadržava -CN, -CO2R7; -C(O)R7; C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, i halogen sve do per halo, s svakim R7 neovisno odabranim između H i ugljika na osnovu polovice sve do 24 atoma ugljika, optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiranog s halogenom, pri čemu Q je -O-, -S-, -N(R7)-, -C(H2)m-, -C(O)-, -CH(OH)-, -C(H2)nO-, -C(H2)mS-, - (CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-C(H2)m-, i -N(R7)(H2)m-, gdje m= 1-3, a Xa je halogen; Ar je 5- ili 6-član aromatske strukture koji sadržava 0-2 člana odabrana iz skupine koja sadržava dušik, kisik i sumpor, koji je optimalno supstituiran halogenom, sve do per halo, i optimalno supstituiran s Zn1 pri čemu ni je O do 3 i svaki Z je neovisno odabran iz skupine koja sadržava -CN, -CO2R; -C(O)NR7R7-; -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, i ugljik na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituiranog s jednim ili više supstituenata slobodno odabranih iz skupine koja sadržava -CN, -CO2R7; C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7, -NR7C(O)OR7, a R7 je gore definiran; i pri čemu je M jedna ili više skupina koje povezuju odabrana iz skupine koja sadržava -O-, -S-, -N(R)-, -C(H2)m-, -C(O)-, -CH(OH)-, -C(H2)mO-, -C(H2)mS-, -(CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-(CH2)n- i -N(R7) (H2)m-, gdje je m= 1-3, a Xa je halogen;38. Compound of formula I A - D - B (I) or a pharmaceutically acceptable salt thereof, characterized in that D is -NH-C(O)-NH- A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L')q, where L is a 6-membered aryl moiety or a 6-membered hetaryl moiety attached directly to D, L' comprises a substituted cyclic moiety with at least 5 members , M is a binding group having at least one atom, q is an integer of 1-3; and each cyclic structure L and L' contains 0-4 members and from a group containing nitrogen, oxygen or sulfur, and B is substituted or unsubstituted, up to a tricyclic or heteroaryl moiety of up to 30 carbon atoms with at least one 6-membered cyclic structure linked directly to D containing 0-4 members of a group containing nitrogen, oxygen or sulphur, wherein L' is substituted with at least one substituent selected from the group consisting of -SO2Rx, -C(O)Rx and -C(NRy)Rz; Ry is hydrogen or carbon based on half up to 24 carbon atoms of optimal heteroatom content selected from N, S and O and optimally halosubstituted, up to per halo, Rz is hydrogen or carbon based on half of up to 30 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally halosubstituted with halogen, hydrogen or carbon based on a substituent of up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and are optimally substituted with halogen; Rx is R2 or NRaRb where Ra and Rb are a) free hydrogen carbon based on half up to 24 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally halosubstituted with halogen, hydrogen or carbon based on a substituent of up to 24 carbon atoms, which optimally contains heteroatoms selected from N, S and O are optimally substituted halogen; or -OSi(Rf)3 where Rf is hydrogen or carbon based on half up to 24 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted with halogen; or b) Ra and Rb together form a 5-7 membered heterocyclic structure of 1-3 heteroatoms selected from N; S and O, or a substituted 5-7 membered heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted with halogen, hydroxy or carbon based on the substituent up to 24 carbon atoms, which optimally contains heteroatoms selected from N, S and O and are optimally substituted with halogen; or c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group connects half of L to form a cyclic structure with at least 5 members, wherein the substituent of the substituted C1-C5 divalent alkyl groups selected from the group containing halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted with halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group containing halogen, up to per halo, and Wn, where n is 0-3; where each W is freely selected from the group -CN, -CO2R7, -C(O)NR7R7-, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar and carbon based on half up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and optimally substituted with one or more substituents freely selected from groups containing -CN, -CO2R7; -C(O)R7; C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, and halogen up to per halo, with each R7 independently selected from H and carbon based on half of up to 24 carbon atoms, optimal heteroatom content selected from N, S, and O and optimally substituted with halogen, where Q is -O-, -S-, -N(R7)-, -C(H2)m-, -C(O)-, -CH(OH)-, -C(H2)nO-, - C(H2)mS-, - (CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-C(H2)m-, and -N(R7)(H2)m-, where m= 1-3, and Xa is halogen; Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group