ES2360502T3 - 2,4-DI (PHENYLAMINE) USEFUL PYRIMIDINS FOR THE TREATMENT OF NEOPLASTIC DISEASES AND INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. - Google Patents

Abstract

Compuesto de formula I **Fórmula** en la que R0 o R2 son en cada caso independientemente hidrogeno, piperazino, N-metilpiperazino o 1-metil-4-piperidiloxi; R1 es hidrogeno, piperazino, N-metilpiperazino, morfolino, 1-metil-4-piperidiniloxi, 3-morfolinopropoxi o 2- morfolinoetoxi; R3 es sulfamoilo, metilsulfamoilo o propilsulfamoilo; o la pareja de sustituyentes adyacentes R0 y R1 o R1 y R2 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R2 y R3 es -CH2-NH-CO- o -CH2-NH-SO2-; R4 es hidrogeno; R5 es hidrogeno, cloro, bromo, trifluorometilo o nitro; R6 es hidrogeno; R7 y R9 son en cada caso independientemente hidrogeno, metilo, isopropilo, trifluorometilo, fenilo, o-, m- o pmetoxifenilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, isopropoxi, fenoxi, 3- morfolinopropoxi, 2-morfolinoetoxi, 2-(1-imidazolil)etoxi, dimetilamino, fluoro, morfolinocarbonilo, piperidinocarbonilo, piperazinocarbonilo o ciclohexilcarbamoilo; R8 es hidrogeno, metilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, trifluoro-metoxi, fenoxi, 1- metil-4-piperidiloxi, 3-morfolino-propoxi, 2-morfolinoetoxi, 3-(N-metilpiperazino)-propoxi, metilamino, fluoro, cloro, sulfamoilo o nitro; y R10 es metilo, butilo, metoxi, etoxi, 2-(1-imidazolil)-etoxi, metilamino, dimetilamino o fluoro; o la pareja de sustituyentes adyacentes R7 y R8 o R8 y R9 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R9 y R10 es -NH-CH=CH-, CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-o -O-CF2-O-; y A es C.Compound of formula I ** Formula ** in which R0 or R2 are independently hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy in each case; R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2- morpholinoethoxy; R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the pair of adjacent substituents R0 and R1 or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO- or -CH2-NH-SO2-; R4 is hydrogen; R5 is hydrogen, chlorine, bromine, trifluoromethyl or nitro; R6 is hydrogen; R7 and R9 are independently hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or pmethoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3- morpholinopropoxy, 2- morpholinoethoxy, 2- (1-imidazolyl) ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoro-methoxy, phenoxy, 1- methyl-4-piperidyloxy, 3-morpholino-propoxy, 2-morpholinoethoxy, 3- (N-methylpiperazino ) -propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R 10 is methyl, butyl, methoxy, ethoxy, 2- (1-imidazolyl) -ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O-, or the pair of adjacent substituents R9 and R10 is -NH-CH = CH-, CH = N-NH-, -CH2- CH2-CH2-, -CH2-CH2-CH2-CH2-or -O-CF2-O-; and A is C.

Description

[0001] La presente invención se refiere a derivados de pirimidina novedosos, a procedimientos para su preparación, a su uso como agentes farmacéuticos y a composiciones farmacéuticas que los comprenden. [0001] The present invention relates to novel pyrimidine derivatives, processes for their preparation, their use as pharmaceutical agents and pharmaceutical compositions comprising them.

[0002] Más concretamente, la presente invención proporciona en un primer aspecto un compuesto de fórmula 10 I [0002] More specifically, the present invention provides in a first aspect a compound of formula 10 I

imagen1image 1

en la que R0 o R2 son en cada caso independientemente hidrógeno, piperazino, N-metilpiperazino o 1-metil-4-piperidiloxi; R1 es hidrógeno, piperazino, N-metilpiperazino, morfolino, 1-metil-4-piperidiniloxi, 3-morfolinopropoxi o 2wherein R0 or R2 are independently hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy in each case; R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2

15 morfolinoetoxi; R3 es sulfamoílo, metilsulfamoílo o propilsulfamoílo; o la pareja de sustituyentes adyacentes R0 y R1 o R1 y R2 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R2 y R3 es -CH2-NH-CO-o -CH2-NH-SO2-; R4 es hidrógeno; Morpholinoethoxy; R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or the couple of adjacent substituents R0 and R1 or R1 and R2 is -O-CH2-O-, or the couple of adjacent substituents R2 and R3 is -CH2-NH-CO-or -CH2-NH-SO2-; R4 is hydrogen;

20 R5 es hidrógeno, cloro, bromo, trifluorometilo o nitro; R6 es hidrógeno; R7 y R9 son en cada caso independientemente hidrógeno, metilo, isopropilo, trifluorometilo, fenilo, o-, m-o pmetoxifenilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, isopropoxi, fenoxi, 3morfolinopropoxi, 2-morfolinoetoxi, 2-(1-imidazolil)etoxi, dimetilamino, fluoro, morfolinocarbonilo, piperidino-carbonilo, R5 is hydrogen, chlorine, bromine, trifluoromethyl or nitro; R6 is hydrogen; R7 and R9 are in each case independently hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, or pmethoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3morpholinopropoxy, 2-morpholinoetho (1-imidazolyl) ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl,

25 piperazinocarbonilo o ciclohexilcarbamoílo; R8 es hidrógeno, metilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, trifluoro-metoxi, fenoxi, 1metil-4-piperidiloxi, 3-morfolino-propoxi, 2-morfolinoetoxi, 3-(N-metilpiperazino)-propoxi, metilamino, fluoro, cloro, sulfamoílo o nitro; y R10 es metilo, butilo, metoxi, etoxi, 2-(1-imidazolil)-etoxi, metilamino, dimetilamino o fluoro; o Piperazinocarbonyl or cyclohexylcarbamoyl; R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoro-methoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholino-propoxy, 2-morpholinoethoxy, 3- (N-methylpiperazino) - propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R 10 is methyl, butyl, methoxy, ethoxy, 2- (1-imidazolyl) -ethoxy, methylamino, dimethylamino or fluoro; or

30 la pareja de sustituyentes adyacentes R7 y R8 o R8 y R9 es -O-CH2-O-o la pareja de sustituyentes adyacentes R9 y R10 es -NH-CH=CH-, CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-o -O-CF2-O-; y A es C, 30 the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-Oo the pair of adjacent substituents R9 and R10 is -NH-CH = CH-, CH = N-NH-, -CH2-CH2-CH2 -, -CH2-CH2-CH2-CH2-or -O-CF2-O-; and A is C,

y sales del mismo. and you leave it.

35 [0003] Los términos generales usados anteriormente y en lo sucesivo en el presente documento tienen preferentemente, salvo que se indique lo contrario, los significados siguientes en el contexto de esta memoria descriptiva: 35 [0003] The general terms used previously and hereinafter preferably have, unless otherwise indicated, the following meanings in the context of this specification:

40 [0004] Cuando los compuestos, las sales y similares se usan en plural, éstos también se refieren a un solo compuesto, sal o similar. [0004] When the compounds, salts and the like are used in the plural, they also refer to a single compound, salt or the like.

[0005] Cualquier átomo de carbono asimétrico puede estar presente en la configuración (R), (S) o (R,S), preferentemente en la configuración (R) o (S). Por lo tanto, los compuestos pueden estar presentes en forma de 45 mezclas de isómeros o como isómeros puros, preferentemente en forma de diaestereoisómeros enantioméricamente puros. [0005] Any asymmetric carbon atom may be present in the (R), (S) or (R, S) configuration, preferably in the (R) or (S) configuration. Therefore, the compounds may be present in the form of mixtures of isomers or as pure isomers, preferably in the form of enantiomerically pure diastereoisomers.

[0006] La invención también se refiere a los posibles tautómeros de los compuestos de fórmula I. [0006] The invention also relates to the possible tautomers of the compounds of formula I.

[0007] Alquilo C1-C8 denota un radical alquilo que presenta entre 1 y hasta 8, especialmente hasta 4 átomos de carbono, siendo los radicales en cuestión lineales o ramificados con ramificaciones simples o múltiples; preferentemente, alquilo C1-C8 es butilo, tal como n-butilo, sec.-butilo, isobutilo, terc-butilo, propilo, tal como n-propilo [0007] C1-C8 alkyl denotes an alkyl radical having between 1 and up to 8, especially up to 4 carbon atoms, the radicals in question being linear or branched with single or multiple branches; preferably, C1-C8 alkyl is butyl, such as n-butyl, sec.-butyl, isobutyl, tert-butyl, propyl, such as n-propyl

o isopropilo, etilo o metilo; especialmente metilo, propilo o terc-butilo. or isopropyl, ethyl or methyl; especially methyl, propyl or tert-butyl.

[0008] Alquenilo C2-C8 denota un radical alquenilo que presenta entre 2 y hasta 8, especialmente hasta 5 átomos de carbono, siendo los radicales en cuestión lineales o ramificados con ramificaciones simples o múltiples; preferentemente, alquenilo C2-C8 es pentenilo, tal como 3-metil-2-buten-2-ilo, butenilo, tal como 1-o 2-butenilo o 2buten-2-ilo, propenilo, tal como 1-propenilo o alilo, o vinilo. [0008] C2-C8 alkenyl denotes an alkenyl radical having between 2 and up to 8, especially up to 5 carbon atoms, the radicals in question being linear or branched with single or multiple branches; preferably, C2-C8 alkenyl is pentenyl, such as 3-methyl-2-buten-2-yl, butenyl, such as 1-or 2-butenyl or 2buten-2-yl, propenyl, such as 1-propenyl or allyl, or vinyl

[0009] Alquinilo C2-C8 denota un radical alquinilo que presenta entre 2 y hasta 8, especialmente hasta 5 átomos de carbono, siendo los radicales en cuestión lineales o ramificados; preferentemente, alquinilo C2-C8 es propinilo, tal como 1-propinilo o propargilo, o acetilenilo. [0009] C2-C8 alkynyl denotes an alkynyl radical having between 2 and up to 8, especially up to 5 carbon atoms, the radicals in question being linear or branched; preferably, C2-C8 alkynyl is propynyl, such as 1-propynyl or propargyl, or acetylenyl.

[0010] Cicloalquilo C3-C8 denota un radical cicloalquilo que presenta entre 3 y hasta 8 átomos de carbono, tal como ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, cicloheptilo o ciclooctilo, preferentemente ciclopropilo, ciclopentilo o ciclohexilo. [0010] C3-C8 cycloalkyl denotes a cycloalkyl radical having between 3 and up to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.

trifluorometilo o pentafluoroetilo. trifluoromethyl or pentafluoroethyl.

[0011] [0011]

Alcoxi C1-C8 es, en especial, metoxi, etoxi, isopropiloxi o terc-butoxi. C1-C8 alkoxy is, in particular, methoxy, ethoxy, isopropyloxy or tert-butoxy.

[0012] [0012]

Hidroxialquilo C1-C8 es, en especial, hidroximetilo, 2-hidroxietilo o 2-hidroxi-2-propilo. C1-C8 hydroxyalkyl is, in particular, hydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.

[0013] [0013]

Hidroxialcoxi C1-C8 es, en especial, 2-hidroxietoxi o 3-hidroxipropoxi. Hydroxyalkoxy C1-C8 is, in particular, 2-hydroxyethoxy or 3-hydroxypropoxy.

[0014] [0014]

Alcoxi-C1-C8-alcoxi-C1-C8 es, en especial, 2-metoxietoxi. Alkoxy-C1-C8-alkoxy-C1-C8 is, in particular, 2-methoxyethoxy.

[0015] [0015]

Alcoxi-C1-C8-alquilo-C1-C8 es, en especial, metoximetilo, 2-metoxietilo o 2-etoxietilo. C1-C8-alkoxy-C1-C8-alkyl is, in particular, methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.

[0016] [0016]

Halógeno es preferentemente flúor, cloro, bromo o yodo, especialmente flúor, cloro o bromo. Halogen is preferably fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

[0017] [0017]

Haloalquilo C1-C8 es preferentemente cloroalquilo C1-C8 o fluoroalquilo C1-C8, especialmente C1-C8 haloalkyl it is preferably C1-C8 chloroalkyl or C1-C8 fluoroalkyl, especially

[0018] Haloalcoxi C1-C8 es preferentemente cloroalcoxi C1-C8 o fluoroalcoxi C1-C8, especialmente trifluorometoxi. [0018] C1-C8 haloalkoxy is preferably C1-C8 chloroalkoxy or C1-C8 fluoroalkoxy, especially trifluoromethoxy.

[0019] Alcoxi-C1-C8-carbonilo es, en especial, terc-butoxicarbonilo, isopropoxicarbonilo, metoxicarbonilo o etoxicarbonilo. [0019] Alkoxy-C1-C8-carbonyl is, in particular, tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.

[0020] Carbamoílo no sustituido o sustituido es carbamoílo sustituido con uno o dos sustituyentes seleccionados entre hidrógeno, alquilo C1-C8, alquenilo C2-C8, alquinilo C2-C8, cicloalquilo C3-C8, cicloalquil-C3-C8alquilo C1-C8, aril-C5-C10-alquilo C1-C8, hidroxialquilo C1-C8, alcoxi-C1-C8-alquilo C1-C8, haloalquilo C1-C8, arilo C5-C10 no sustituido o sustituido, o aminoalquilo C1-C8 o carbamoílo, en el que los sustituyentes y el átomo de nitrógeno del grupo carbamoílo representan heterociclilo de 5 a 6 miembros que comprende adicionalmente 0, 1 o 2 heteroátomos seleccionados entre N, O y S; y es preferentemente carbamoílo, metilcarbamoílo, dimetil-carbamoílo, propilcarbamoílo, hidroxietilmetil-carbamoílo, di(hidroxietil)carbamoílo, dimetilaminoetil-carbamoílo, o pirrolidinocarbonilo, piperidinocarbonilo, N-metil-piperazinocarbonilo o morfolinocarbonilo, especialmente carbamoílo [0020] Unsubstituted or substituted carbamoyl is carbamoyl substituted with one or two substituents selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 cycloalkyl, C1-C8 alkyl, aryl -C5-C10-C1-C8 alkyl, hydroxy C1-C8 alkyl, C1-C8 alkoxy-C1-C8 alkyl, C1-C8 haloalkyl, unsubstituted or substituted C5-C10 aryl, or C1-C8 aminoalkyl or carbamoyl, in the that the substituents and the nitrogen atom of the carbamoyl group represent 5- to 6-membered heterocyclyl additionally comprising 0, 1 or 2 heteroatoms selected from N, O and S; and it is preferably carbamoyl, methylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl, hydroxyethylmethylcarbamoyl, di (hydroxyethyl) carbamoyl, dimethylaminoethylcarbamoyl, or pyrrolidinocarbonyl, piperidinocarbonyl, N-methyl-piperazinocarbonyl or carbonylcarbonylobonylcarbonyl

o dimetilcarbamoílo. or dimethylcarbamoyl.

[0021] Sulfamoílo no sustituido o sustituido es sulfamoílo sustituido con uno o dos sustituyentes seleccionados entre hidrógeno, alquilo C1-C8, alquenilo C2-C8, alquinilo C2-C8, cicloalquilo C3-C8, cicloalquil-C3-C8-alquilo C1-C8, arilC5-C10-alquilo C1-C8, hidroxialquilo C1-C8, alcoxi-C1-C8-alquilo C1-C8, haloalquilo C1-C8, arilo C5-C10 no sustituido o sustituido, o aminoalquilo C1-C8 o sulfamoílo, en el que los sustituyentes y el átomo de nitrógeno del grupo sulfamoílo representan heterociclilo de 5 a 6 miembros que comprende adicionalmente 0, 1 o 2 heteroátomos seleccionados entre N, O y S; y es preferentemente sulfamoílo, metilsulfamoílo, propilsulfamoílo, ciclopropilmetilsulfamoílo, 2,2,2-trifluoroetilsulfamoílo, dimetilaminoetilsulfamoílo, dimetilsulfamoílo, hidroxietilmetilsulfamoílo, di(hidroxietil)sulfamoílo, o pirrolidinosulfonilo, piperidinosulfonilo, N-metilpiperazinosulfonilo [0021] Unsubstituted or substituted sulfamoyl is sulfamoyl substituted with one or two substituents selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C8 alkyl , arylC5-C10-C1-C8 alkyl, hydroxy C1-C8 alkyl, C1-C8 alkoxy-C1-C8 alkyl, C1-C8 haloalkyl, unsubstituted or substituted C5-C10 aryl, or C1-C8 aminoalkyl or sulfamoyl, in the that the substituents and the sulfamoyl group nitrogen atom represent 5 to 6 membered heterocyclyl additionally comprising 0, 1 or 2 heteroatoms selected from N, O and S; and is preferably sulfamoyl, methylsulfamoyl, propylsulfamoyl, cyclopropylmethylsulfamoyl, 2,2,2-trifluoroethylsulfamoyl, dimethylaminoethylsulfamoyl, dimethylsulfamoyl, hydroxyethylmethylsulfamoyl, di (hydroxyethyl) sulfamoyl, or pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, pyrrolidinosulfyl, methyl

o morfolinosulfonilo, especialmente sulfamoílo o metilsulfamoílo. or morpholinosulfonyl, especially sulfamoyl or methylsulfamoyl.