containing nitrogen, oxygen, and sulfur, which is optimally substituted with halogen, up to per halo, and optimally substituted with Zn1, wherein ni is O to 3 and each Z is independently selected from the group consisting of -CN, -CO2R; -C(O)NR7R7-; -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, and carbon based on half up to 24 carbon atoms, optimally containing heteroatoms selected from N, S, and O and optimally substituted with one or more substituents freely selected from the group consisting of -CN, -CO2R7; C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7, -NR7C(O)OR7, and R7 is as defined above; and wherein M is one or more linking groups selected from the group consisting of -O-, -S-, -N(R)-, -C(H2)m-, -C(O)-, -CH(OH) -, -C(H2)mO-, -C(H2)mS-, -(CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-(CH2)n- and -N(R7) (H2)m-, where m= 1-3, and Xa is halogen; 39. Spoj formule I: A - D – B (I) ili njegova farmaceutski prihvatljiva sol, naznačen time, da je D je -NH-C(O)-NH- A je supstituirana polovica sve do 40 atoma ugljika u formuli: -L-(M-L')q, gdje je L supstituirani ili nesupstituirani fenil ili peritonealna polovica vezana direktno na D, L' sadržava supstituirani fenil, peritonealnu ili pirimidilnu polovicu , M je skupina koja povezuje i ima najmanje jedan atom, q je cijeli oblik 1-3; i B je supstituirana ili nesupstituirana fenil ili piridin skupina direktno vezana na D, pri čemu je L' supstituiran s najmanje jednim supstituentom odabranim iz skupine koja sadržava -SO2RX; -C(O)Rx i -C(NRY)Rz, Ry je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika optimalnog sadržaja heteroatoma odabranog između N, S i O i optimalno halosupstituiran, sve do per halo, Rz je vodik ili ugljik na osnovu polovice sve do 30 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiran halogenom, hidroksi ili ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i oni su optimalno supstituirani halogenom, Rx je Rz ili NRaRb gdje Ra i Rb su a) slobodni vodik ugljik na osnovu polovice sve do 30 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiran halogenom, hidroksi ili ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i oni su optimalno supstituirani halogenom; ili -OSi(Rf)3 gdje Rf je vodik ili ugljik na osnovu polovice sve do 24 atoma ugljika optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiran s halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O i optimalno su supstituirani halogenom; ili b) Ra i Rb zajedno su oblika 5-7 elane heterocikličke strukture od 1-3 heteroatoma odabranih između N; S i O, ili supstituirani 5-7 član heterocikličke strukture od 1-3 heteroatoma odabranih između N, S i O supstituirani halogenom, hidroksi ili ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom; ili c) jedan od Ra i Rb je -C(O)-, Cl-C5 divelentna alkilen skupina ili supstituirana C1-C5 divalentna alkilna skupina vezana s polovicom L do oblika cikličke strukture s najmanje 5 čalnova, pri čemu je supstituent supstituirane Cl-C5 divalentne alkilne skupine odabran iz skupine koja sadržava halogen, hidroksi i ugljik na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržavaju heteroatome odabrane između N, S i O koji su optimalno supstituirani s halogenom; gdje je B supstituiran, L je supstituiran ili L' dodatno supstituiran, supstituenti su odabrani iz skupine koja sadržava halogen, sve do per halo, i Wn, gdje n je 0-3; pri čemu je svaki W slobodno odabran iz skupine -CN, -CO2R7; -C(O)NR7R7-; -C(O)-R7; -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar i ugljik na osnovu polovice sve do 24 atoma ugljika, optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituiranog s jednim ili više supstituenata slobodno odabranih iz skupine koja sadržava -CN, -CO2R; -C(O)R; C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, i halogen sve do per halo; sa svakim R7 neovisno odabranim između H ili ugljika na osnovu polovice sve do 24 atoma ugljika, optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiranih s halogenom, pri čemu Q je -O-, -S-, -N (R7)-, -C(H2)m-, -C(O)-, -CH(OH)-, -C(H2)mO-, -C(H2)mS-, - (CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-C(H2)m-, i -N(R7)(CH2)m-, gdje je m= 1-3, a Xa je halogen; Ar je 5- ili 6-član aromatske strukture koji sadržava 0-2 člana odabrana iz skupine koja sadržava dušik, kisik i sumpor, koji je optimalno supstituiran halogenom, sve do per halo, i optimalno supstituiran s Zn1, pri čemu je ni 0-3 i svaki Z slobodno odabran iz skupine koja ssdržava -CN, -CO2R7; -C(O)NR7R7-; -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, i ugljik na osnovu polovice sve do 24 atoma ugljika, optimalnog sadržaja heteroatoma odabranih između N, S i O i optimalno supstituiranog s jednim ili više supstituenata slobodno odabranih iz skupine koja sadržava -CN, -CO2R7; -C(O)R7; C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7 i -NR7C(O)OR7; pri čemu je M jedna ili više skupina koje povezuju odabrana iz skupine koja sadržava -O-, -S-, -N(R7)-, -C(H2)m-, -C(O)-, -CH(OH)-, -C(H2)mO-, -C(H2)mS-, -(CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-C(H2)m-, i -N(R7)(CH2)m-, gdje je m= 1-3, a Xa je halogen;39. Compound of formula I: A - D - B (I) or a pharmaceutically acceptable salt thereof, characterized in that D is -NH-C(O)-NH- A is a substituted moiety of up to 40 carbon atoms in the formula: -L-(M-L')q, where L is a substituted or unsubstituted phenyl or peritoneal moiety attached directly to D, L' contains a substituted phenyl, peritoneal or pyrimidyl moiety, M is a linking group having at least one atom, q is an integer of the form 1-3; and B is a substituted or unsubstituted phenyl or pyridine group directly attached to D, wherein L' is substituted with at least one substituent selected from the group consisting of -SO2RX; -C(O)Rx and -C(NRY)Rz, Ry is hydrogen or carbon based on half up to 24 carbon atoms of optimal heteroatom content selected from N, S and O and optimally halosubstituted, up to per halo, Rz is hydrogen or carbon based on half of up to 30 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy or carbon based on a substituent of up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and they are optimally substituted with halogen, Rx is Rz or NRaRb where Ra and Rb are a) free hydrogen carbon based on half up to 30 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy or carbon based on the substituent up to 24 carbon atoms, which optimally contains heteroatoms selected from N, S and O and they are optimally substituted by halogen; or -OSi(Rf)3 where Rf is hydrogen or carbon based on half up to 24 carbon atoms with an optimal content of heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O and are optimally substituted by halogen; or b) Ra and Rb together form a 5-7 membered heterocyclic structure of 1-3 heteroatoms selected from N; S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted with halogen, hydroxy or carbon based on the substituent up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and are optimally substituted with halogen; or c) one of Ra and Rb is -C(O)-, a Cl-C5 divalent alkylene group or a substituted C1-C5 divalent alkyl group bound with half of L to form a cyclic structure with at least 5 members, wherein the substituent is substituted Cl-C5 divalent alkyl groups selected from the group containing halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contain heteroatoms selected from N, S and O which are optimally substituted with halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group containing halogen, up to per halo, and Wn, where n is 0-3; where each W is freely selected from the group -CN, -CO2R7; -C(O)NR7R7-; -C(O)-R7; -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar and carbon based on half up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and optimally substituted with one or more substituents freely selected from groups containing -CN, -CO2R; -C(O)R; C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7, and halogen up to per halo; with each R7 independently selected from H or carbon based on half of up to 24 carbon atoms, optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, where Q is -O-, -S-, -N (R7)-, -C(H2)m-, -C(O)-, -CH(OH)-, -C(H2)mO-, - C(H2)mS-, - (CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-C(H2)m-, and -N(R7)(CH2)m-, where m= 1-3, and Xa is halogen; Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group containing nitrogen, oxygen and sulfur, which is optimally substituted with halogen, up to per halo, and optimally substituted with Zn1, where neither 0- 3 and each Z is freely selected from the group consisting of -CN, -CO2R7; -C(O)NR7R7-; -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, and carbon based on half up to 24 carbon atoms, optimal heteroatom content selected from N, S, and O and optimally substituted with one or more substituents freely selected from the group consisting of -CN, -CO2R7; -C(O)R7; C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7 and -NR7C(O)OR7; wherein M is one or more linking groups selected from the group consisting of -O-, -S-, -N(R7)-, -C(H2)m-, -C(O)-, -CH(OH) -, -C(H2)mO-, -C(H2)mS-, -(CH2)m-N(R7)-, -O(CH2)m-, CHXa, CXa2-, -S-C(H2)m-, and -N(R7)(CH2)m-, where m= 1-3 and Xa is halogen; 40. Spoj prema zahtjevu 38, naznačen time, da ciklička struktura B i L, povezana direktno na D, nije supstituirana u orto položaju s -OH.40. Compound according to claim 38, characterized in that the cyclic structure B and L, connected directly to D, is not substituted in the ortho position with -OH. 41. Spoj prema zahtjevu 38, naznačen time, da ciklička struktura B i L, povezana direktno na D, nije supstituirana