[0022] Amino no sustituido o sustituido es amino sustituido con uno o dos sustituyentes seleccionados entre hidrógeno, alquilo C1-C8, alquenilo C2-C8, alquinilo C2-C8, cicloalquilo C3-C8, cicloalquil-C3-C8-alquilo C1-C8, aril-C5C10-alquilo C1-C8, hidroxialquilo C1-C8, alcoxi-C1-C8-alquilo C1-C8, haloalquilo C1-C8, arilo C5-C10 no sustituido o sustituido, aminoalquilo C1-C8, acilo, por ejemplo formilo, alquil-C1-C8-carbonilo, aril-C5-C10-carbonilo, alquil-C1-C8sulfonilo o aril-C5-C10-sulfonilo, y es preferentemente amino, metilamino, dimetilamino, propilamino, bencilamino, hidroxietilmetilamino, di(hidroxietil)amino, dimetilamino-etilamino, acetilamino, acetil-metilamino, benzoilamino, metilsulfonilamino o fenilsulfonilamino, especialmente amino o dimetilamino. [0022] Unsubstituted or substituted amino is amino substituted with one or two substituents selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C8 alkyl , aryl-C5C10-C1-C8 alkyl, hydroxy C1-C8 alkyl, C1-C8 alkoxy-C1-C8 alkyl, C1-C8 haloalkyl, unsubstituted or substituted C5-C10 aryl, C1-C8 aminoalkyl, acyl, for example formyl , C1-C8-alkylcarbonyl, aryl-C5-C10-carbonyl, C1-C8-sulfonyl or aryl-C5-C10-sulfonyl, and is preferably amino, methylamino, dimethylamino, propylamino, benzylamino, hydroxyethylmethylamino, di (hydroxyethyl) amino, dimethylamino-ethylamino, acetylamino, acetyl-methylamino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, especially amino or dimethylamino.

[0023] Aminoalquilo C1-C8 es, en especial, aminoetilo, metilaminoetilo, dimetilaminoetilo o dimetilaminopropilo. [0023] C1-C8 aminoalkyl is, in particular, aminoethyl, methylaminoethyl, dimethylaminoethyl or dimethylaminopropyl.

[0024] Arilo C5-C10 no sustituido o sustituido es, por ejemplo, fenilo, indenilo, indanilo, naftilo o 1,2,3,4tetrahidronaftalenilo, sustituido opcionalmente con alquilo C1-C8, alcoxi-C1-C8-alquilo C1-C8, haloalquilo C1-C8, hidroxi, alcoxi C1-C8, metilendioxi, amino, amino sustituido, halógeno, carboxi, alcoxi-C1-C8-carbonilo, carbamoílo, sulfamoílo, ciano o nitro; preferentemente fenilo, tolilo, trifluorometilfenilo, metoxifenilo, dimetoxifenilo, metilendioxifenilo, clorofenilo o bromofenilo, pudiendo encontrarse los sustituyentes en posición orto, meta o para, preferentemente meta o para. [0024] C5-C10 unsubstituted or substituted aryl is, for example, phenyl, indenyl, indanyl, naphthyl or 1,2,3,4-tetrahydronaphthalenyl, optionally substituted with C1-C8 alkyl, C1-C8 alkoxy-C1-C8 alkyl , C1-C8 haloalkyl, hydroxy, C1-C8 alkoxy, methylenedioxy, amino, substituted amino, halogen, carboxy, C1-C8-alkoxycarbonyl, carbamoyl, sulfamoyl, cyano or nitro; preferably phenyl, tolyl, trifluoromethylphenyl, methoxyphenyl, dimethoxyphenyl, methylenedioxyphenyl, chlorophenyl or bromophenyl, the substituents being found in ortho, meta or para position, preferably meta or para.

seleccionados entre N, O y S puede estar insaturado, parcialmente insaturado o saturado y estar condensado selected from N, O and S may be unsaturated, partially unsaturated or saturated and condensed

[0025] [0025]

Ariloxi C5-C10 es, en especial, fenoxi o metoxifenoxi, por ejemplo, p-metoxifenoxi. C5-C10 aryloxy is, in particular, phenoxy or methoxyphenoxy, for example, p-methoxyphenoxy.

[0026] [0026]

Aril-C5-C10-alquilo C1-C8 es, en especial, bencilo o 2-feniletilo. Aryl-C5-C10-C1-C8 alkyl is, in particular, benzyl or 2-phenylethyl.

[0027] [0027]

Aril-C5-C10-alcoxi C1-C8 es, en especial, benciloxi o 2-feniletoxi. Aryl-C5-C10-C1-C8 alkoxy is, in particular, benzyloxy or 2-phenylethoxy.

[0028] [0028]

Heterociclilo de 5 o 6 miembros no sustituido o sustituido que comprende 1, 2 o 3 heteroátomos 5 or 6-membered unsubstituted or substituted heterocyclyl comprising 1, 2 or 3 heteroatoms

adicionalmente con un grupo benzo o un grupo heterociclilo de 5 o 6 miembros, y puede estar unido a través de un heteroátomo o un átomo de carbono y es, por ejemplo, pirrolilo, indolilo, pirrolidinilo, imidazolilo, benzimidazolilo, pirazolilo, triazolilo, benzotriazolilo, tetrazolilo, piridilo, quinolinilo, isoquinolinilo, 1,2,3,4-tetrahidroquinolinilo, piperidilo, pirimidinilo, pirazinilo, piperazinilo, purinilo, tetrazinilo, oxazolilo, isoxalilo, morfolinilo, tiazolilo, benzotiazolilo, oxadiazolilo y benzoxadiazolilo. Los sustituyentes considerados son alquilo C1-C8, hidroxialquilo C1C8, alcoxi-C1-C8-alquilo C1-C8, alcoxi-C1-C8-alcoxi C1-C8, haloalquilo C1-C8, hidroxi, amino, amino sustituido, alcoxi C1-C8, halógeno, carboxi, alquil-C1-C8-carbonilo, alcoxi-C1-C8-carbonilo, carbamoílo, alquil-C1-C8-carbamoílo, ciano, oxo, o heterociclilo de 5 o 6 miembros no sustituido o sustituido como se define en este párrafo. Heterociclilo de 5 o 6 miembros comprende preferentemente 1 o 2 heteroátomos seleccionados entre N, O y S y es especialmente indolilo, pirrolidinilo, pirrolidonilo, imidazolilo, N-metilimidazolilo, benzimidazolilo, S,S-dioxoisotiazolidinilo, piperidilo, 4-acetilaminopiperidilo, 4-metilcarbamoilpiperidilo, 4-piperidinopiperidilo, 4-cianopiperidilo, piperazinilo, Nmetilpiperazinilo, N-(2-hidroxietil)piperazinilo, morfolinilo, 1-aza-2,2-dioxo-2-tiaciclohexilo o sulfolanilo. additionally with a benzo group or a 5- or 6-membered heterocyclyl group, and may be linked through a heteroatom or a carbon atom and is, for example, pyrrolyl, indolyl, pyrrolidinyl, imidazolyl, benzimidazolyl, pyrazolyl, triazolyl, benzotriazolyl , tetrazolyl, pyridyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, piperidyl, pyrimidinyl, pyrazinyl, piperazinyl, purinyl, tetrazinyl, oxazolyl, isoxalyl, morpholinyl, thiazolyl, benzothiazolyl, oxadiazolyl and benzoxadiazolyl. The substituents considered are C1-C8 alkyl, C1C8 hydroxyalkyl, C1-C8 alkoxy-C1-C8 alkyl, C1-C8 alkoxy-C1-C8 alkoxy, C1-C8 haloalkyl, hydroxy, amino, substituted amino, C1-C8 alkoxy , halogen, carboxy, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, carbamoyl, C1-C8 alkylcarbamoyl, cyano, oxo, or unsubstituted or substituted 5 or 6 membered heterocyclyl as defined in this paragraph. 5 or 6-membered heterocyclyl preferably comprises 1 or 2 heteroatoms selected from N, O and S and is especially indolyl, pyrrolidinyl, pyrrolidonyl, imidazolyl, N-methylimidazolyl, benzimidazolyl, S, S-dioxoisothiazolidinyl, piperidyl, 4-acetylaminopiperidyl, methylcarbamoylpiperidyl, 4-piperidinopiperidyl, 4-cyanopiperidyl, piperazinyl, Nmethylpiperazinyl, N- (2-hydroxyethyl) piperazinyl, morpholinyl, 1-aza-2,2-dioxo-2-thiacyclohexyl or sulfolanyl.

[0029] En heterocicliloxilo no sustituido o sustituido, heterociclilo presenta el significado antes definido y es especialmente N-metil-4-piperidiloxi. En heterociclil-alcoxi C1-C8 no sustituido o sustituido, heterociclilo presenta el significado antes definido y es especialmente 2-pirrolidinoetoxi, 2-morfolinoetoxi, 3-morfolinopropoxi, 1-metilpiperidin3-il-metoxi, 3-(N-metilpiperazino)propoxi o 2-(1-imidazolil)etoxi. [0029] In unsubstituted or substituted heterocyclyloxy, heterocyclyl has the meaning defined above and is especially N-methyl-4-piperidyloxy. In unsubstituted or substituted heterocyclyl-C1-C8 alkoxy, heterocyclyl has the meaning defined above and is especially 2-pyrrolidinoethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 1-methylpiperidin-3-yl-methoxy, 3- (N-methylpiperazino) propoxy or 2- (1-imidazolyl) ethoxy.

[0030] En un anillo carbocíclico o heterocíclico de 5 o 6 miembros que comprende 0, 1, 2 o 3 heteroátomos seleccionados entre N, O y S y que está formado por dos sustituyentes adyacentes junto con el anillo de benceno, el anillo puede estar sustituido adicionalmente, por ejemplo por alquilo C1-C8, alcoxi C1-C8, haloalquilo C1-C8, hidroxi, amino, aminosustituido, alcoxi C1-C8, halógeno, carboxi, alcoxi-C1-C8-carbonilo, carbamoílo, ciano u oxo. Los dos sustituyentes adyacentes que forman este anillo son preferentemente propileno, butileno, 1-aza-2-propilideno, 3-aza1-propilideno, 1,2-diaza-2-propilideno, 2,3-diaza-1-propilideno, 1-oxapropileno, 1-oxapropilideno, metilendioxi, difluorometilendioxi, 2-aza-1-oxopropileno, 2-aza-2-metil-1-oxopropileno, 1-aza-2-oxopropileno, 2-aza-1,1-dioxo-1tiapropileno o los derivados correspondientes de butileno que forman un anillo de 6 miembros. [0030] In a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S and which is formed by two adjacent substituents together with the benzene ring, the ring may be additionally substituted, for example by C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxy, amino, aminosubstituted, C1-C8 alkoxy, halogen, carboxy, C1-C8-alkoxycarbonyl, carbamoyl, cyano or oxo. The two adjacent substituents that form this ring are preferably propylene, butylene, 1-aza-2-propylidene, 3-aza1-propylidene, 1,2-diaza-2-propylidene, 2,3-diaza-1-propylidene, 1- oxapropylene, 1-oxapropylidene, methylenedioxy, difluoromethylenedioxy, 2-aza-1-oxopropylene, 2-aza-2-methyl-1-oxopropylene, 1-aza-2-oxopropylene, 2-aza-1,1-dioxo-1-thiapropylene or the corresponding butylene derivatives that form a 6-member ring.

[0031] Las sales son, en especial, las sales farmacéuticamente aceptables de los compuestos de fórmula I. [0032] Tales sales se forman, por ejemplo, como sales de adición de ácido, preferentemente con ácidos orgánicos o inorgánicos, a partir de los compuestos de fórmula I con un átomo de nitrógeno básico, especialmente las sales farmacéuticamente aceptables. Los ácidos inorgánicos adecuados son, por ejemplo, haloácidos, tales como ácido clorhídrico, ácido sulfúrico o ácido fosfórico. Los ácidos orgánicos adecuados son, por ejemplo, ácidos carboxílicos, fosfónicos o sulfámicos, por ejemplo ácido acético, ácido propiónico, ácido octanoico, ácido decanoico, ácido dodecanoico, ácido glicólico, ácido láctico, ácido fumárico, ácido succínico, ácido adípico, ácido pimélico, ácido subérico, ácido acelaico, ácido málico, ácido tartárico, ácido cítrico, aminoácidos, tales como ácido glutámico o ácido aspártico, ácido maleico, ácido hidroximaleico, ácido metilmaleico, ácido ciclohexanocarboxílico, ácido adamantanocarboxílico, ácido benzoico, ácido salicílico, ácido 4-aminosalicílico, ácido ftálico, ácido fenilacético, ácido mandélico, ácido cinámico, ácido metano-o etanosulfónico, ácido 2-hidroxietanosulfónico, ácido etano-1,2disulfónico, ácido bencenosulfónico, ácido 2-naftalenosulfónico, ácido 1,5-naftalenodisulfónico, ácido 2-, 3-o 4metilbencenosulfónico, ácido metilsulfúrico, ácido etilsulfúrico, ácido dodecilsulfúrico, ácido N-ciclohexilsulfámico, ácido N-metil-, N-etil-o N-propil-sulfámico u otros ácidos protónicos orgánicos, tales como ácido ascórbico. [0031] The salts are, in particular, the pharmaceutically acceptable salts of the compounds of formula I. [0032] Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from the compounds of formula I with a basic nitrogen atom, especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halo acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid , subic acid, acelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroximaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4- aminosalicylic, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2- , 3-or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid or other organic protonic acids, such as ascorbic acid.

[0033] Para fines de aislamiento o de purificación también es posible usar sales farmacéuticamente inaceptables, por ejemplo picratos o percloratos. Para el uso terapéutico se usan únicamente sales farmacéuticamente aceptables o los compuestos libres (si se pueden administrar en forma de preparaciones farmacéuticas) y, por lo tanto, se prefieren. [0033] For the purpose of isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use only pharmaceutically acceptable salts or free compounds are used (if they can be administered in the form of pharmaceutical preparations) and, therefore, are preferred.

[0034] En vista de la estrecha relación existente entre los nuevos compuestos en forma libre y los que están presentes en forma de sus sales, incluidas las sales que se pueden usar como productos intermedios, por ejemplo en la purificación o identificación de los nuevos compuestos, se entenderá que cualquier referencia que se haga anteriormente o en lo sucesivo a los compuestos libres se refiere también, cuando resulte apropiado y oportuno, a las sales correspondientes. [0034] In view of the close relationship between new compounds in free form and those present in the form of their salts, including salts that can be used as intermediates, for example in the purification or identification of new compounds , it will be understood that any reference made previously or hereafter to the free compounds also refers, when appropriate and appropriate, to the corresponding salts.

[0035] Los compuestos de fórmula I poseen valiosas propiedades farmacológicas, como se ha descrito anteriormente y se describirá en lo sucesivo. [0035] The compounds of formula I possess valuable pharmacological properties, as described above and will be described hereinafter.