u orto položaju s polovicom ioniziranog vodika i pKa je 10 ili manje.41. The compound according to claim 38, characterized in that the cyclic structure B and L, connected directly to D, is not substituted in the ortho position with half of the ionized hydrogen and the pKa is 10 or less. 42. Spoj prema zahtjevu 39, naznačen time, da ciklička struktura B i L povezana direktno na D, nije supstituirana u orto položaju s -OH.42. The compound according to claim 39, characterized in that the cyclic structure B and L connected directly to D is not substituted in the ortho position with -OH. 43. Spoj prema zahtjevu 39, naznačen time, da ciklička struktura B i L povezana direktno na D nije supstituirana u orto položaju s polovicom ioniziranog vodika i pKa je 10 ili manje.43. The compound according to claim 39, characterized in that the cyclic structure B and L connected directly to D is not substituted in the ortho position with half of the ionized hydrogen and the pKa is 10 or less. 44. Spoj prema zahtjevu 38, naznačen time, da su supstituenti za B i L i dodatni supstituent za L', odabrani iz skupine C1-C10 alkil sve do per halo supstituirani C1-C10 alkil, CN, OH, halogen, C1-C10 alkoksi i sve do per halo supstituirani C1-C10 alkoksi.44. The compound according to claim 38, characterized in that the substituents for B and L and the additional substituent for L' are selected from the group C1-C10 alkyl up to per halo substituted C1-C10 alkyl, CN, OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy. 45. Spoj prema zahtjevu 39, naznačen time, da su supstituenti za B i L i dodatni supstituent za L', odabrani iz skupine C1-C10 alkil sve do per halo supstituirani C1-C10 alkil, CN, OH, halogen, C1-C10 alkoksi i sve do per halo supstituirani C1-C10 alkoksi.45. Compound according to claim 39, characterized in that the substituents for B and L and the additional substituent for L' are selected from the group C1-C10 alkyl up to per halo substituted C1-C10 alkyl, CN, OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy. 46. Spoj prema zahtjevu 38, naznačen time, da je L' supstituiran s C(O)RX ili S(O2)RX.46. Compound according to claim 38, characterized in that L' is substituted with C(O)RX or S(O2)RX. 47. Spoj prema zahtjevu 39, naznačen time, da je L' supstituiran s C(O)RX ili S(O2)RX.47. Compound according to claim 39, characterized in that L' is substituted with C(O)RX or S(O2)RX. 48. Spoj prema zahtjevu 46, naznačen time, da Rx je NRaRb i Ra i Rb su neovisno odabrani vodik i ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom.48. The compound according to claim 46, characterized in that Rx is NRaRb and Ra and Rb are independently selected hydrogen and carbon based on half of up to 30 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen. 49. Spoj prema zahtjevu 47, naznačen time, da Rx je NRaRb i Ra i Rb su neovisno odabrani vodik i ugljik na osnovu polovice sve do 30 atoma ugljika optimalno sadržava heteroatome odabrane između N, S i O i optimalno supstituirane halogenom, hidroksi i ugljikom na osnovu supstituenta sve do 24 atoma ugljika, koji optimalno sadržava heteroatome odabrane između N, S i O i optimalno su supstituirani s halogenom.49. The compound according to claim 47, characterized in that Rx is NRaRb and Ra and Rb are independently selected hydrogen and carbon based on half of up to 30 carbon atoms optimally containing heteroatoms selected from N, S and O and optimally substituted with halogen, hydroxy and carbon based on the substituent up to 24 carbon atoms, which optimally contains heteroatoms selected from N, S and O and optimally substituted with halogen. 50. Spoj prema zahtjevu 1, koji je farmaceutski prihvatljiva sol spoja formule 1, naznačen time, da je odabran iz skupine sadržane od a) soli baza organskih kiselina i anorganskih kiselina odabranih iz skupine koja sadržava klorovodičnu kiselinu, bromovodičnu kiselinu, sumpornu kiselinu, fosfornu kiselinu, metansulfonsku kiselinu, trifluorsulfonsku kiselinu, p-toluen sulfonsku kiselinu (tosylat sol), 1-naftalen sulfonsku kiselinu, 2-naftalen sulfonsku kiselinu, octenu kiselinu, trifluoroctenu kiselinu, jabučnu kiselinu, vinsku kiselinu, limunsku kiselinu, mliječnu kiselinu, oksalnu kiselinu, sukcinsku kiselinu, fumarnu kiselinu, maleičnu kiselinu, benzojevu kiselinu, salicilnu kiselinu, feniloctenu kiselinu, i bademovu kiselinu; i b) soli organskih i anorganskih kiselina na osnovu sadržaja kationa odabranih između skupine koja sadržava alkalne katione, zemljane alkalne katione, amonijeve katione, alifatski supstituirane amonijeve katione i aromatski supstituirane amonijeve katione.50. The compound according to claim 1, which is a pharmaceutically acceptable salt of the compound of formula 1, characterized in that it is selected from the group consisting of a) salts of bases of organic acids and inorganic acids selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2- naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) salts of organic and inorganic acids based on the content of cations selected from the group containing alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 51. Spoj prema zahtjevu 2, koji je farmaceutski prihvatljiva sol spoja formule 1, naznačen time, da je odabran iz skupine koja se sastoji od a) soli baza organskih kiselina i anorganskih kiselina odabranih iz skupine koja sadržava klorovodičnu kiselinu, bromovodičnu kiselinu, sumpornu kiselinu, fosfornu kiselinu, metansulfonsku kiselinu, trifluorsulfonsku kiselinu, p-toluen sulfonsku kiselinu (tosylat sol) , 1-naftalen sulfonsku kiselinu, 2-naftalen sulfonsku kiselinu, octenu kiselinu, trifluoroctenu kiselinu, jabučnu kiselinu, vinsku kiselinu, limunsku kiselinu, mliječnu kiselinu, oksalnu kiselinu, sukcinsku kiselinu, fumarnu kiselinu, maleičnu kiselinu, benzojevu kiselinu, salicilnu kiselinu, feniloctenu kiselinu, i bademovu kiselinu; i b) soli organskih i anorganskih kiselina na osnovu sadržaja kationa odabranih između skupine koja sadržava alkalne katione, zemljane alkalne katione, amonijeve katione, alifatski supstituirane amonijeve katione i aromatski supstituirane amonijeve katione.51. The compound according to claim 2, which is a pharmaceutically acceptable salt of the compound of formula 1, characterized in that it is selected from the group consisting of a) salts of bases of organic acids and inorganic acids selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2- naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) salts of organic and inorganic acids based on the content of cations selected from the group containing alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 52. Spoj prema zahtjevu 33, koji je farmaceutski prihvatljiva sol spoja formule 1, naznačen time, da je odabran iz skupine koja se sastoji od a) soli baza organskih kiselina i anorganskih kiselina odabranih iz skupune koja sadržava klorovodičnu kiselinu, bromovodičnu kiselinu, sumpornu kiselinu, fosfornu kiselinu, metansulfonsku kiselinu, trifluorsulfonsku kiselinu, p-toluen sulfonsku kiselinu (tosylat sol), 1-naftalen sulfonsku kiselinu, 2-naftalen sulfonsku kiselinu, octenu kiselinu, trifluoroctenu kiselinu, jabučnu kiselinu, vinsku kiselinu, limunsku kiselinu, mliječnu kiselinu, oksalnu kiselinu, sukcinsku kiselinu, fumarnu kiselinu, maleičnu kiselinu, benzojevu kiselinu, salicilnu kiselinu, feniloctenu kiselinu, i bademovu kiselinu; i b) soli organskih i anorganskih kiselina na osnovu sadržaja kationa odabranih između skupine koja sadržava alkalne katione, zemljane alkalne katione, amonijeve katione, alifatski supstituirane amonijeve katione i aromatski supstituirane amonijeve katione.52. The compound according to claim 33, which is a pharmaceutically acceptable salt of the compound of formula 1, characterized in that it is selected from the group consisting of a) salts of bases of organic acids and inorganic acids selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2- naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) salts of organic and inorganic acids based on the content of cations selected from the group containing alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 53. Spoj prema zahtjevu 38, koji je farmaceutski prihvatljiva sol spoja formule 1, naznačen time, da je odabran iz skupine koja se sastoji od a) soli baza organskih kiselina i anorganskih kiselina odabranih iz skupune koja sadržava klorovodičnu kiselinu, bromovodičnu kiselinu, sumpornu kiselinu, fosfornu kiselinu, metansulfonsku kiselinu, trifluorsulfonsku kiselinu, p-toluen sulfonsku kiselinu (tosylat sol), 1-naftalen sulfonsku kiselinu, 2-naftalen sulfonsku kiselinu, octenu kiselinu, trifluoroctenu kiselinu, jabučnu kiselinu, vinsku kiselinu, limunsku kiselinu, mliječnu kiselinu, oksalnu kiselinu, sukcinsku kiselinu, fumarnu kiselinu, maleičnu kiselinu, benzojevu kiselinu, salicilnu kiselinu, feniloctenu kiselinu, i bademovu kiselinu; i b) soli organskih i anorganskih kiselina na osnovu sadržaja kationa odabranih između skupine koja sadržava alkalne katione, zemljane alkalne katione, amonijeve katione, alifatski supstituirane amonijeve katione i aromatski supstituirane amonijeve katione.53. The compound according to claim 38, which is a pharmaceutically acceptable salt of the compound of formula 1, characterized in that it is selected from the group consisting of a) salts of bases of organic acids and inorganic acids selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2- naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) salts of organic and inorganic acids based on the content of cations selected from the group containing alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 54. Spoj prema