[0036] En la fórmula I se prefieren los significados siguientes independientemente, colectivamente o en cualquier combinación o subcombinación. En cada uno de los significados siguientes, A es C: [0036] In formula I the following meanings are preferred independently, collectively or in any combination or sub-combination. In each of the following meanings, A is C:

(a)(to)

R0 o R2 son en cada caso independientemente hidrógeno, N-metilpiperazino o 1-metil-4-piperidiloxi, en particular hidrógeno;  R0 or R2 are in each case independently hydrogen, N-methylpiperazino or 1-methyl-4-piperidyloxy, in particular hydrogen;

(b)(b)

R1 es hidrógeno, piperazino, N-metilpiperazino, morfolino, 1-metil-4-piperidiniloxi, 3-morfolinopropoxi o 2morfolinoetoxi, en particular hidrógeno;  R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2morpholinoethoxy, in particular hydrogen;

(c)(C)

R3 es sulfamoílo, metilsulfamoílo o propilsulfamoílo;  R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl;

(d)(d)

la pareja de sustituyentes adyacentes R0 y R1 o R1 y R2 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R2 y R3 es -CH2-NH-CO-;  the pair of adjacent substituents R0 and R1 or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO-;

(e)(and)

R4 es hidrógeno;  R4 is hydrogen;

(f)(F)

R5 es cloro, bromo, trifluorometilo o nitro, en particular cloro o bromo;  R5 is chlorine, bromine, trifluoromethyl or nitro, in particular chlorine or bromine;

(g)(g)

R6 es hidrógeno;  R6 is hydrogen;

(h)(h)

R7 y R9 son en cada caso independientemente hidrógeno, metilo, isopropilo, trifluorometilo, o-, m-o pmetoxifenilo, morfolino, piperidino, piperazino, N-metilpiperazino, metoxi, etoxi, isopropoxi, fenoxi, 2-(1imidazolil)etoxi, 3-morfolinopropoxi, 2-morfolinoetoxi, dimetilamino, fluoro, morfolinocarbonilo, piperidino-carbonilo, piperazinocarbonilo o ciclohexilcarbamoílo;  R7 and R9 are in each case independently hydrogen, methyl, isopropyl, trifluoromethyl, o-, or pmethoxyphenyl, morpholino, piperidino, piperazino, N-methylpiperazino, methoxy, ethoxy, isopropoxy, phenoxy, 2- (1imidazolyl) ethoxy, 3-morpholinopro , 2-morpholinoethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;

(i)(i)

R8 es hidrógeno, metilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, trifluoro-metoxi, fenoxi, 1-metil-4-piperidiloxi, 3-morfolino-propoxi, 2-morfolinoetoxi, 3-(N-metilpiperazino)-propoxi, metilamino, fluoro, cloro, sulfamoílo o nitro;  R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoro-methoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholino-propoxy, 2-morpholinoethoxy, 3- (N-methylpiperazino ) -propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;

(j)(j)

R10 es metilo, butilo, metoxi, etoxi, 2-(1-imidazolil)-etoxi, metilamino, dimetilamino o fluoro; y  R 10 is methyl, butyl, methoxy, ethoxy, 2- (1-imidazolyl) -ethoxy, methylamino, dimethylamino or fluoro; Y

(k)(k)

la pareja de sustituyentes adyacentes R7 y R8 o R8 y R9 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R9 y R10 es -NH-CH=CH-, CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-o -O-CF2-O-.  the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O-, or the pair of adjacent substituents R9 and R10 is -NH-CH = CH-, CH = N-NH-, -CH2-CH2 -CH2-, -CH2-CH2-CH2-CH2-or -O-CF2-O-.

[0037] Se prefieren especialmente los significados siguientes independientemente, colectivamente o en cualquier combinación o subcombinación: [0037] The following meanings are especially preferred independently, collectively or in any combination or sub-combination:

(a’) R0 o R2 son en cada caso independientemente hidrógeno; (b’) R1 es (c’) R3 es (d’) la pareja de sustituyentes adyacentes R0 y R1 o R1 yR2 es -O-CH2-O-; o la pareja de sustituyentes adyacentes R2 y R3 es -CH2-NH-CO-o -CH2-NH-SO2-; (e’) R4 es hidrógeno; -CH2-NH-CO-o -CH2-NH-SO2-; (f’) R5 es bromo; (g’) R6 es hidrógeno; (h’) R7 y R9 son en cada caso independientemente hidrógeno o metoxi; (a ’) R0 or R2 are independently hydrogen in each case; (b ’) R1 is (c ’) R3 is (d ’) the pair of adjacent substituents R0 and R1 or R1 and R2 is -O-CH2-O-; or the couple of adjacent substituents R2 and R3 is -CH2-NH-CO-or -CH2-NH-SO2-; (e ’) R4 is hydrogen; -CH2-NH-CO-or -CH2-NH-SO2-; (f ’) R5 is bromine; (g ’) R6 is hydrogen; (h ’) R7 and R9 are independently hydrogen or methoxy in each case;

(i’) R8 es hidrógeno; (i ’) R8 is hydrogen;

(j’) R10 es y (j ’) R10 is and

(k’) la pareja de sustituyentes adyacentes R9 y R10 es CH2-CH2-CH2. (k ’) the pair of adjacent substituents R9 and R10 is CH2-CH2-CH2.

5 [0038] Los compuestos de fórmula I más preferidos son aquellos en los que los sustituyentes presentan el significado indicado en los ejemplos. [0038] The most preferred compounds of formula I are those in which the substituents have the meaning indicated in the examples.

imagen2image2

con un compuesto de fórmula III with a compound of formula III

[0040] La reacción se puede llevar a cabo de manera conocida por sí misma, dependiendo las condiciones de reacción especialmente de la reactividad del grupo saliente Y y de la reactividad del grupo amino de la anilina de fórmula III, habitualmente en presencia de un disolvente o diluyente adecuado o de una mezcla de ellos y, si es [0040] The reaction can be carried out in a manner known per se, depending on the reaction conditions especially on the reactivity of the leaving group Y and the reactivity of the amino group of the aniline of formula III, usually in the presence of a solvent. or suitable diluent or a mixture of them and, if it is

25 necesario, en presencia de un ácido o una base, con refrigeración o, preferentemente, calentamiento, por ejemplo en un intervalo de temperaturas de aproximadamente -30ºC a aproximadamente +150ºC, en especial de aproximadamente 0ºC a +100ºC, preferentemente de temperatura ambiente (aproximadamente +20ºC) a +80ºC, en un recipiente de reacción abierto o cerrado y/o bajo una atmósfera de un gas inerte, por ejemplo nitrógeno. 25 necessary, in the presence of an acid or a base, with cooling or, preferably, heating, for example in a temperature range of from about -30 ° C to about + 150 ° C, especially from about 0 ° C to + 100 ° C, preferably at room temperature ( approximately + 20 ° C) at + 80 ° C, in an open or closed reaction vessel and / or under an atmosphere of an inert gas, for example nitrogen.

30 [0041] Si uno o más grupos funcionales, por ejemplo carboxi, hidroxi o amino, están o deben estar protegidos en un compuesto de fórmula II o III porque no deben participar en la reacción, éstos son los grupos que se usan normalmente en la síntesis de compuestos peptídicos, cefalosporinas y penicilinas, así como de derivados de ácido nucleico y azúcares. [0041] If one or more functional groups, for example carboxy, hydroxy or amino, are or must be protected in a compound of formula II or III because they should not participate in the reaction, these are the groups normally used in the synthesis of peptide compounds, cephalosporins and penicillins, as well as derivatives of nucleic acid and sugars.

35 [0042] Los grupos protectores pueden estar presentes ya en los precursores y proteger los grupos funcionales en cuestión frente a reacciones secundarias no deseadas, tales como una reacción de sustitución o solvolisis. Una característica de los grupos protectores es que se eliminan con facilidad, es decir, sin reacciones secundarias no deseadas, típicamente por solvolisis, reducción, fotolisis o también por actividad enzimática, por ejemplo en condiciones análogas a las condiciones fisiológicas, y que no están presentes en los productos finales. El experto sabe o puede establecer con facilidad qué grupos protectores son adecuados para las reacciones antes mencionadas. [0042] The protecting groups may already be present in the precursors and protect the functional groups in question against unwanted side reactions, such as a substitution reaction or solvolysis. A characteristic of the protective groups is that they are easily removed, that is, without unwanted side reactions, typically by solvolysis, reduction, photolysis or also by enzymatic activity, for example under conditions analogous to physiological conditions, and which are not present. in the final products. The expert knows or can easily establish which protecting groups are suitable for the aforementioned reactions.

imagen3image3

5 [0043] Las sales de un compuesto de fórmula I con un grupo formador de sal se pueden preparar de manera conocida en sí. Así, las sales de adición de ácido de los compuestos de fórmula I se pueden obtener mediante el tratamiento con un ácido o con un reactivo de intercambio aniónico adecuado. [0043] The salts of a compound of formula I with a salt forming group can be prepared in a manner known per se. Thus, the acid addition salts of the compounds of formula I can be obtained by treatment with an acid or with a suitable anion exchange reagent.

[0044] Las sales generalmente se pueden convertir en compuestos libres, por ejemplo mediante el tratamiento [0044] Salts can generally be converted into free compounds, for example by treatment

10 con agentes básicos adecuados, por ejemplo con carbonatos de metales alcalinos, hidrogenocarbonatos de metales alcalinos o hidróxidos de metales alcalinos, típicamente con carbonato potásico o hidróxido de sodio. 10 with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates or alkali metal hydroxides, typically with potassium carbonate or sodium hydroxide.

[0045] Las mezclas estereoisoméricas, por ejemplo las mezclas de diaestereoisómeros, se pueden separar de manera conocida en sí en sus isómeros correspondientes por medio de procedimientos de separación adecuados. 15 Las mezclas de diaestereoisómeros, por ejemplo, se pueden separar en sus diaestereoisómeros individuales por cristalización fraccionada, cromatografía, distribución en disolventes y procedimientos similares. Esta separación se puede llevar a cabo bien a nivel de un compuesto de partida o bien en un compuesto de fórmula I propiamente dicho. Los enantiómeros se pueden separar mediante la formación de sales diaestereoisoméricas, por ejemplo por formación de sales con un ácido quiral enantioméricamente puro, o mediante cromatografía, por ejemplo por HPLC, [0045] Stereoisomeric mixtures, for example mixtures of diastereoisomers, can be separated in a manner known per se in their corresponding isomers by means of suitable separation procedures. The mixtures of diastereoisomers, for example, can be separated into their individual diastereoisomers by fractional crystallization, chromatography, solvent distribution and similar procedures. This separation can be carried out either at the level of a starting compound or in a compound of formula I itself. The enantiomers can be separated by the formation of diastereoisomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by chromatography, for example by HPLC,

20 usando sustratos cromatográficos con ligandos quirales. 20 using chromatographic substrates with chiral ligands.

[0046] Cabe destacar que también se pueden realizar reacciones análogas a las conversiones mencionadas en este capítulo a nivel de los productos intermedios apropiados. [0046] It should be noted that reactions similar to the conversions mentioned in this chapter can also be carried out at the level of appropriate intermediate products.

25 [0047] Los compuestos de fórmula I, incluidas sus sales, también se pueden obtener en forma de hidratos, o sus cristales pueden incluir, por ejemplo, el disolvente usado para la cristalización (presentes en forma de solvatos). [0047] The compounds of formula I, including their salts, can also be obtained in the form of hydrates, or their crystals may include, for example, the solvent used for crystallization (present in the form of solvates).

[0048] El compuesto de fórmula II usado como material de partida se puede obtener por reacción de un [0048] The compound of formula II used as starting material can be obtained by reacting a

imagen4image4

imagen5image5

[0049] Los compuestos de las fórmulas IV y V son conocidos o se pueden producir de acuerdo con procedimientos conocidos. [0049] The compounds of formulas IV and V are known or can be produced according to known procedures.

40 [0050] Los compuestos de fórmula I y sus sales farmacéuticamente aceptables muestran valiosas propiedades farmacológicas cuando se ensayan in vitro en ensayos de cinasa sin células y en ensayos celulares y, por lo tanto, son útiles como agentes farmacéuticos. En particular, los compuestos de la invención son inhibidores de la cinasa de adhesión focal y son útiles como agentes farmacéuticos para el tratamiento de estados causados por un mal funcionamiento de las cascadas de señalización asociadas con la cinasa de adhesión focal, en particular de tumores, como se describirá más adelante. [0050] The compounds of formula I and their pharmaceutically acceptable salts show valuable pharmacological properties when tested in vitro in cellless kinase assays and in cellular assays and, therefore, are useful as pharmaceutical agents. In particular, the compounds of the invention are inhibitors of focal adhesion kinase and are useful as pharmaceutical agents for the treatment of conditions caused by a malfunction of signaling cascades associated with focal adhesion kinase, in particular tumors, as will be described later.

[0051] La cinasa de adhesión focal (FAK) es una enzima clave en la cascada de señalización exterior-interior mediada por integrinas (D. Schlaepfer y col., Prog Biophys Mol Biol 1999, 71, 435-478). La interacción entre las células y las proteínas de la matriz extracelular (MEC) se transduce en señales intracelulares importantes para el crecimiento, la supervivencia y la migración a través de receptores de la superficie celular, las integrinas. La FAK desempeña un papel esencial en estas cascadas de señalización exterior-interior mediadas por integrinas. La cascada de transducción de señales es desencadenada por la autofosforilación de Y397. La Y397 fosforilada es un sitio de acoplamiento SH2 para las tirosina cinasas de la familia Src. La cinasa c-Src unida fosforila otros restos tirosina en la FAK. Entre ellos, la Y925 fosforilada se convierte en un sitio de unión para el sitio SH2 de la proteína adaptadora pequeña Grb2. Esta unión directa de la Grb2 a la FAK es una de las etapas clave para la activación de dianas cascada abajo, tales como la cascada de cinasas Ras-ERK2/MAP. [0051] Focal adhesion kinase (FAK) is a key enzyme in the outer-inner signaling cascade mediated by integrins (D. Schlaepfer et al., Prog Biophys Mol Biol 1999, 71, 435-478). The interaction between cells and extracellular matrix (MEC) proteins is transduced into intracellular signals important for growth, survival and migration through cell surface receptors, integrins. The FAK plays an essential role in these exterior-interior signaling cascades mediated by integrins. The signal transduction cascade is triggered by the autophosphorylation of Y397. Phosphorylated Y397 is an SH2 coupling site for tyrosine kinases of the Src family. The bound c-Src kinase phosphorylates other tyrosine residues in the FAK. Among them, phosphorylated Y925 becomes a binding site for the SH2 site of the small Grb2 adapter protein. This direct binding of Grb2 to FAK is one of the key stages for the activation of cascade targets below, such as the Ras-ERK2 / MAP kinase cascade.

[0052] La inhibición de la señalización mediada por FAK endógena reduce la motilidad y, en algunos casos, induce la muerte celular. Por otra parte, la potenciación de la señalización mediada por FAK mediante expresión exógena aumenta la motilidad celular y la transmisión de una señal de supervivencia celular desde la MEC. Además, la FAK se expresa en exceso en los cánceres epiteliales, mesenquimales, tiroideos y prostáticos invasivos y metastásicos. En consecuencia, un inhibidor de la FAK puede constituir un fármaco contra el crecimiento tumoral y las metástasis. Así, por ejemplo, los compuestos de la invención están indicados para prevenir y/o tratar a un vertebrado y, más concretamente, a un mamífero que padece una enfermedad neoplásica, en particular un tumor de mama, un cáncer de intestino (colon y recto), un cáncer de estómago y cáncer de ovario y de próstata, un cáncer pulmonar de células no pequeñas, un cáncer pulmonar de células pequeñas, un cáncer de hígado, un melanoma, un tumor de vejiga y un cáncer de cabeza y cuello. [0052] Inhibition of endogenous FAK-mediated signaling reduces motility and, in some cases, induces cell death. On the other hand, the enhancement of FAK-mediated signaling by exogenous expression increases cell motility and the transmission of a cell survival signal from the MEC. In addition, FAK is expressed in excess in invasive and metastatic epithelial, mesenchymal, thyroid and prostate cancers. Consequently, a FAK inhibitor may constitute a drug against tumor growth and metastasis. Thus, for example, the compounds of the invention are indicated to prevent and / or treat a vertebrate and, more specifically, a mammal suffering from a neoplastic disease, in particular a breast tumor, a bowel cancer (colon and rectum). ), stomach cancer and ovarian and prostate cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, melanoma, bladder tumor and head and neck cancer.

[0053] En G.A. van Seventer y col., Eur. J. Immunol. 2001, 31, 1417-1427, por ejemplo, se describe la relación entre la inhibición de la FAK y el sistema inmune. Por lo tanto, los compuestos de la invención son útiles, por ejemplo, para prevenir y/o tratar un vertebrado, más concretamente un mamífero, que padece trastornos del sistema inmune, enfermedades o trastornos mediados por linfocitos T, linfocitos B, células cebadas y/o eosinófilos, por ejemplo rechazo agudo o crónico de alo-o xenoinjertos de órganos o tejidos, aterosclerosis, oclusión vascular debida a lesiones vasculares tales como angioplastia, reestenosis, hipertensión, insuficiencia cardiaca, enfermedad pulmonar obstructiva crónica, enfermedades del SNC tales como la enfermedad de Alzheimer o la esclerosis lateral amiotrófica, cáncer, enfermedades infecciosas tales como SIDA, choque séptico o el síndrome de dificultad respiratoria en adultos, isquemia/ lesión por reperfusión, por ejemplo infarto de miocardio, ictus, isquemia intestinal, insuficiencia renal o choque hemorrágico, o choque traumático. Los agentes de la invención también son útiles para el tratamiento y/o la prevención de enfermedades o trastornos inflamatorios agudos o crónicos o enfermedades autoinmunes, por ejemplo artritis reumatoide, osteoartritis, lupus eritematoso sistémico, tiroiditis de Hashimoto, esclerosis múltiple, miastenia grave, diabetes (tipos I y II) y los trastornos asociados con ella, enfermedades respiratorias tales como asma o lesión hepática inflamatoria, lesión glomerular inflamatoria, manifestaciones cutáneas de trastornos o enfermedades mediados por el sistema inmune, enfermedades cutáneas inflamatorias e hiperproliferativas (tales como psoriasis, dermatitis atópica, dermatitis alérgica por contacto, dermatitis irritativa por contacto y otras dermatitis eccematosas, dermatitis seborreica), enfermedades inflamatorias del ojo, por ejemplo el síndrome de Sjoegren, queratoconjuntivitis o uveítis, enfermedad inflamatoria intestinal, la enfermedad de Crohn o colitis ulcerosa. [0053] In G.A. van Seventer et al., Eur. J. Immunol. 2001, 31, 1417-1427, for example, describes the relationship between inhibition of FAK and the immune system. Therefore, the compounds of the invention are useful, for example, to prevent and / or treat a vertebrate, more specifically a mammal, suffering from immune system disorders, diseases or disorders mediated by T lymphocytes, B lymphocytes, primed cells and / or eosinophils, for example acute or chronic rejection of allo-or xenografts of organs or tissues, atherosclerosis, vascular occlusion due to vascular lesions such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer's disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or respiratory distress syndrome in adults, ischemia / reperfusion injury, for example myocardial infarction, stroke, intestinal ischemia, renal failure or hemorrhagic shock , or traumatic shock. The agents of the invention are also useful for the treatment and / or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases, for example rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (types I and II) and disorders associated with it, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular lesion, skin manifestations of disorders or diseases mediated by the immune system, inflammatory and hyperproliferative skin diseases (such as psoriasis, dermatitis atopic, allergic contact dermatitis, irritant contact dermatitis and other eczematous dermatitis, seborrheic dermatitis), inflammatory diseases of the eye, for example Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.