zahtjevu 39, koji je farmaceutski prihvatljiva sol spoja formule 1, naznačen time, da je odabran iz skupine koja se sastoji od a) soli baza organskih kiselina i anorganskih kiselina odabranih iz skupune koja sadržava klorovodičnu kiselinu, bromovodičnu kiselinu, sumpornu kiselinu, fosfornu kiselinu, metansulfonsku kiselinu, trifluorsulfonsku kiselinu, p-toluen sulfonsku kiselinu (tosylat sol), 1-naftalen sulfonsku kiselinu, 2-naftalen sulfonsku kiselinu, octenu kiselinu, trifluoroctenu kiselinu, jabučnu kiselinu, vinsku kiselinu, limunsku kiselinu, mliječnu kiselinu, oksalnu kiselinu, sukcinsku kiselinu, fumarnu kiselinu, maleičnu kiselinu, benzojevu kiselinu, salicilnu kiselinu, feniloctenu kiselinu, i bademovu kiselinu; i b) soli organskih i anorganskih kiselina na osnovu sadržaja kationa odabranih između skupine koja sadržava alkalne katione, zemljane alkalne katione, amonijeve katione, alifatski supstituirane amonijeve katione i aromatski supstituirane amonijeve katione.54. The compound according to claim 39, which is a pharmaceutically acceptable salt of the compound of formula 1, characterized in that it is selected from the group consisting of a) salts of bases of organic acids and inorganic acids selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2- naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) salts of organic and inorganic acids based on the content of cations selected from the group containing alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 55. Farmaceutski sastav, naznačen time, da obuhvaća spoj iz zahtjeva l ili farmaceutski prihvatljivu sol spoja formule I i fiziološki prihvatljivi nosač.55. Pharmaceutical composition, characterized in that it comprises the compound of claim 1 or a pharmaceutically acceptable salt of the compound of formula I and a physiologically acceptable carrier. 56. Farmaceutski sastav, naznačen time, da obuhvaća spoj iz zahtjeva 2 koji u sastavu ima formulu I ili njegovu farmaceutski prihvatljivu sol, i fiziološki prihvatljivi nosač.56. Pharmaceutical composition, characterized in that it comprises the compound from claim 2, which has formula I or its pharmaceutically acceptable salt, and a physiologically acceptable carrier. 57. Farmaceutski sastav, naznačen time, da obuhvaća spoj iz zahtjeva 33, koji u sastavu ima formulu I ili njegovu farmaceutski prihvatljivu sol, i fiziološki prihvatljivi nosač.57. Pharmaceutical composition, characterized in that it comprises the compound from claim 33, which has formula I or its pharmaceutically acceptable salt in the composition, and a physiologically acceptable carrier. 58. Farmaceutski sastav, naznačen time, da obuhvaća spoj iz zahtjeva 38, koji u sastavu ima formulu I ili njegovu farmaceutski prihvatljivu sol, i fiziološki prihvatljivi nosač.58. A pharmaceutical composition, characterized in that it comprises a compound from claim 38, which has formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 59. Farmaceutski sastav, naznačen time, da obuhvaća spoj iz zahtjeva 39, koji u sastavu ima formulu I ili njegovu farmaceutski prihvatljivu sol, i fiziološki prihvatljivi nosač.59. Pharmaceutical composition, characterized in that it comprises the compound from claim 39, which has formula I or its pharmaceutically acceptable salt in the composition, and a physiologically acceptable carrier. 60. Spoj, naznačen time, da je odabran iz skupine koja se sastoji od 3-tert butil fenil uree u gore navedenoj Tablici 1; 5-tert butil-2-metoksi fenil uree u gore navedenoj Tablici 2; 5-(trifluormetil)-2-fenil uree u gore navedenoj Tablici 3; 3-(trifluormetil)-4-klorfenil uree u gore navedenoj Tablici 4; 3-(trifluormetil)-4-bromfenil uree u gore navedenoj Tablici 5; 5-(trifluormetil)-4-klor-2-metoksifenil uree u gore navedenoj Tablici 6; uree 101 - 103 u gore navedenoj Tablici 7;60. A compound selected from the group consisting of 3-tert butyl phenyl urea in Table 1 above; 5-tert butyl-2-methoxy phenyl urea in Table 2 above; 5-(trifluoromethyl)-2-phenyl urea in Table 3 above; 3-(trifluoromethyl)-4-chlorophenyl urea in Table 4 above; 3-(trifluoromethyl)-4-bromophenyl urea in Table 5 above; 5-(trifluoromethyl)-4-chloro-2-methoxyphenyl urea in Table 6 above; urea 101 - 103 in the above Table 7; 61. Spoj, naznačen time, da je odabran iz skupine koja se sastoji od 3-te.rt-butil fenil uree: N-(3-tert-butilfenil)-N'-(4-(3-(N-metilkarbamoil)fenoksi) fenil urea i N-(3-tert-butilfenil)-N'-(4-(4-acetilfenoksi) fenil urea; 5-tert-butil fenil uree: N-(5-tert-butil-2-metoksifenil)-N'-(4-(1,3-dioksoindolin-5-il oksi)fenil) urea i N-(5-tert-butil-2-metoksifenil)-N'-(4-(1-oksoizoindolin-5-il oksi)fenil) urea i N-(5-tert-butil-2-metoksifenil)-N'-(4-(4-(-metoksi-3-(N-metil karbamoil)fenoksi)fenil) urea i N-(5-terfr-butil-2-metoksifenil)-N'-(4-(3-(N-metilkarbamoil) fenoksi)fenil) urea; 