[0054] Los compuestos de la invención son activos en un sistema de ensayo de la FAK descrito en los ejemplos y muestran una concentración inhibidora CI50 comprendida en el intervalo de 1 nM a 100 nM. Son especialmente activos los compuestos de los ejemplos nº 3-12 y nº 3-17 descritos más adelante, que muestran valores de CI50 comprendidos en el intervalo de 1 a 5 nM. [0054] The compounds of the invention are active in an FAK test system described in the examples and show an inhibitory concentration IC50 in the range of 1 nM to 100 nM. Especially active are the compounds of Examples No. 3-12 and No. 3-17 described below, which show IC50 values in the range of 1 to 5 nM.

[0055] Algunos de los compuestos de la invención muestran también una actividad inhibidora de la proteína tirosina cinasa ZAP-70 (proteína de 70 kD asociada a la cadena zeta). La interacción de los agentes de la invención con la proteína tirosina cinasa ZAP-70 se puede demostrar mediante su capacidad para inhibir la fosforilación de, por ejemplo, LAT-11 (conector para la activación de linfocitos T) por la proteína tirosina cinasa ZAP-70 humana en disolución acuosa, como se describe en los ejemplos. Por lo tanto, los compuestos de la invención también están indicados para la prevención o el tratamiento de trastornos o enfermedades en los que está implicada la inhibición de Zap-70. Los compuestos de la invención son activos en un sistema de ensayo de ZAP-70 descrito en los ejemplos y muestran una concentración inhibidora CI50 comprendida en el intervalo de 1 μM a 10 μM, por ejemplo los compuestos de los ejemplos nº 2 y nº 3-2 descritos más adelante. [0055] Some of the compounds of the invention also show an inhibitory activity of the ZAP-70 tyrosine kinase protein (70 kD protein associated with the zeta chain). The interaction of the agents of the invention with the ZAP-70 tyrosine kinase protein can be demonstrated by their ability to inhibit phosphorylation of, for example, LAT-11 (T lymphocyte activation linker) by the ZAP-tyrosine kinase protein. 70 human in aqueous solution, as described in the examples. Therefore, the compounds of the invention are also indicated for the prevention or treatment of disorders or diseases in which Zap-70 inhibition is involved. The compounds of the invention are active in a ZAP-70 test system described in the examples and show an inhibitory concentration IC50 in the range of 1 μM to 10 μM, for example the compounds of examples No. 2 and No. 3- 2 described below.

[0056] Los compuestos de la presente invención también son buenos inhibidores del IGF-IR (receptor del factor de crecimiento similar a la insulina I) y, por lo tanto, son útiles en el tratamiento de enfermedades mediadas por el IGF-IR; tales enfermedades incluyen, por ejemplo, enfermedades proliferativas, tales como tumores como, por ejemplo, tumores de mama, renales, de próstata, colorrectales, de tiroides, de ovario, de páncreas, neuronales, de pulmón, de útero y gastrointestinales, así como osteosarcomas y melanomas. La eficacia de los compuestos de la invención como inhibidores de la actividad tirosina cinasa del IGF-IR se puede demostrar usando un “ELISA de captura” celular. En este ensayo se determina la actividad de los compuestos de la invención frente a la autofosforilación del IGF-IR inducida por el factor de crecimiento similar a la insulina I (IGF-I). [0056] The compounds of the present invention are also good inhibitors of IGF-IR (insulin-like growth factor receptor I) and, therefore, are useful in the treatment of diseases mediated by IGF-IR; such diseases include, for example, proliferative diseases, such as tumors such as, for example, breast, kidney, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastrointestinal tumors, as well as osteosarcomas and melanomas. The efficacy of the compounds of the invention as inhibitors of IGF-IR tyrosine kinase activity can be demonstrated using a cellular "capture ELISA". In this assay, the activity of the compounds of the invention against the autophosphorylation of IGF-IR induced by insulin-like growth factor I (IGF-I) is determined.

[0057] Los compuestos de la presente invención muestran también una potente inhibición de la actividad tirosina cinasa de la cinasa de linfoma anaplásico (ALK) y de la proteína de fusión NPM-ALK. Esta proteína tirosina cinasa es el resultado de una fusión génica de la nucleofosmina (NPM) y la cinasa de linfoma anaplásico (ALK) que hace que la actividad proteína tirosina cinasa de ALK se vuelva independiente de ligando. La NPM-ALK desempeña un papel clave en la transmisión de señales en numerosas células hematopoyéticas y en otras células humanas, conduciendo a enfermedades hematológicas y neoplásicas, por ejemplo al linfoma anaplásico de células grandes (ALCL) y linfomas no Hodgkin (NHL), especialmente NHL ALK+ o Alkomas, tumores miofibroblásticos inflamatorios (IMT) y neuroblastomas (Duyster J y col. 2001 Oncogene 20, 5623-5637). Además de la NPM-ALK se han identificado otras fusiones génicas en enfermedades hematológicas y neoplásicas humanas, principalmente TPM3ALK (una fusión de tropomiosina no muscular con ALK). [0057] The compounds of the present invention also show a potent inhibition of the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and of the NPM-ALK fusion protein. This protein tyrosine kinase is the result of a gene fusion of nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) that causes ALK protein tyrosine kinase activity to become ligand independent. NPM-ALK plays a key role in the transmission of signals in numerous hematopoietic cells and other human cells, leading to hematological and neoplastic diseases, for example to anaplastic large cell lymphoma (ALCL) and non-Hodgkin lymphomas (NHL), especially NHL ALK + or Alkomas, inflammatory myofibroblastic tumors (IMT) and neuroblastomas (Duyster J et al. 2001 Oncogene 20, 5623-5637). In addition to NPM-ALK, other gene fusions have been identified in human hematological and neoplastic diseases, mainly TPM3ALK (a fusion of non-muscular tropomyosin with ALK).

[0058] La inhibición de la actividad tirosina cinasa de ALK se puede demostrar usando procedimientos conocidos, por ejemplo usando el dominio cinasa recombinante de la ALK en analogía al ensayo de la cinasa VEGFR descrito en J. Wood y col. Cancer Res. 60, 2178-2189 (2000). Los ensayos enzimáticos in vitro en los que se usa la proteína tirosina cinasa GST-ALK se realizan en placas de 96 pocillos en forma de un ensayo de unión a filtros en Tris-HCl 20 mM, pH = 7,5, MgCl2 3 mM, MnCl2 10 mM, DTT 1 mM, 0,1 μCi/ensayo (= 30 μl) de [γ-33P]-ATP, ATP 2 μM, 3 μg/ml poli (Glu, Tyr 4:1) Poli-EY (Sigma P-0275), 1% de DMSO, 25 ng de enzima ALK. Los ensayos se incuban durante 10 min a temperatura ambiente. Las reacciones se terminan añadiendo 50 μl de EDTA 125 mM, y la mezcla de reacción se transfiere a una placa MAIP Multiscreen (Millipore, Bedford, MA, EE.UU.) humedecida previamente con metanol y rehidratada durante 5 min con H2O. Una vez lavadas (0,5% de H3PO4), las placas se someten al recuento en un contador de centelleo líquido. Los valores CI50 se calculan mediante un análisis de regresión lineal del porcentaje de inhibición. En comparación con el control sin inhibidor, los compuestos de fórmula I inhiben la actividad enzimática en un 50% (CI50) a una concentración de, por ejemplo, 0,001 a 0,5 μM, en especial de 0,01 a 0,1 μM. [0058] The inhibition of ALK tyrosine kinase activity can be demonstrated using known methods, for example using the recombinant ALK kinase domain in analogy to the VEGFR kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000). In vitro enzyme assays in which the GST-ALK protein tyrosine kinase is used are performed in 96-well plates in the form of a filter binding assay in 20 mM Tris-HCl, pH = 7.5, 3 mM MgCl2, 10 mM MnCl2, 1 mM DTT, 0.1 μCi / assay (= 30 μl) of [γ-33P] -ATP, 2 μM ATP, 3 μg / ml poly (Glu, Tyr 4: 1) Poly-EY (Sigma P-0275), 1% DMSO, 25 ng of ALK enzyme. The assays are incubated for 10 min at room temperature. The reactions are terminated by adding 50 μl of 125 mM EDTA, and the reaction mixture is transferred to a MAIP Multiscreen plate (Millipore, Bedford, MA, USA) previously moistened with methanol and rehydrated for 5 min with H2O. Once washed (0.5% H3PO4), the plates are counted in a liquid scintillation counter. IC50 values are calculated by a linear regression analysis of the percentage of inhibition. Compared to the control without inhibitor, the compounds of formula I inhibit 50% enzymatic activity (IC50) at a concentration of, for example, 0.001 to 0.5 μM, especially 0.01 to 0.1 μM .

[0059] Los compuestos de fórmula I inhiben fuertemente el crecimiento de células BaF3 murinas que expresan en exceso la NPM-ALK humana (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Alemania). La expresión de NPM-ALK se logra transfectando la línea celular BaF3 con un vector de expresión pClneoTM (Promega Corp., Madison, WI, EE.UU.) que codifica la NPM-ALK y seleccionando seguidamente las células resistentes a G418. Las células BaF3 no transfectadas dependen de la IL-3 para la supervivencia de las células. Por el contrario, las células BaF3 que expresan la NPM-ALK (denominadas en lo sucesivo BaF3-NPM-ALK) pueden proliferar en ausencia de IL-3 puesto que obtienen la señal de proliferación a través de la cinasa NPM-ALK. Así, los posibles inhibidores de la cinasa NPM-ALK anulan la señal de crecimiento e inducen una actividad antiproliferativa. Sin embargo, la actividad antiproliferativa de los posibles inhibidores de la cinasa NPM-ALK se puede suprimir mediante la adición de IL-3, que proporciona señales de crecimiento a través de un mecanismo independiente de NPM-ALK. [Para un sistema celular análogo en el que se usa la cinasa FLT3, véase E. Weisberg y col. Cancer Cell; 1, 433-443 (2002)]. La actividad inhibidora de los compuestos de fórmula I se determina, brevemente, de la siguiente manera: Se transfieren células BaF3-NPM-ALK (15.000/pocillo de la placa de microvaloración) a placas de microvaloración de 96 pocillos. Los compuestos de ensayo [disueltos en dimetilsulfóxido (DMSO)] se añaden en una serie de concentraciones (serie de dilución) de tal manera que la concentración final de DMSO no supere el 1% (v/v). Después de la adición, las placas se incuban durante dos días, periodo durante el cual los cultivos de control sin compuesto de ensayo pueden sufrir dos ciclos de división celular. El crecimiento de las células BaF3-NPM-ALK se mide por tinción con YoproTM [T Idziorek y col. J. Immunol. Methods; [0059] The compounds of formula I strongly inhibit the growth of murine BaF3 cells that overexpress human NPM-ALK (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany). NPM-ALK expression is achieved by transfecting the BaF3 cell line with a pClneoTM expression vector (Promega Corp., Madison, WI, USA) that encodes NPM-ALK and then selecting G418 resistant cells. Untransfected BaF3 cells depend on IL-3 for cell survival. In contrast, BaF3 cells expressing NPM-ALK (hereinafter referred to as BaF3-NPM-ALK) can proliferate in the absence of IL-3 since they obtain the proliferation signal through the NPM-ALK kinase. Thus, the possible NPM-ALK kinase inhibitors nullify the growth signal and induce an antiproliferative activity. However, the antiproliferative activity of possible NPM-ALK kinase inhibitors can be suppressed by the addition of IL-3, which provides growth signals through an independent NPM-ALK mechanism. [For an analogous cellular system in which FLT3 kinase is used, see E. Weisberg et al. Cancer cell; 1, 433-443 (2002)]. The inhibitory activity of the compounds of formula I is determined, briefly, as follows: BaF3-NPM-ALK cells (15,000 / well of the microtiter plate) are transferred to 96-well microtiter plates. Test compounds [dissolved in dimethylsulfoxide (DMSO)] are added in a series of concentrations (dilution series) such that the final concentration of DMSO does not exceed 1% (v / v). After the addition, the plates are incubated for two days, during which time control cultures without test compound can undergo two cycles of cell division. BaF3-NPM-ALK cell growth is measured by staining with YoproTM [T Idziorek et al. J. Immunol. Methods;

185: 249-258 (1995)]: se añaden a cada pocillo 25 μl del tampón de lisis compuesto por citrato sódico 20 mM, pH 4,0, cloruro sódico 26,8 mM, 0,4% de NP40, EDTA 20 mM. La lisis celular se completa en un plazo de 60 min a temperatura ambiente, y la cantidad total de Yopro unida al ADN se determina por medición en el lector de placas de 96 pocillos Cytofluor II (PerSeptive Biosystems) con los ajustes siguientes: excitación (nm) 485/20 y emisión (nm) 530/25. 185: 249-258 (1995)]: 25 µl of the lysis buffer composed of 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4% NP40, 20 mM EDTA are added to each well . Cell lysis is completed within 60 min at room temperature, and the total amount of Yopro bound to DNA is determined by measurement in the Cytofluor II 96-well plate reader (PerSeptive Biosystems) with the following settings: excitation (nm ) 485/20 and emission (nm) 530/25.

Los valores de la CI50 se determinan mediante un sistema asistido por ordenador mediante la fórmula: The IC50 values are determined by a computer-assisted system using the formula:

CI50 = [(ABSensayo -ABSinicial)/(ABScontrol -ABSinicial)] x 100. (ABS = absorción) IC50 = [(ABS-Initial Test) / (ABS-Control Initial)] x 100. (ABS = absorption)

En estos experimentos, el valor de la CI50 es aquella concentración del compuesto de ensayo en cuestión que proporciona un recuento celular que es un 50% menor que el obtenido con el control sin inhibidor. Los compuestos de fórmula I muestran una actividad inhibidora con una CI50 comprendida en el intervalo de aproximadamente 0,01 a 1 μM. In these experiments, the IC50 value is that concentration of the test compound in question that provides a cell count that is 50% lower than that obtained with the control without inhibitor. Compounds of formula I show an inhibitory activity with an IC50 in the range of about 0.01 to 1 µM.

[0060] La actividad antiproliferativa de los compuestos de fórmula I también se puede determinar en la línea celular de linfoma humano KARPAS-299 (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Alemania) [descrita en WG Dirks y col. Int. J. Cancer 100, 49-56 (2002)] usando la misma metodología descrita anteriormente para la línea celular BaF3-NPM-ALK. Los compuestos de fórmula I muestran una actividad inhibidora con una CI50 comprendida en el intervalo de aproximadamente 0,01 a 1 μM. [0060] The antiproliferative activity of the compounds of formula I can also be determined in the human lymphoma cell line KARPAS-299 (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany) [described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002)] using the same methodology described above for the BaF3-NPM-ALK cell line. Compounds of formula I show an inhibitory activity with an IC50 in the range of about 0.01 to 1 µM.

[0061] La actividad de los compuestos de fórmula I sobre la autofosforilación de la ALK se puede determinar en la línea celular de linfoma humano KARPAS-299 mediante una inmunotransferencia como se describe en WG Dirks y col. Int. J. Cancer 100, 49-56 (2002). En ese ensayo, los compuestos de fórmula I muestran una CI50 de aproximadamente 0,001 a 1 μM. [0061] The activity of the compounds of formula I on the autophosphorylation of ALK can be determined in the human lymphoma cell line KARPAS-299 by an immunoblot as described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002). In that test, the compounds of formula I show an IC50 of about 0.001 to 1 µM.

[0062] Entre los compuestos descritos en la presente memoria, el ejemplo de referencia 7A, a saber, la 2-[5cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-N-metilbenzamida, es un inhibidor especialmente potente de la ALK, puesto que este compuesto inhibe el crecimiento de las células BaF3-NPM-ALK con una CI50 de 97 nM. Otros compuestos especialmente preferidos que inhiben la actividad tirosina cinasa de la cinasa de linfoma anaplásico (ALK) son los compuestos descritos más adelante en los ejemplos de referencia 7A y 7B, así como 7-2, 7-15, 7-36, 7-39, 7-44 y 7-52, respectivamente, que presentan todos ellos una CI50 comprendida en el intervalo de < 0,5 a 200 nM. [0062] Among the compounds described herein, reference example 7A, namely 2- [5-chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino ] -N-methylbenzamide, is an especially potent inhibitor of ALK, since this compound inhibits the growth of BaF3-NPM-ALK cells with an IC50 of 97 nM. Other especially preferred compounds that inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) are the compounds described below in reference examples 7A and 7B, as well as 7-2, 7-15, 7-36, 7- 39, 7-44 and 7-52, respectively, which all have an IC50 in the range of <0.5 to 200 nM.

[0063] Por los documentos WO 03/018021, WO 01/60816, WO 00/39101, WO 97/19065, WO 01/64655 y WO 03/078404 se conocen derivados de pirimidina como inhibidores del IGF-IR, inhibidores de la FAK o inhibidores de la ZAP-70. [0063] From WO 03/018021, WO 01/60816, WO 00/39101, WO 97/19065, WO 01/64655 and WO 03/078404, pyrimidine derivatives are known as IGF-IR inhibitors, inhibitors of FAK or ZAP-70 inhibitors.

[0064] Para los usos anteriores en el tratamiento de enfermedades neoplásicas y de trastornos del sistema inmune, la dosis requerida variará lógicamente en función del modo de administración, la afección concreta que se ha de tratar y el efecto deseado. En general, se obtienen resultados satisfactorios de forma sistémica a dosis diarias de aproximadamente 0,1 a aproximadamente 100 mg/kg de peso corporal. Una dosis diaria indicada para un mamífero más grande, por ejemplo para seres humanos, se encuentra en el intervalo de aproximadamente 0,5 mg a aproximadamente 2.000 mg, administrada convenientemente, por ejemplo, hasta cuatro veces al día en dosis divididas o en una forma de liberación retardada. [0064] For previous uses in the treatment of neoplastic diseases and immune system disorders, the required dose will logically vary depending on the mode of administration, the specific condition to be treated and the desired effect. In general, satisfactory results are obtained systemically at daily doses of about 0.1 to about 100 mg / kg body weight. A daily dose indicated for a larger mammal, for example for humans, is in the range of about 0.5 mg to about 2,000 mg, conveniently administered, for example, up to four times a day in divided doses or in a form delayed release.

[0065] Los compuestos de la invención se pueden administrar por cualquier vía convencional, en particular por vía parenteral, por ejemplo en forma de soluciones o suspensiones inyectables, enteral, preferentemente oral, por ejemplo en forma de comprimidos o cápsulas, tópica, por ejemplo en forma de lociones, geles, pomadas o cremas, o en una forma nasal o de supositorio. Las composiciones farmacéuticas que comprenden un compuesto de la invención junto con al menos un vehículo o diluyente farmacéuticamente aceptable se pueden preparar de manera convencional por mezclado con un vehículo o diluyente farmacéuticamente aceptable. Las formas de dosis unitarias para la administración oral contienen, por ejemplo, entre aproximadamente 0,1 mg y aproximadamente 500 mg de principio activo. La administración tópica se realiza, por ejemplo, en la piel. Otra forma de administración tópica es la oftálmica. [0065] The compounds of the invention can be administered by any conventional route, in particular parenterally, for example in the form of injectable, enteral, preferably oral solutions or suspensions, for example in the form of tablets or capsules, topically, for example. in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the invention together with at least one pharmaceutically acceptable carrier or diluent can be prepared in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, between about 0.1 mg and about 500 mg of active ingredient. Topical administration is performed, for example, on the skin. Another form of topical administration is ophthalmic.

[0066] Las composiciones farmacéuticas de la presente invención se preparan de manera conocida por sí mismas, por ejemplo mediante procedimientos convencionales de mezclado, granulación, recubrimiento, disolución o liofilización. [0066] The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by conventional methods of mixing, granulating, coating, dissolving or lyophilizing.

[0067] Se prefiere el uso de disoluciones del ingrediente activo, así como suspensiones o dispersiones, especialmente soluciones, dispersiones o suspensiones acuosas isotónicas que se pueden preparar antes del uso, por ejemplo en el caso de las composiciones liofilizadas que comprenden el ingrediente activo solo o junto con un vehículo, por ejemplo manitol. Las composiciones farmacéuticas se pueden esterilizar y/o pueden comprender excipientes, por ejemplo conservantes, estabilizadores, humectantes y/o emulsionantes, solubilizadores, sales para regular la presión osmótica y/o tampones, y se preparan de manera conocida en sí, por ejemplo mediante procesos convencionales de disolución y liofilización. Dichas soluciones o suspensiones pueden comprender agentes que aumentan la viscosidad, típicamente carboximetilcelulosa sódica, carboximetilcelulosa, dextrano, polivinil-pirrolidona [0067] The use of solutions of the active ingredient, as well as suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions that can be prepared before use, for example in the case of lyophilized compositions comprising the active ingredient alone is preferred or together with a vehicle, for example mannitol. The pharmaceutical compositions may be sterilized and / or may comprise excipients, for example preservatives, stabilizers, humectants and / or emulsifiers, solubilizers, salts for regulating osmotic pressure and / or buffers, and are prepared in a manner known per se, for example by conventional dissolution and lyophilization processes. Such solutions or suspensions may comprise agents that increase viscosity, typically sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinyl pyrrolidone

o gelatinas, o también solubilizadores, por ejemplo Tween 80® (monooleato de polioxietilen (20) sorbitán). or gelatins, or also solubilizers, for example Tween 80® (polyoxyethylene (20) sorbitan monooleate).

[0068] Las suspensiones en aceite comprenden como componente oleoso los aceites vegetales, sintéticos o semisintéticos habituales para fines de inyección. A este respecto, son de mencionar especialmente ésteres de ácidos grasos líquidos que contienen como componente ácido un ácido graso de cadena larga que presenta entre 8 y 22, en especial entre 12 y 22, átomos de carbono, por ejemplo ácido láurico, ácido tridecílico, ácido mirístico, ácido pentadecílico, ácido palmítico, ácido margárico, ácido esteárico, ácido araquídico, ácido behénico o los ácidos insaturados correspondientes, por ejemplo ácido oleico, ácido elaídico, ácido erúcico, ácido brasídico o ácido linoleico, si se desea con la adición de antioxidantes, por ejemplo vitamina E, β-caroteno o 0,5-di-terc-butil-4hidroxitolueno. El componente alcohólico de estos ésteres de ácidos grasos presenta un máximo de 6 átomos de carbono y es un alcohol monofuncional o polifuncional, por ejemplo mono-, di-o trifuncional, por ejemplo metanol, etanol, propanol, butanol o pentanol o los isómeros de los mismos, pero especialmente glicol y glicerol. Como ésteres de ácidos grasos se mencionan, por lo tanto, los siguientes: oleato de etilo, miristato de isopropilo, palmitato de isopropilo, “Labrafil M 2375” (polioxietilenglicol), “Labrafil M 1944 CS” (glicéridos poliglicolizados insaturados preparados por alcoholisis de aceite de hueso de albaricoque y formados por glicéridos y éster de polietilenglicol), “Labrasol” (glicéridos poliglicolizados saturados preparados por alcoholisis de TCM y formados por glicéridos y éster de polietilenglicol; se pueden adquirir todos de Gattefossé, Francia) y/o “Miglyol 812” (triglicérido de ácidos grasos saturados con una longitud de cadena de C8 a C12, de Hüls AG, Alemania), pero especialmente aceites vegetales tales como aceite de semilla de algodón, aceite de almendras, aceite de oliva, aceite de ricino, aceite de sésamo, aceite de soja y, muy especialmente, aceite de cacahuete. [0068] The oil suspensions comprise as an oily component the usual vegetable, synthetic or semi-synthetic oils for injection purposes. In this regard, it is especially worth mentioning esters of liquid fatty acids containing as an acid component a long chain fatty acid having between 8 and 22, especially between 12 and 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, carbonic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, β-carotene or 0,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monofunctional or polyfunctional alcohol, for example mono-, di-or trifunctional, for example methanol, ethanol, propanol, butanol or pentanol or the isomers of the same, but especially glycol and glycerol. As fatty acid esters, therefore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycol), "Labrafil M 1944 CS" (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and formed by glycerides and polyethylene glycol ester), "Labrasol" (saturated polyglycolized glycerides prepared by TCM alcoholysis and formed by glycerides and polyethylene glycol ester; all of them can be purchased from Gattefossé, France) and / or "Miglyol 812 ”(saturated fatty acid triglyceride with a chain length of C8 to C12, from Hüls AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, oil sesame, soybean oil and, especially, peanut oil.

[0069] La elaboración de preparaciones inyectables se realiza generalmente en condiciones estériles, al igual que el llenado en, por ejemplo, ampollas o viales y el sellado de los envases. [0069] The preparation of injectable preparations is generally carried out under sterile conditions, as is the filling in, for example, ampoules or vials and the sealing of the containers.

[0070] Las composiciones farmacéuticas para la administración oral se pueden obtener, por ejemplo, combinando el principio activo con uno o más vehículos sólidos, granulando la mezcla resultante, si se desea, y procesando la mezcla o los gránulos, si se desea o si es necesario, mediante la inclusión de excipientes adicionales para formar comprimidos o núcleos de comprimidos. [0070] Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, granulating the resulting mixture, if desired, and processing the mixture or granules, if desired or if It is necessary, by including additional excipients to form tablets or tablet cores.

[0071] Los vehículos adecuados son, en especial, cargas, tales como azúcares, por ejemplo lactosa, sacarosa, manitol o sorbitol, preparados de celulosa y/o fosfatos cálcicos, por ejemplo fosfato tricálcico o hidrogenofosfato cálcico, así como aglutinantes, tales como almidones, por ejemplo almidón de maíz, trigo, arroz o patata, metilcelulosa, hidroxipropilmetilcelulosa, carboximetilcelulosa sódica y/o polivinilpirrolidona, y/o, si se desea, desintegrantes, tales como los almidones antes mencionados, así como carboximetilalmidón, polivinilpirrolidona reticulada, ácido algínico o una sal suya, tal como alginato sódico. Excipientes adicionales son, en especial, fluidificantes y lubricantes, por ejemplo ácido silícico, talco, ácido esteárico o sales del mismo, tales como estearato de magnesio o de calcio, y/o polietilenglicol o derivados del mismo. [0071] Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starches, for example corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the aforementioned starches, as well as carboxymethyl starch, polyvinylpyrrolidone acid alginic or a salt of yours, such as sodium alginate. Additional excipients are, in particular, fluidizers and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol or derivatives thereof.

[0072] Los núcleos de comprimidos se pueden proveer de recubrimientos adecuados, opcionalmente entéricos, mediante el uso de, entre otros, disoluciones concentradas de azúcar que pueden comprender goma arábica, talco, polivinilpirrolidona, polietilenglicol y/o dióxido de titanio, o disoluciones de recubrimiento en disolventes orgánicos adecuados o mezclas de disolventes o, para la preparación de recubrimientos entéricos, soluciones de preparados de celulosa adecuados, tales como ftalato de acetilcelulosa o ftalato de hidroxipropilmetilcelulosa. Se pueden añadir colorantes o pigmentos a los comprimidos o a los recubrimientos de los comprimidos, por ejemplo con fines de identificación o para indicar diferentes dosis del principio activo. [0072] The tablet cores may be provided with suitable, optionally enteric, coatings by using, among others, concentrated sugar solutions that may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or solutions of coating in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or to the tablet coatings, for example for identification purposes or to indicate different doses of the active substance.

[0073] Las composiciones farmacéuticas para la administración oral también incluyen cápsulas duras formadas por gelatina, así como cápsulas blandas selladas formadas por gelatina y un plastificante, tal como glicerol [0073] Pharmaceutical compositions for oral administration also include hard capsules formed by gelatin, as well as sealed soft capsules formed by gelatin and a plasticizer, such as glycerol.

o sorbitol. Las cápsulas duras pueden contener el principio activo en forma de gránulos, por ejemplo en mezcla con cargas, tales como almidón de maíz, aglutinantes y/o deslizantes, tales como talco o estearato de magnesio, y, opcionalmente, estabilizadores. En las cápsulas blandas, el principio activo preferentemente está disuelto o suspendido en excipientes líquidos adecuados, tales como aceites grasos, aceite de parafina o polietilenglicoles líquidos o ésteres de ácidos grasos de etilenglicol o propilenglicol, a los cuales se pueden añadir asimismo estabilizadores y detergentes, por ejemplo del tipo de los ésteres de ácido graso y polietilensorbitán. or sorbitol The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and / or glidants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents can also be added, for example of the type of fatty acid esters and polyethylene sorbitan.

[0074] Las composiciones farmacéuticas adecuadas para la administración rectal son, por ejemplo, supositorios formados por una combinación del principio activo y una base de supositorio. Las bases de supositorio adecuadas son, por ejemplo, triglicéridos naturales o sintéticos, hidrocarburos parafínicos, polietilenglicoles o alcanoles superiores. [0074] Pharmaceutical compositions suitable for rectal administration are, for example, suppositories formed by a combination of the active substance and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols.

[0075] Para la administración parenteral son especialmente adecuadas las soluciones acuosas de un principio activo en forma hidrosoluble, por ejemplo de una sal hidrosoluble, o las suspensiones acuosas para inyección que contienen sustancias que aumentan la viscosidad, por ejemplo carboximetilcelulosa sódica, sorbitol y/o dextrano, y, si se desea, estabilizadores. El principio activo, opcionalmente junto con excipientes, también puede encontrarse en forma de un liofilizado y se puede solubilizar antes de la administración parenteral mediante la adición de disolventes adecuados. [0075] For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous suspension for injection containing substances that increase viscosity, for example sodium carboxymethyl cellulose, sorbitol and / or are especially suitable or dextran, and, if desired, stabilizers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate and can be solubilized before parenteral administration by the addition of suitable solvents.

[0076] Las disoluciones que se usan, por ejemplo, para la administración parenteral también se pueden utilizar como soluciones para infusión. [0076] The solutions that are used, for example, for parenteral administration can also be used as infusion solutions.

[0077] Los conservantes preferidos son, por ejemplo, antioxidantes, tales como ácido ascórbico, o microbicidas, tales como ácido sórbico o ácido benzoico. [0077] Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.

[0078] Los compuestos de la invención se pueden administrar como principio activo único o junto con otros fármacos útiles frente a enfermedades neoplásicas o útiles en regímenes inmunomoduladores. Por ejemplo, los agentes de la invención se pueden usar de acuerdo con la invención en combinación con composiciones farmacéuticas eficaces en diversas enfermedades descritas anteriormente, por ejemplo con ciclofosfamida, 5fluorouracilo, fludarabina, gemcitabina, cisplatino, carboplatino, vincristina, vinblastina, etopósido, irinotecán, paclitaxel, docetaxel, rituxan, doxorrubicina, gefitinib o imitanib; o también con ciclosporinas, rapamicinas, ascomicinas o sus análogos inmunosupresores, por ejemplo ciclosporina A, ciclosporina G, FK-506, sirolimus o everolimus, corticosteroides, por ejemplo prednisona, ciclofosfamida, azatiopreno, metotrexato, sales de oro, sulfasalazina, antimaláricos, brequinar, leflunomida, mizoribina, ácido micofenólico, micofenolato, mofetil, 15desoxispergualina, anticuerpos monoclonales inmunosupresores, por ejemplo anticuerpos monoclonales contra receptores de leucocitos, por ejemplo MHC, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 o sus ligandos, u otros compuestos inmunomoduladores, por ejemplo CTLA41g. [0078] The compounds of the invention can be administered as a single active ingredient or together with other drugs useful against neoplastic diseases or useful in immunomodulatory regimens. For example, the agents of the invention can be used according to the invention in combination with pharmaceutical compositions effective in various diseases described above, for example with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan , paclitaxel, docetaxel, rituxan, doxorubicin, gefitinib or imitanib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogues, for example cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, for example prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarial, antimalarial drugs , leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, deoxispergualine, immunosuppressive monoclonal antibodies, for example monoclonal antibodies against leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80 , CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or its ligands, or other immunomodulatory compounds, for example CTLA41g.