2-metoksi-5-trifluormetil)fenil uree: N-(2-metoksi-5-(trifluormetil)fenil)-N'-(3-(2-karbamoil-4-piridiloksi)fenil urea i N-(2-metoksi-5-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(karbamoil-4-piridiloksi)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiltio)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(2-klor-4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, i N-(2-metoksi-5-(trifluormetil)fenil)-N'-(3-klor-4-(2-(N-metilkarbamoil) (4-piridiloksi) fenil urea; 4-klor-3-(trifluormetil)fenil uree: N-(4-klor-3-(trifluormetil)fenil)-N'-(3-(2-karbamoil-4-piridiloksi)fenil urea i N-(4-klor-3-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, N-(4-klor-3-(trifluormetil)fenil)-N'-(4-(2-karbamoil-4-piridiloksi)fenil urea, N-(4-klor-3-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea. 4-brom-3-(trifluormetil)fenil uree: N-(4-brom-3-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil-4-piridiloksi)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil-4-piridiloksi)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil-4-piridiltio)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N-(2-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(3-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi)fenil ureaf i 2-metoksi-4-klor-5-(trifluormetil)fenil uree: N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N'-(3-(2-(N-metil karbamoil)-4-piridiloksi)fenil urea, N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N'-(4-(2-(N-metil karbamoil)-4-piridiloksi) fenil urea i N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N'-(2-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi)fenil urea i N-(2-metoksi-4-klor-5-(trifluormetil) fenil)-N'-(3-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi)fenil urea.61. A compound selected from the group consisting of 3-tert-butyl phenyl urea: N-(3-tert-butylphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and N-(3-tert-butylphenyl)-N'-(4-(4-acetylphenoxy)phenyl urea; 5-tert-butyl phenyl urea: N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1,3-dioxoindolin-5-yl oxy)phenyl)urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1-oxoisoindolin-5-yl oxy)phenyl)urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(4-(-methoxy-3-(N-methyl carbamoyl)phenoxy)phenyl) urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl)urea; 2-methoxy-5-trifluoromethyl)phenyl urea: N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl urea and N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(carbamoyl-4-pyridyloxy)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, and N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy) phenyl urea); 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea. 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl-4-pyridyloxy)phenyl urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-4-pyridyloxy)phenyl urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl-4-pyridylthio)phenyl urea and 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 ureaph and 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methyl carbamoyl)-4-pyridyloxy)phenyl urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methyl carbamoyl)-4-pyridyloxy)phenyl urea and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl urea and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl urea). 62. Postupak tretiranja rasta kancerogenih stanica posredovanjem raf kinaze, naznačen time, da uključuje upotrebu spoja formule I iz zahtjeva 1.62. A method of treating the growth of cancerous cells mediated by raf kinase, characterized in that it includes the use of the compound of formula I from claim 1. 63. Postupak tretiranja rasta kancerogenih stanica posredovanjem raf kinaze, naznačen time, da uključuje upotrebu spoja formule I iz zahtjeva 33.63. A method of treating the growth of cancerous cells mediated by raf kinase, characterized in that it includes the use of a compound of formula I from claim 33. 64. Postupak tretiranja rasta kancerogenih stanica posredovanjem raf kinaze, naznačen time, da uključuje upotrebu spoja formule I iz zahtjeva 38.64. A method of treating cancer cell growth mediated by raf kinase, characterized in that it includes the use of a compound of formula I from claim 38. 65. Postupak tretiranja rasta kancerogenih stanica posredovanjem raf kinaze, naznačen time, da uključuje upotrebu spoja formule I iz zahtjeva 39.65. A method of treating cancerous cell growth mediated by raf kinase, characterized in that it includes the use of a compound of formula I from claim 39. 