[0079] De acuerdo con lo anterior, la presente invención proporciona asimismo: [0079] In accordance with the foregoing, the present invention also provides:

(1)(one)

un compuesto de la invención para uso como agente farmacéutico;  a compound of the invention for use as a pharmaceutical agent;

(2)(2)

un compuesto de la invención para uso como inhibidor de la FAK, inhibidor de la ALK y/o inhibidor de la ZAP-70, por ejemplo para el uso en cualquiera de las indicaciones concretas expuestas anteriormente;  a compound of the invention for use as an inhibitor of FAK, inhibitor of ALK and / or inhibitor of ZAP-70, for example for use in any of the specific indications set forth above;

(3)(3)

una composición farmacéutica, por ejemplo para uso en cualquiera de las indicaciones expuestas anteriormente, que comprende un compuesto de la invención como principio activo junto con uno o más diluyentes o vehículos farmacéuticamente aceptables;  a pharmaceutical composition, for example for use in any of the indications set forth above, comprising a compound of the invention as an active ingredient together with one or more pharmaceutically acceptable diluents or carriers;

(4)(4)

el uso de un compuesto de la invención para la preparación de un medicamento para el tratamiento o la prevención de una enfermedad o estado en el que desempeñe un papel o esté implicada la activación de FAK, ALK y/o ZAP-70;  the use of a compound of the invention for the preparation of a medicament for the treatment or prevention of a disease or condition in which it plays a role or the activation of FAK, ALK and / or ZAP-70 is involved;

(5) (5)

una combinación que comprende una cantidad terapéuticamente eficaz de un compuesto de la invención y una o más sustancias farmacéuticas adicionales, siendo dicha sustancia farmacéutica útil en cualquiera de las indicaciones concretas expuestas anteriormente; a combination comprising a therapeutically effective amount of a compound of the invention and one or more additional pharmaceutical substances, said pharmaceutical substance being useful in any of the specific indications set forth above;

(6)(6)

uso de un compuesto de la invención para la preparación de un medicamento para el tratamiento o la prevención de una enfermedad que responda a la inhibición de la cinasa de linfoma anaplásico;  use of a compound of the invention for the preparation of a medicament for the treatment or prevention of a disease that responds to the inhibition of anaplastic lymphoma kinase;

(7)(7)

el uso de acuerdo con el punto (6), en el que la enfermedad que se ha de tratar se selecciona entre linfoma anaplásico de células grandes, linfomas no Hodgkin, tumores miofibroblásticos inflamatorios y neuroblastomas;  the use according to item (6), in which the disease to be treated is selected from anaplastic large cell lymphoma, non-Hodgkin lymphomas, inflammatory myofibroblastic tumors and neuroblastomas;

(8)(8)

el uso de acuerdo con los puntos (6) o (7), en el que el compuesto es cualquiera de los compuestos descritos a continuación en los ejemplos de acuerdo con la invención o una sal farmacéuticamente aceptable de cualquiera de ellos.  the use according to items (6) or (7), wherein the compound is any of the compounds described below in the examples according to the invention or a pharmaceutically acceptable salt of any of them.

[0080] La presente invención describe asimismo: [0080] The present invention also describes:

(9)(9)

un procedimiento para el tratamiento de cualquier indicación concreta expuesta anteriormente en un sujeto que lo necesite, que comprende la administración de una cantidad eficaz de un compuesto de la invención o de una  a method for the treatment of any specific indication set forth above in a subject in need thereof, which comprises the administration of an effective amount of a compound of the invention or of a

composición farmacéutica que lo comprende; pharmaceutical composition comprising it;

(10)(10)

el procedimiento definido anteriormente en el punto (9) que comprende la administración simultánea, por ejemplo concomitante o sucesiva, de una cantidad terapéuticamente eficaz de un compuesto de la invención y una o más sustancias farmacéuticas adicionales, siendo dichas sustancias farmacéuticas adicionales útiles en cualquiera  the method defined above in item (9) comprising the simultaneous administration, for example concomitant or successive, of a therapeutically effective amount of a compound of the invention and one or more additional pharmaceutical substances, said additional pharmaceutical substances being useful in any

5 de las indicaciones concretas expuestas anteriormente; 5 of the specific indications set forth above;

(11) un procedimiento para el tratamiento de una enfermedad que responda a la inhibición de la cinasa de linfoma anaplásico, en especial una enfermedad seleccionada entre linfoma anaplásico de células grandes, linfomas no Hodgkin, tumores miofibroblásticos inflamatorios y neuroblastomas, que comprende la administración de una cantidad eficaz de un compuesto de la invención, en especial del ejemplo de referencia 7A, a saber, la 2-[5-cloro-2(11) a procedure for the treatment of a disease that responds to the inhibition of anaplastic lymphoma kinase, especially a disease selected from anaplastic large cell lymphoma, non-Hodgkin lymphomas, inflammatory myofibroblastic tumors and neuroblastomas, comprising the administration of an effective amount of a compound of the invention, especially reference example 7A, namely 2- [5-chloro-2

10 (2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-N-metil-benzamida, o una sal farmacéuticamente aceptable del mismo. 10 (2-Methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -N-methyl-benzamide, or a pharmaceutically acceptable salt thereof.

[0081] Otro compuesto igualmente preferido de acuerdo con la presente invención que resulta útil en el sentido antes descrito es un compuesto mencionado específicamente en los ejemplos de acuerdo con la invención. [0081] Another equally preferred compound according to the present invention that is useful in the sense described above is a compound specifically mentioned in the examples according to the invention.

15 [0082] Otros compuestos adicionales especialmente preferidos de acuerdo con la presente invención que resultan útiles como inhibidores de la FAK, como inhibidores de la ALK o para la inhibición de ambas y que se pueden preparar esencialmente de acuerdo con los procedimientos descritos anteriormente son los siguientes: [0082] Other additionally especially preferred compounds according to the present invention that are useful as inhibitors of FAK, as inhibitors of ALK or for inhibition of both and which can be prepared essentially in accordance with the procedures described above are the following:

20 2-{5-Cloro-2-[2-metoxi-4-(4-metilpiperazin-1-il)-fenil-amino]-pirimidin-4-ilamino}-N-isopropil-benceno-sulfonamida, 2-[5-Bromo-2-(2-metoxi-5-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-N-metilbencenosulfonamida, N-[5-Bromo-2-(2,5-dimetoxifenilamino)-pirimidin-4-il]-N-(4-morfolin-4-il-fenil)-metanosulfonamida, 2-[5-Cloro-2-(2-metoxi-4-piperazin-1-il-fenilamino)-pirimidin-4-ilamino]-N-metilbencenosulfonamida, 2-[5-Bromo-2-(5-fluoro-2-metoxi-fenilamino)-pirimidin-4-ilamino]-N-metilbencenosulfonamida, 20 2- {5-Chloro-2- [2-methoxy-4- (4-methylpiperazin-1-yl) -phenyl-amino] -pyrimidin-4-ylamino} -N-isopropyl-benzene-sulfonamide, 2- [ 5-Bromo-2- (2-methoxy-5-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -N-methylbenzenesulfonamide, N- [5-Bromo-2- (2,5-dimethoxyphenylamino) - pyrimidin-4-yl] -N- (4-morpholin-4-yl-phenyl) -methanesulfonamide, 2- [5-Chloro-2- (2-methoxy-4-piperazin-1-yl-phenylamino) -pyrimidin- 4-ylamino] -N-methylbenzenesulfonamide, 2- [5-Bromo-2- (5-fluoro-2-methoxy-phenylamino) -pyrimidin-4-ylamino] -N-methylbenzenesulfonamide,

25 2-{5-Cloro-2-[2-metoxi-5-(4-metilpiperazin-1-ilmetil)-fenilamino]-pirimidin-4-ilamino}-N-metil-benceno-sulfonamida. 2- {5-Chloro-2- [2-methoxy-5- (4-methylpiperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-ylamino} -N-methyl-benzene-sulfonamide.

[0083] Los ejemplos siguientes sirven para ilustrar la invención sin limitar el alcance de la invención. [0083] The following examples serve to illustrate the invention without limiting the scope of the invention.

Ejemplos Examples

30 Abreviaturas 30 Abbreviations

[0084] AcOH = ácido acético, ALK = cinasa de linfoma anaplásico, ATP = 5’-trifosfato de adenosina, salmuera = disolución saturada de cloruro sódico, ASB = albúmina de suero bovino, DIAD = azodicarboxilato de diisopropilo, [0084] AcOH = acetic acid, ALK = anaplastic lymphoma kinase, ATP = 5′-adenosine triphosphate, brine = saturated sodium chloride solution, ASB = bovine serum albumin, DIAD = diisopropyl azodicarboxylate,

35 DIPCDI = N,N’-diisopropilcarbodiimida, DMAP = 4-dimetilaminopiridina, DMF = N,N-dimetilformamida, DTT = 1,4ditio-D,L-treitol, EDTA = ácido etilendiaminotetraacético, Et = etilo, EtOAc = acetato de etilo, EtOH = etanol, Eu-PT66 = anticuerpo contra fosfotirosina marcado con europio W1024 LANCETM (Perkin Elmer), FAK = cinasa de adhesión focal, FRET = transferencia de energía por resonancia de fluorescencia, HEPES = ácido N-2-hidroxietilpiperazina-N’2-etanosulfónico, HOAt = 1-hidroxi-7-azabenzotriazol, Me = metilo, RT-PCR = reacción en cadena de la polimerasa DIPCDI = N, N'-diisopropylcarbodiimide, DMAP = 4-dimethylaminopyridine, DMF = N, N-dimethylformamide, DTT = 1,4-dithio-D, L-treitol, EDTA = ethylenediaminetetraacetic acid, Et = ethyl, EtOAc = ethyl acetate , EtOH = ethanol, Eu-PT66 = W1024 LANCETM (Perkin Elmer) Europium-labeled phosphotyrosine antibody, FAK = focal adhesion kinase, FRET = fluorescence resonance energy transfer, HEPES = N-2-hydroxyethylpiperazine-N 'acid 2-ethanesulfonic acid, HOAt = 1-hydroxy-7-azabenzotriazole, Me = methyl, RT-PCR = polymerase chain reaction

40 de transcripción inversa, SA-(SL)APC = estreptavidina conjugada con aloficocianina SuperLightTM (Perkin Elmer), sust. = sustituido, TBTU = tetrafluoroborato de O-(benzotriazol-1-il)-N,N,N’,N’-tetrametilamonio, THF = tetrahidrofurano. 40 reverse transcription, SA- (SL) APC = streptavidin conjugated with allophycocyanin SuperLightTM (Perkin Elmer), sub. = substituted, TBTU = O- (benzotriazol-1-yl) -N, N, N ’, N’-tetramethylammonium tetrafluoroborate, THF = tetrahydrofuran.

Ejemplo 1: 2-[2-(2,5-Dimetoxi-fenilamino)-5-nitro-pirimidin-4-ilamino]-N-metilbencenosulfonamida 45 Example 1: 2- [2- (2,5-Dimethoxy-phenylamino) -5-nitro-pyrimidin-4-ylamino] -N-methylbenzenesulfonamide

imagen6image6

[0086] A una disolución de 2-(2-cloro-5-nitro-pirimidin-4-ilamino)-N-metilbencenosulfonamida (100 mg, 0,29 [0086] To a solution of 2- (2-Chloro-5-nitro-pyrimidin-4-ylamino) -N-methylbenzenesulfonamide (100 mg, 0.29

mmoles) en EtOH (3 ml) se añade 2,5-dimetoxianilina (49 mg, 0,32 mmoles) a temperatura ambiente. La mezcla se calienta a 78ºC durante 5 h. El disolvente se evapora y la mezcla se purifica mediante HPLC de fase inversa para proporcionar el producto del título. Rf = 0,47 (n-hexano: acetato de etilo = 1:1). 1H-RMN (400 MHz, CDCl3), δ (ppm): 2,36 (d, 3H), 3,57 (s, 3H), 3,73 (s, 3H), 6,72 (d, 1H), 6,99 (d, 1H), 7,17 (s, 1H), 7,35 (t, 1H), 7,4-7,6 (m, 1H), 7,63 (d, mmol) in EtOH (3 ml) 2,5-dimethoxyaniline (49 mg, 0.32 mmol) is added at room temperature. The mixture is heated at 78 ° C for 5 h. The solvent is evaporated and the mixture is purified by reverse phase HPLC to provide the title product. Rf = 0.47 (n-hexane: ethyl acetate = 1: 1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.36 (d, 3H), 3.57 (s, 3H), 3.73 (s, 3H), 6.72 (d, 1H) , 6.99 (d, 1H), 7.17 (s, 1H), 7.35 (t, 1H), 7.4-7.6 (m, 1H), 7.63 (d,

5 1H), 7,81 (d, 1H), 8,0-8,2 (m, 1H), 9,13 (s, 1H), 9,41 (sa, 1H), 11,0 (s, 1H). 5 1H), 7.81 (d, 1H), 8.0-8.2 (m, 1H), 9.13 (s, 1H), 9.41 (sa, 1H), 11.0 (s, 1 HOUR).

Preparación de 2-(2-cloro-5-nitro-pirimidin-4-ilamino)-N-metil-bencenosulfonamida Preparation of 2- (2-Chloro-5-nitro-pyrimidin-4-ylamino) -N-methyl-benzenesulfonamide

[0087] Se disuelven 2,4-dicloro-5-nitropirimidina (1,94 g, 10 mmoles) y 2-amino-N-metil-bencenosulfonamida [0087] 2,4-Dichloro-5-nitropyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide are dissolved

10 (1,86 g, 10 mmoles) en CHCl3 (30 ml). La mezcla de reacción se calienta a 61ºC durante 2 h. El disolvente se evapora y el residuo se lava con éter para dar el producto del título. 10 (1.86 g, 10 mmol) in CHCl3 (30 ml). The reaction mixture is heated at 61 ° C for 2 h. The solvent is evaporated and the residue is washed with ether to give the title product.

Rf = 0,5 (n-hexano: acetato de etilo = 1:1). 1H-RMN (400 MHz, CDCl3), δ (ppm): 2,67 (d, 3H), 4,6-4,7 (m, 2H), 7,41 (dd, 1H), 7,7 (dd, 1H), 8,04 (d, 1H), 8,15 (d, 1H), 9,21 (s, 1H), 11,2 (s, 1H). Rf = 0.5 (n-hexane: ethyl acetate = 1: 1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.67 (d, 3H), 4.6-4.7 (m, 2H), 7.41 (dd, 1H), 7.7 ( dd, 1H), 8.04 (d, 1H), 8.15 (d, 1H), 9.21 (s, 1H), 11.2 (s, 1H).

15 Ejemplo 2: 2-[5-Bromo-2-(2,4-dimetoxi-fenilamino)-pirimidin-4-ilamino]-N-metil-bencenosulfonamida Example 2: 2- [5-Bromo-2- (2,4-dimethoxy-phenylamino) -pyrimidin-4-ylamino] -N-methyl-benzenesulfonamide

imagen7image7

20 [0089] A una disolución de 2-(5-bromo-2-cloro-pirimidin-4-ilamino)-N-metil-bencenosulfonamida (300 mg, 0,79 mmoles) y 2,4-dimetoxianilina (181,5 mg, 1,18 mmoles) en etanol (3 ml) se añade ácido clorhídrico 1N (0,03 ml) y se agita a reflujo durante 5 horas. La mezcla de reacción se enfría a temperatura ambiente, se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava sucesivamente con agua y salmuera, se seca [0089] To a solution of 2- (5-bromo-2-chloro-pyrimidin-4-ylamino) -N-methyl-benzenesulfonamide (300 mg, 0.79 mmol) and 2,4-dimethoxyaniline (181.5 mg, 1.18 mmol) in ethanol (3 ml), 1N hydrochloric acid (0.03 ml) is added and stirred at reflux for 5 hours. The reaction mixture is cooled to room temperature, poured into water and extracted twice with ethyl acetate. The organic phase is washed successively with water and brine, dried

25 mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica por cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1 a 1:1) para proporcionar el compuesto del título. 25 by magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 to 1: 1) to provide the title compound.

1H-RMN (CDCl3), δ (ppm): 8,95 (s, 1H), 8,44 (d, 1H), 8,20 (s, 1H), 7,98 (dd, 1H), 7,58 (ddd, 1H), 7,22-7,32 (m, 1H), 6,51 (d, 1H), 6,40 (d, 1H), 4,56-4,48 (m, 1H), 3,86 (s, 3H), 3,81 (s, 3H), 2,64 (d, 3H). Rf (n-hexano: acetato de etilo = 30 1:1): 0,31. 1H-NMR (CDCl3), δ (ppm): 8.95 (s, 1H), 8.44 (d, 1H), 8.20 (s, 1H), 7.98 (dd, 1H), 7, 58 (ddd, 1H), 7.22-7.32 (m, 1H), 6.51 (d, 1H), 6.40 (d, 1H), 4.56-4.48 (m, 1H) , 3.86 (s, 3H), 3.81 (s, 3H), 2.64 (d, 3H). Rf (n-hexane: ethyl acetate = 30 1: 1): 0.31.

Preparación de 2-(5-bromo-2-cloro-pirimidin-4-ilamino)-N-metil-bencenosulfonamida Preparation of 2- (5-Bromo-2-chloro-pyrimidin-4-ylamino) -N-methyl-benzenesulfonamide

[0090] Se agita durante 23 horas a temperatura ambiente una disolución de 5-bromo-2,4-dicloropirimidina [0090] A solution of 5-bromo-2,4-dichloropyrimidine is stirred for 23 hours at room temperature

35 (684 mg, 3,0 mmoles) y 2-amino-N-metil-bencenosulfonamida (559 mg, 3,0 mmoles) en N,N-dimetilformamida (10 ml) que contiene carbonato potásico (830 mg, 6,0 mmoles). Se añade cloruro de amonio acuoso saturado y la mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con salmuera, se seca mediante sulfato sódico y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (gradiente de n-hexano -acetato de etilo) para proporcionar el compuesto del título en forma de un sólido 35 (684 mg, 3.0 mmol) and 2-amino-N-methyl-benzenesulfonamide (559 mg, 3.0 mmol) in N, N-dimethylformamide (10 mL) containing potassium carbonate (830 mg, 6.0 mmoles). Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient of n-hexane-ethyl acetate) to provide the title compound as a solid.

40 ligeramente amarillento. 40 slightly yellowish.

1H-RMN (CDCl3), δ (ppm): 2,67 (d, 3H), 4,79 (c, 1H), 7,26 (s, 1H), 7,29 (ddd, 1H), 7,66 (ddd, 1H), 7,95 (dd, 1H), 8,37 (s, 1H), 8,48 (d, 1H), 9,52 (s, 1H). Rf (n-hexano: acetato de etilo = 10:3): 0,33. 1H-NMR (CDCl3), δ (ppm): 2.67 (d, 3H), 4.79 (c, 1H), 7.26 (s, 1H), 7.29 (ddd, 1H), 7, 66 (ddd, 1H), 7.95 (dd, 1H), 8.37 (s, 1H), 8.48 (d, 1H), 9.52 (s, 1H). Rf (n-hexane: ethyl acetate = 10: 3): 0.33.

45 Ejemplo 3: 45 Example 3:

[0091] El ejemplo 3 engloba ejemplos de la invención y ejemplos de referencia. Las 2-[5-bromo-2-(fenilamino sust.)-pirimidin-4-ilamino-N-metil-benceno-sulfonamidas siguientes se preparan a partir de 2-(5-bromo-2-cloropirimidin-4-ilamino)-N-metil-benceno-sulfonamida y la anilina correspondiente según el procedimiento del ejemplo 2 (un (*) indica un ejemplo de referencia): [0091] Example 3 encompasses examples of the invention and reference examples. The following 2- [5-bromo-2- (phenylamino) - pyrimidin-4-ylamino-N-methyl-benzene-sulfonamides are prepared from 2- (5-bromo-2-chloropyrimidin-4-ylamino) -N-methyl-benzene-sulfonamide and the corresponding aniline according to the procedure of Example 2 (a (*) indicates a reference example):

imagen1image 1

5 5

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM 1H-RMN (400 MHz), δ (ppm): Rx Rf (solvent) or MS 1 H-NMR (400 MHz), δ (ppm):

3-1 3-1

0,48 (n-hexano:AcOEt = 1:1) CDCl3: 2,64 (d, 3H), 4,48-4,40 (m, 1H), 6,78 (d, 1H), 6,87 (sa, 1H), 6,99 (dd, 1H), 6,82 (s, 1H), 7,54 (ddd, 1H), 7,79 (d, 1H), 7,97 (dd, 1H), 8,28 (s, 1H), 8,32 (dd, 1H), 9,07 (s, 1H) 0.48 (n-hexane: AcOEt = 1: 1) CDCl3: 2.64 (d, 3H), 4.48-4.40 (m, 1H), 6.78 (d, 1H), 6.87 (sa, 1H), 6.99 (dd, 1H) , 6.82 (s, 1H), 7.54 (ddd, 1H), 7.79 (d, 1H), 7.97 (dd, 1H), 8.28 (s, 1H), 8.32 ( dd, 1H), 9.07 (s, 1H)

3-2 3-2

0,58 (n-hexano:AcOEt = 1:1) CDCl3: 2,25 (s, 3H), 2,33 (s, 3H), 2,63 (d, 3H), 4,53-4,45 (m, 1H), 6,61 (sa, 1H), 6,99 (dd, 1H), 7,04 (s, 1H), 7,18 (ddd, 1H), 7,43 (ddd, 1H), 7,56 (d, 1H), 7,92 (dd, 1H), 8,19 (s, 1H), 8,41 (dd, 1H), 9,08 (s, 1H) 0.58 (n-hexane: AcOEt = 1: 1) CDCl3: 2.25 (s, 3H), 2.33 (s, 3H), 2.63 (d, 3H), 4.53-4.45 (m, 1H), 6.61 (sa, 1H) , 6.99 (dd, 1H), 7.04 (s, 1H), 7.18 (ddd, 1H), 7.43 (ddd, 1H), 7.56 (d, 1H), 7.92 ( dd, 1H), 8.19 (s, 1H), 8.41 (dd, 1H), 9.08 (s, 1H)

3-3 3-3

0,36 (n-hexano:AcOEt = 1:1) CDCl3: 2,23 (s, 3H), 2,62 (d, 3H), 3,69 (s, 3H), 4,53-4,44 (m, 1H), 6,62 (dd, 1H), 6,69 (sa, 1H), 7,10 (d, 1H), 7,19 (dd, 1H), 7,48 (d, 1H), 7,51 (dd, 1H), 7,93 (dd, 1H), 8,22 (s, 1H), 8,44 (dd, 1H), 9,09 (s, 1H) 0.36 (n-hexane: AcOEt = 1: 1) CDCl3: 2.23 (s, 3H), 2.62 (d, 3H), 3.69 (s, 3H), 4.53-4.44 (m, 1H), 6.62 (dd, 1H) , 6.69 (sa, 1H), 7.10 (d, 1H), 7.19 (dd, 1H), 7.48 (d, 1H), 7.51 (dd, 1H), 7.93 ( dd, 1H), 8.22 (s, 1H), 8.44 (dd, 1H), 9.09 (s, 1H)

3-4 3-4

0,41 (n-hexano:AcOEt = 1:1) CDCl3: 2,32 (s, 3H), 2,63 (d, 3H), 4,45-4,44 (m, 1H), 6,85 (d, 1H), 6,91 (d, 1H), 7,00 (sa, 1H), 7,28-7,24 (m, 1H), 7,57 (dd, 1H), 7,99 (dd, 1H), 8,25 (s, 1H), 8,39 (d, 1H), 9,00 (sa, 1H) 0.41 (n-hexane: AcOEt = 1: 1) CDCl3: 2.32 (s, 3H), 2.63 (d, 3H), 4.45-4.44 (m, 1H), 6.85 (d, 1H), 6.91 (d, 1H) , 7.00 (sa, 1H), 7.28-7.24 (m, 1H), 7.57 (dd, 1H), 7.99 (dd, 1H), 8.25 (s, 1H), 8.39 (d, 1H), 9.00 (sa, 1H)

3-5 3-5

0,39 (n-hexano:AcOEt = 1:1) CDCl3: 2,33 (s, 3H), 2,63 (d, 3H), 3,87 (s, 3H), 4,46-4,44 (m, 1H), 6,66 (d, 1H), 6,71 (s, 1H), 7,48 (sa, 1H), 7,63-7,59 (m, 1H), 7,97 (dd, 1H), 8,05 (d, 1H), 8,23 (s, 1H), 8,44 (d, 1H), 8,92 (sa, 1H) 0.39 (n-hexane: AcOEt = 1: 1) CDCl3: 2.33 (s, 3H), 2.63 (d, 3H), 3.87 (s, 3H), 4.46-4.44 (m, 1H), 6.66 (d, 1H) , 6.71 (s, 1H), 7.48 (sa, 1H), 7.63-7.59 (m, 1H), 7.97 (dd, 1H), 8.05 (d, 1H), 8.23 (s, 1H), 8.44 (d, 1H), 8.92 (sa, 1H)

3-6 3-6

0,27 (n-hexano:AcOEt = 3:1) CDCl3: 2,63 (d, 3H), 3,90 (s, 3H), 4,45-4,40 (m, 1H), 6,90-6,86 (m, 2H), 7,00-6,96 (m, 1H), 7,23-7,17 (m, 3H), 7,45 (dd, 1H), 7,50-7,60 (m, 2H), 7,97 (dd, 1H), 8,22 (d, 1H), 8,26 (s, 1H), 8,43 (d, 1H), 8,94 (sa, 1H) 0.27 (n-hexane: AcOEt = 3: 1) CDCl3: 2.63 (d, 3H), 3.90 (s, 3H), 4.45-4.40 (m, 1H), 6.90-6.86 (m, 2H), 7.00- 6.96 (m, 1H), 7.23-7.17 (m, 3H), 7.45 (dd, 1H), 7.50-7.60 (m, 2H), 7.97 (dd, 1H), 8.22 (d, 1H), 8.26 (s, 1H), 8.43 (d, 1H), 8.94 (sa, 1H)

3-7 3-7

0,34 (n-hexano:AcOEt = 3:1) CDCl3: 2,30 (s, 3H), 2,63 (d, 3H), 4,44-4,43 (m, 1H), 6,68 (sa, 1H), 7,00-6,68 (m, 1H), 7,23-7,17 (m, 2H), 7,46-7,43 (m, 1H), 7,76 (d, 1H), 7,93 (dd, 1H), 8,22 (s, 1H), 8,40 (d, 1H), 9,01 (sa, 1H) 0.34 (n-hexane: AcOEt = 3: 1) CDCl3: 2.30 (s, 3H), 2.63 (d, 3H), 4.44-4.43 (m, 1H), 6.68 (sa, 1H), 7.00-6.68 ( m, 1H), 7.23-7.17 (m, 2H), 7.46-7.43 (m, 1H), 7.76 (d, 1H), 7.93 (dd, 1H), 8 , 22 (s, 1H), 8.40 (d, 1H), 9.01 (sa, 1H)

3-8 3-8

0,12 (n-hexano:AcOEt = 3:1) CDCl3: 2,62 (d, 3H), 2,81 (s, 3H), 4,07-3,98 (m, 1H), 4,52-4,45 (m, 1H), 6,37 (sa, 1H), 6,77-6,73 (m, 2H), 7,12 (dd, 1H), 7,24-7,20 (m, 1H), 7,30-7,27 (m, 1H), 7,35 (dd, 1H), 7,88 (dd, 1H), 8,18 (s, 1H), 8,41 (d, 1H), 9,19 (sa, 1H) 0.12 (n-hexane: AcOEt = 3: 1) CDCl3: 2.62 (d, 3H), 2.81 (s, 3H), 4.07-3.98 (m, 1H), 4.52-4.45 (m, 1H), 6.37 ( sa, 1H), 6.77-6.73 (m, 2H), 7.12 (dd, 1H), 7.24-7.20 (m, 1H), 7.30-7.27 (m, 1H), 7.35 (dd, 1H), 7.88 (dd, 1H), 8.18 (s, 1H), 8.41 (d, 1H), 9.19 (sa, 1H)

3-9 3-9

0,28 (n-hexano:AcOEt = 3:1) CDCl3: 2,62 (d, 3H), 3,94 (s, 3H), 4,49-4,43 (m, 1H), 6,99-6,90 (m, 3H), 7,18-7,23 (m, 1H), 7,31-7,24 (m, 3H), 7,63 (sa, 1H), 7,93-7,86 (m, 1H), 8,28-8,23 (m, 1H), 8,28 (s, 1H), 8,45 (sa, 1H), 8,89 (sa, 1H) 0.28 (n-hexane: AcOEt = 3: 1) CDCl3: 2.62 (d, 3H), 3.94 (s, 3H), 4.49-4.43 (m, 1H), 6.99-6.90 (m, 3H), 7.18- 7.23 (m, 1H), 7.31-7.24 (m, 3H), 7.63 (sa, 1H), 7.93-7.86 (m, 1H), 8.28-8, 23 (m, 1H), 8.28 (s, 1H), 8.45 (sa, 1H), 8.89 (sa, 1H)

3-10 3-10

0,23 (n-hexano:AcOEt = 3:1) CDCl3: 0,91 (t, 3H), 1,37 (dd, 2H), 1,64-1,55 (m, 2H), 2,64-2,60 (m, 2H), 4,45-4,40 (m, 1H), 6,69 (sa, 1H), 7,23-7,10 (m, 1H), 7,46-7,38 (m, 1H), 7,73 (d, 1H), 7,92 (d, 1H), 8,21 (s, 1H), 8,38-8,46 (m, 1H), 9,09 (sa, 1H) 0.23 (n-hexane: AcOEt = 3: 1) CDCl3: 0.91 (t, 3H), 1.37 (dd, 2H), 1.64-1.55 (m, 2H), 2.64-2.60 (m, 2H), 4.45- 4.40 (m, 1H), 6.69 (sa, 1H), 7.23-7.10 (m, 1H), 7.46-7.38 (m, 1H), 7.73 (d, 1H), 7.92 (d, 1H), 8.21 (s, 1H), 8.38-8.46 (m, 1H), 9.09 (sa, 1H)

3-11 3-11

0,12 (n-hexano:AcOEt = 3:1) CDCl3: 2,63 (d, 3H), 4,15-4,10 (m, 1H), 6,58 (sa, 1H), 7,31-7,10 (m, 4H), 7,53-7,49 (m, 1H), 7,71 (d, 1H), 7,95 (d, 1H), 8,30-8,23 (m, 1H), 8,26 (s, 1H), 8,45 (d, 1H), 9,03 (sa, 1H) 0.12 (n-hexane: AcOEt = 3: 1) CDCl3: 2.63 (d, 3H), 4.15-4.10 (m, 1H), 6.58 (sa, 1H), 7.31-7.10 (m, 4H), 7.53- 7.49 (m, 1H), 7.71 (d, 1H), 7.95 (d, 1H), 8.30-8.23 (m, 1H), 8.26 (s, 1H), 8 , 45 (d, 1H), 9.03 (sa, 1H)

3-12 3-12

0,4 (n-hexano:AcOEt = 3:1) CDCl3: 2,09 (dd, 2H), 2,63 (d, 3H), 2,85 (t, 2H), 2,96 (t, 2H), 4,46-4,43 (m, 2H), 6,73 (sa, 1H), 6,99 (d, 1H), 7,09 (dd, 1H), 7,25-7,20 (m, 1H), 7,52 (dd, 1H), 7,74 (d, 1H), 7,92 (dd, 1H), 8,22 (s, 1H), 8,42 (d, 1H), 9,02 (sa, 1H) 0.4 (n-hexane: AcOEt = 3: 1) CDCl3: 2.09 (dd, 2H), 2.63 (d, 3H), 2.85 (t, 2H), 2.96 (t, 2H), 4.46-4.43 (m, 2H) , 6.73 (sa, 1H), 6.99 (d, 1H), 7.09 (dd, 1H), 7.25-7.20 (m, 1H), 7.52 (dd, 1H), 7.74 (d, 1H), 7.92 (dd, 1H), 8.22 (s, 1H), 8.42 (d, 1H), 9.02 (sa, 1H)

3-13 3-13

0,33 (AcOEt) CDCl3: 2,63 (d, 3H), 4,63-4,64 (m, 1H), 7,11 (d, 2H), 7,18 (dd, 1H), 7,427,34 (m, 1H), 7,58-7,55 (m, 1H), 7,96 (d, 1H), 8,07 (s, 1H), 8,19-8,10 (m, 1H), 8,24 (s, 1H), 9,15 (s, 1H), 11,611,4 (m, 1H) 0.33 (AcOEt) CDCl3: 2.63 (d, 3H), 4.63-4.64 (m, 1H), 7.11 (d, 2H), 7.18 (dd, 1H), 7,427.34 (m, 1H) , 7.58-7.55 (m, 1H), 7.96 (d, 1H), 8.07 (s, 1H), 8.19-8.10 (m, 1H), 8.24 (s , 1H), 9.15 (s, 1H), 11.611.4 (m, 1H)

3-14 3-14

0,28 (n-hexano:AcOEt = 3:1) CDCl3: 2,63 (d, 3H), 3,88 (s, 3H), 3,89 (s, 3H), 4,47-4,41 (m, 1H), 6,60 (d, 1H), 6,92 (dd, 1H), 7,64 (dd, 1H), 7,66-7,61 (m, 1H), 7,89 (d, 1H), 7,98 (dd, 1H), 8,26 (s, 1H), 8,43 (d, 1H), 8,95 (s, 1H) 0.28 (n-hexane: AcOEt = 3: 1) CDCl3: 2.63 (d, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.47-4.41 (m, 1H), 6.60 (d, 1H) , 6.92 (dd, 1H), 7.64 (dd, 1H), 7.66-7.61 (m, 1H), 7.89 (d, 1H), 7.98 (dd, 1H), 8.26 (s, 1H), 8.43 (d, 1H), 8.95 (s, 1H)