66. Postupak tretiranja rasta kancerogenih stanica posredovanjem raf kinaze, naznačen time, da uključuje upotrebu spoja odabranog iz skupine koja sadržava 3-tert butil fenil urea iz gore navedene Tablice 1; 5-tert butil-2-metoksi fenil uree iz gore navedene Tablice 2; 5-(trifluormetil)-2-fenil urea iz gore navedene Tablice 3; 3-(trifluormetil)-4-klorfenil urea iz gore navedene Tablice 4; 3-(trifluormetil)-4-bromfenil urea iz gore navedene Tablice 5; 5-(trifluormetil)-4-klor-2-metoksifenil urea iz gore navedene Tablice 6; uree 101 - 103 iz gore navedene Tablice 7;66. A method of treating cancerous cell growth mediated by raf kinase, characterized in that it includes the use of a compound selected from the group consisting of 3-tert butyl phenyl urea from the above Table 1; 5-tert butyl-2-methoxy phenyl urea from Table 2 above; 5-(trifluoromethyl)-2-phenyl urea from Table 3 above; 3-(trifluoromethyl)-4-chlorophenyl urea from Table 4 above; 3-(trifluoromethyl)-4-bromophenyl urea from Table 5 above; 5-(trifluoromethyl)-4-chloro-2-methoxyphenyl urea from Table 6 above; urea 101 - 103 from the above Table 7; 67. Postupak tretiranja rasta kancerognih stanica posredovanjem raf kinaze, naznačen time, da uključuje upotrebu spoja odabranog iz skupine koja sadržava 3-tert-butil fenil uree: N-(3-tert-butilfenil)-N'-(4-(3-(N-metilkarbamoil)fenoksi) fenil urea i N-(3-tert-butilfenil)-N'-(4-(4-acetilfenoksi) fenil urea; 5-tert-butil-2-metoksifenil uree: N-(5-tert-butil-2-metoksifenil)-N'-(4-(1,3-dioksoizoindolin-5-iloksi)fenil urea i N-(5-tert-butil-2-metoksifenil)-N'-(4-(1-oksoizoindolin-5-iloksi)fenil urea i N-(5-tert-butil-2-metoksifenil)-N'-(4-(4-(-metoksi-3-(N-metilkarbamoil)fenoksi)fenil urea, i N-(5-tert-butil-2-metoksifenil)-N'-(4-(3-Cimeti! karbamoil) fenoksi)fenil urea; 2-metoksi-5-trifluormetil)fenil uree: N-(2-metoksi-5-(trifluormetil)fenil)-N'-(3-(2-karbamoil-4-piridiloksi)fenil urea i N-(2-metoksi-5-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(karbamoil-4-piridiloksi)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiltio)fenil urea, N-(2-metoksi-5-(trifluormetil)fenil)-N'-(2-klor-4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, i N-(2-metoksi-5-(trifluormetil)fenil)-N'-(3-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi)fenil urea, i 4-klor-3-(trifluormetil)fenil uree: N-(4-klor-3-(trifluormetil)fenil)-N'-(3-(2-karbamoil-4-piridiloksi)fenil urea i N-(4-klor-3-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea, N-(4-klor-3-(trifluormetil)fenil)-N'-(4-(2-karbamoil-4-piridiloksi)fenil urea, N-(4-klor-3-(trifluormetil)fenil)-N'-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea; 4-brom-3-(trifluormetil)fenil uree: N-(4-brom-3-(trifluormetil)fenil)-N'-(3-(2-metilkarbamoil-4-piridiloksi)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(4-(2-metilkarbamoil-4-piridiloksi)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil-4-piridiltio)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(2-klor-4-(2-(N-metilkarbamoil-4-piridiloksi)fenil urea i N-(4-brom-3-(trifluormetil)fenil)-N'-(3-klor-4-(2-(N-metilkarbamoil-4-piridiloksi)fenil urea i 2-metoksi-4-klor-5-(trifluormetil)fenil uree: N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N'-(3-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea i N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N-(4-(2-(N-metilkarbamoil)-4-piridiloksi)fenil urea i N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N'-(2-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi) fenil urea i N-(2-metoksi-4-klor-5-(trifluormetil)fenil)-N'-(3-klor-4-(2-(N-metilkarbamoil)(4-piridiloksi)fenil urea.67. A method of treating cancer cell growth mediated by raf kinase, characterized in that it includes the use of a compound selected from the group consisting of 3-tert-butyl phenyl urea: N-(3-tert-butylphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and N-(3-tert-butylphenyl)-N'-(4-(4-acetylphenoxy)phenyl urea; 5-tert-butyl-2-methoxyphenyl urea: N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1-oxoisoindolin-5-yloxy)phenyl urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(4-(-methoxy-3-(N-methylcarbamoyl)phenoxy)phenyl urea, and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-Cymethylcarbamoyl)phenoxy)phenyl urea; 2-methoxy-5-trifluoromethyl)phenyl urea: N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl urea and N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(carbamoyl-4-pyridyloxy)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, and N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl urea, and 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea; 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-methylcarbamoyl-4-pyridyloxy)phenyl urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-methylcarbamoyl-4-pyridyloxy)phenyl urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl-4-pyridylthio)phenyl urea and 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)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl urea and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl urea).
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