3-15 3-15

0,30 (n-hexano:AcOEt = 3:1) CDCl3: 2,63 (d, 3H), 3,66 (s, 3H), 3,85 (s, 3H), 4,45-4,44 (m, 1H), 6,48 (dd, 1H), 6,79 (d, 1H), 7,64 (dd, 1H), 7,97 (dd, 2H), 8,26 (s, 1H), 8,44 (d, 1H), 8,96 (s, 1H) 0.30 (n-hexane: AcOEt = 3: 1) CDCl3: 2.63 (d, 3H), 3.66 (s, 3H), 3.85 (s, 3H), 4.45-4.44 (m, 1H), 6.48 (dd, 1H) , 6.79 (d, 1H), 7.64 (dd, 1H), 7.97 (dd, 2H), 8.26 (s, 1H), 8.44 (d, 1H), 8.96 ( s, 1H)

3-16 3-16

0,22 (n-hexano:AcOEt = 3:1) CDCl3: 2,17 (s, 3H), 2,22 (s, 3H), 2,64 (s, 3H), 2,63 (d, 3H), 4,46-4,44 (m, 1H), 6,57 (sa, 1H), 7,00 (s, 1H), 7,17 (dd, 1H), 7,44-7,40 (m, 1H), 7,44 (s, 1H), 7,93 (dd, 1H), 8,19 (s, 1H), 8,43 (d, 1H), 9,06 (s, 1H) 0.22 (n-hexane: AcOEt = 3: 1) CDCl3: 2.17 (s, 3H), 2.22 (s, 3H), 2.64 (s, 3H), 2.63 (d, 3H), 4.46-4.44 (m, 1H) , 6.57 (sa, 1H), 7.00 (s, 1H), 7.17 (dd, 1H), 7.44-7.40 (m, 1H), 7.44 (s, 1H), 7.93 (dd, 1H), 8.19 (s, 1H), 8.43 (d, 1H), 9.06 (s, 1H)

3-17 3-17

0,46 (AcOEt) CDCl3: 2,22 (s, 3H), 2,63 (d, 3H), 2,68 (s, 3H), 3,89 (s, 3H), 4,52-4,47 (m, 1H), 6,51 (s, 1H), 6,74 (s, 1H), 7,12 (s, 1H), 7,16-7,12 (m, 1H), 7,40 (dd, 1H), 7,91 (dd, 1H), 8,19 (s, 1H), 8,42 (d, 1H), 9,12 (s, 1H) 0.46 (AcOEt) CDCl3: 2.22 (s, 3H), 2.63 (d, 3H), 2.68 (s, 3H), 3.89 (s, 3H), 4.52-4.47 (m, 1H) , 6.51 (s, 1H), 6.74 (s, 1H), 7.12 (s, 1H), 7.16-7.12 (m, 1H), 7.40 (dd, 1H), 7.91 (dd, 1H), 8.19 (s, 1H), 8.42 (d, 1H), 9.12 (s, 1H)

3-18 3-18

0,35 (n-hexano:AcOEt = 3:1) CDCl3: 1,16 (d, 6H), 2,25 (s, 3H), 2,62 (d, 3H), 2,77 (t, 1H), 4,49-4,48 (m, 1H), 7,00 (s, 1H), 7,15 (d, 1H), 7,41-7,37 (m, 1H), 7,49 (d, 2H), 7,54 (dd, 1H), 7,92 (dd, 1H), 8,21 (s, 1H), 8,32 (d, 1H), 9,02 (s, 1H) 0.35 (n-hexane: AcOEt = 3: 1) CDCl3: 1.16 (d, 6H), 2.25 (s, 3H), 2.62 (d, 3H), 2.77 (t, 1H), 4.49-4.48 (m, 1H) , 7.00 (s, 1H), 7.15 (d, 1H), 7.41-7.37 (m, 1H), 7.49 (d, 2H), 7.54 (dd, 1H), 7.92 (dd, 1H), 8.21 (s, 1H), 8.32 (d, 1H), 9.02 (s, 1H)

3-19 3-19

0,23 (n-hexano:AcOEt = 1:1) CDCl3: 2,63 (d, 3H), 3,13-3,10 (m, 4H), 3,87 (s, 3H), 3,89-3,86 (m, 4H), 4,97-4,93 (m, 1H), 6,41 (dd, 1H), 6,52 (d, 1H), 7,24-7,22 (m, 1H), 7,32 (s, 1H), 7,57 (dd, 1H), 7,96 (dd, 1H), 8,01 (d, 1H), 8,14 (s, 1H), 8,44 (d, 1H), 8,98 (s, 1H) 0.23 (n-hexane: AcOEt = 1: 1) CDCl3: 2.63 (d, 3H), 3.13-3.10 (m, 4H), 3.87 (s, 3H), 3.89-3.86 (m, 4H), 4.97- 4.93 (m, 1H), 6.41 (dd, 1H), 6.52 (d, 1H), 7.24-7.22 (m, 1H), 7.32 (s, 1H), 7 , 57 (dd, 1H), 7.96 (dd, 1H), 8.01 (d, 1H), 8.14 (s, 1H), 8.44 (d, 1H), 8.98 (s, 1 HOUR)

3-20 3-20

0,36 (n-hexano:AcOEt = 1:1) CDCl3: 2,22 (s, 3H), 2,64 (d, 3H), 3,00-3,297 (m, 4H), 3,76-3,74 (m, 4H), 4,54-4,50 (m, 1H), 6,64 (d, 1H), 6,66 (dd, 1H), 7,11 (d, 1H), 7,18 (dd, 1H), 7,37 (d, 1H), 7,46 (dd, 1H), 7,93 (dd, 1H), 8,22 (s, 1H), 8,42 (d, 1H), 9,09 (s, 1H) 0.36 (n-hexane: AcOEt = 1: 1) CDCl3: 2.22 (s, 3H), 2.64 (d, 3H), 3.00-3.297 (m, 4H), 3.76-3.74 (m, 4H), 4.54-4, 50 (m, 1H), 6.64 (d, 1H), 6.66 (dd, 1H), 7.11 (d, 1H), 7.18 (dd, 1H), 7.37 (d, 1H ), 7.46 (dd, 1H), 7.93 (dd, 1H), 8.22 (s, 1H), 8.42 (d, 1H), 9.09 (s, 1H)

3-22 3-22

0,27 (AcOEt) CDCl3: 2,33 (s, 3H), 2,65 (d, 3H), 3,60-3,45 (m, 8H), 4,53-4,49 (m, 1H), 6,74 (s, 1H), 7,11 (d, 1H), 7,22-7,18 (m, 1H), 7,58-7,54 (m, 1H), 7,94 (dd, 1H), 8,00 (d, 1H), 8,22 (s, 1H), 8,37 (d, 1H), 9,13 (s, 1H) 0.27 (AcOEt) CDCl3: 2.33 (s, 3H), 2.65 (d, 3H), 3.60-3.45 (m, 8H), 4.53-4.49 (m, 1H), 6.74 ( s, 1H), 7.11 (d, 1H), 7.22-7.18 (m, 1H), 7.58-7.54 (m, 1H), 7.94 (dd, 1H), 8 , 00 (d, 1H), 8.22 (s, 1H), 8.37 (d, 1H), 9.13 (s, 1H)

3-23 3-23

0,38 (AcOEt) CDCl3: 1,24-1,08 (m, 2H), 1,46-1,32 (m, 2H), 1,76-1,67 (m, 2H), 1,98-1,90 (m, 2H), 2,33 (s, 3H), 2,64 (d, 3H), 3,95-3,90 (m, 1H), 4,49-4,47 (m, 1H), 5,89-5,80 (m, 1H), 6,66 (s, 1H), 7,15 (dd, 1H), 7,48-7,31 (m, 2H), 7,91 (dd, 1H), 8,12 (s, 1H), 8,23 (s, 1H), 8,41 (d, 1H), 9,18 (s, 1H) 0.38 (AcOEt) CDCl3: 1.24-1.08 (m, 2H), 1.46-1.32 (m, 2H), 1.76-1.67 (m, 2H), 1.98-1.90 (m , 2H), 2.33 (s, 3H), 2.64 (d, 3H), 3.95-3.90 (m, 1H), 4.49-4.47 (m, 1H), 5, 89-5.80 (m, 1H), 6.66 (s, 1H), 7.15 (dd, 1H), 7.48-7.31 (m, 2H), 7.91 (dd, 1H) , 8.12 (s, 1H), 8.23 (s, 1H), 8.41 (d, 1H), 9.18 (s, 1H)

3-24 3-24

0,11 (AcOEt) CDCl3: 2,35 (s, 3H), 2,71 (s, 3H), 3,07-2,73 (m, 2H), 3,86-3,31 (m, 6H), 6,85 (s, 1H), 7,10 (d, 1H), 7,24-7,19 (m, 1H), 7,52-7,48 (m, 1H), 7,66-7,59 (m, 2H), 7,93 (d, 1H), 8,06 (s, 1H), 8,27-8,21 (m, 1H), 8,23 (s, 1H), 9,11 (s, 1H) 0.11 (AcOEt) CDCl3: 2.35 (s, 3H), 2.71 (s, 3H), 3.07-2.73 (m, 2H), 3.86-3.31 (m, 6H), 6.85 ( s, 1H), 7.10 (d, 1H), 7.24-7.19 (m, 1H), 7.52-7.48 (m, 1H), 7.66-7.59 (m, 2H), 7.93 (d, 1H), 8.06 (s, 1H), 8.27-8.21 (m, 1H), 8.23 (s, 1H), 9.11 (s, 1H )

3-25 3-25

0,5 (n-hexano:AcOEt = 1:1) CDCl3: 2,52 (d, 3H), 2,62 (s, 3H), 4,36-4,32 (m, 1H), 6,74 (s, 1H), 6,87 (d, 2H), 7,00-6,91 (m, 2H), 7,00-6,97 (m, 2H), 7,38 (dd, 2H), 7,86 (dd, 1H), 7,98 (s, 1H), 8,23 (s, 1H), 8,28 (d, 1H), 9,04 (s, 1H) 0.5 (n-hexane: AcOEt = 1: 1) CDCl3: 2.52 (d, 3H), 2.62 (s, 3H), 4.36-4.32 (m, 1H), 6.74 (s, 1H), 6.87 (d, 2H) , 7.00-6.91 (m, 2H), 7.00-6.97 (m, 2H), 7.38 (dd, 2H), 7.86 (dd, 1H), 7.98 (s , 1H), 8.23 (s, 1H), 8.28 (d, 1H), 9.04 (s, 1H)

3-26 3-26

0,45 (n-hexano:AcOEt = 1:1) CDCl3: 1,62-1,34 (m, 6H), 2,13 (s, 3H), 2,56 (d, 3H), 3,01-2,87 (m, 4H), 4,54-4,38 (m, 1H), 6,59 (s, 1H), 6,696,59 (m, 1H), 7,02 (d, 1H), 7,10-7,07 (m, 1H), 7,37 (dd, 1H), 7,84 (dd, 1H), 8,15 (s, 1H), 8,34 (d, 1H), 9,01 (s, 1H) 0.45 (n-hexane: AcOEt = 1: 1) CDCl3: 1.62-1.34 (m, 6H), 2.13 (s, 3H), 2.56 (d, 3H), 3.01-2.87 (m, 4H), 4.54- 4.38 (m, 1H), 6.59 (s, 1H), 6,696.59 (m, 1H), 7.02 (d, 1H), 7.10-7.07 (m, 1H), 7 , 37 (dd, 1H), 7.84 (dd, 1H), 8.15 (s, 1H), 8.34 (d, 1H), 9.01 (s, 1H)

3-27 3-27

0,45 (n-hexano:AcOEt = 1:1) CDCl3: 2,32 (s, 3H), 2,58 (d, 3H), 3,75 (s, 3H), 4,37-4,44 (m, 1H), 6,776,73 (m, 1H), 6,89-6,82 (m, 1H), 6,976,91 (m, 2H), 6,96 (d, 1H), 7,20 (dd, 1H), 7,25-7,24 (m, 1H), 7,33-7,29 (m, 1H) 0.45 (n-hexane: AcOEt = 1: 1) CDCl3: 2.32 (s, 3H), 2.58 (d, 3H), 3.75 (s, 3H), 4.37-4.44 (m, 1H), 6.776.73 (m, 1H) , 6.89-6.82 (m, 1H), 6.976.91 (m, 2H), 6.96 (d, 1H), 7.20 (dd, 1H), 7.25-7.24 (m , 1H), 7.33-7.29 (m, 1H)

3-28 3-28

0,35 (n-hexano:AcOEt = 1:1) CDCl3: 2,34 (s, 3H), 2,64 (d, 3H), 3,81 (s, 3H), 4,57-4,50 (m, 1H), 6,76 (sa, 1H), 6,91-6,84 (m, 41H), 7,04 (d, 1H), 7,83 (dd, 1H), 8,06 (d, 1H), 8,19 (dd, 1H), 8,23 (s, 1H), 9,00 (s, 1H) 0.35 (n-hexane: AcOEt = 1: 1) CDCl3: 2.34 (s, 3H), 2.64 (d, 3H), 3.81 (s, 3H), 4.57-4.50 (m, 1H), 6.76 (sa, 1H) , 6.91-6.84 (m, 41H), 7.04 (d, 1H), 7.83 (dd, 1H), 8.06 (d, 1H), 8.19 (dd, 1H), 8.23 (s, 1H), 9.00 (s, 1H)

3-29 3-29

0,45 (n-hexano:AcOEt = 1:1) CDCl3: 1,50 (t, 3H), 2,62 (d, 3H), 4,17 (dd, 2H), 4,51-4,44 (m, 1H), 6,95-6,89 (m, 2H), 6,94 (d, 1H), 7,16 (dd, 1H), 7,31-7,23 (m, 5H), 7,67 (s, 1H), 7,11 (dd, 1H), 7,23 (d, 2H), 7,65 (s, 1H), 7,88 (dd, 1H), 8,28-8,23 (m, 1H), 8,28 (s, 1H), 8,43 (s, 1H), 8,89 (s, 1H) 0.45 (n-hexane: AcOEt = 1: 1) CDCl3: 1.50 (t, 3H), 2.62 (d, 3H), 4.17 (dd, 2H), 4.51-4.44 (m, 1H), 6.95-6.89 ( m, 2H), 6.94 (d, 1H), 7.16 (dd, 1H), 7.31-7.23 (m, 5H), 7.67 (s, 1H), 7.11 (dd , 1H), 7.23 (d, 2H), 7.65 (s, 1H), 7.88 (dd, 1H), 8.28-8.23 (m, 1H), 8.28 (s, 1H), 8.43 (s, 1H), 8.89 (s, 1H)

3-30 3-30

0,45 (n-hexano:AcOEt = 1:1) CDCl3: 1,49 (t, 3H), 2,63 (d, 3H), 3,85 (s, 3H), 4,16 (dd, 2H), 4,55-4,48 (m, 1H), 6,81 (dd, 1H), 6,95-6,91 (m, 3H), 7,11 (dd, 1H), 7,23 (d, 2H), 7,65 (s, 1H), 7,90-7,88 (m, 1H), 8,28-8,26 (m, 1H), 8,27 (s, 1H), 8,39 (s, 1H), 8,90 (s, 1H) 0.45 (n-hexane: AcOEt = 1: 1) CDCl3: 1.49 (t, 3H), 2.63 (d, 3H), 3.85 (s, 3H), 4.16 (dd, 2H), 4.55-4.48 (m, 1H) , 6.81 (dd, 1H), 6.95-6.91 (m, 3H), 7.11 (dd, 1H), 7.23 (d, 2H), 7.65 (s, 1H), 7.90-7.88 (m, 1H), 8.28-8.26 (m, 1H), 8.27 (s, 1H), 8.39 (s, 1H), 8.90 (s, 1 HOUR)

3-31 3-31

0,29 1H-RMN: (CDCl3) 1,83-1,72 (4H, m), 0.29 1H-NMR: (CDCl3) 1.83-1.72 (4H, m),

(n-hexano:AcOEt = 1:1) (n-hexane: AcOEt = 1: 1)

2,63 (3H, d), 2,66-2,62 (2H, m), 2,80 2.63 (3H, d), 2.66-2.62 (2H, m), 2.80

(2H, t), 4,41-4,44 (1H, m), 6,64 (1H, (2H, t), 4.41-4.44 (1H, m), 6.64 (1H,

sa), 6,92 (1H, d), 7,09 (1H, dd), 7,18 sa), 6.92 (1H, d), 7.09 (1H, dd), 7.18

(1H, dd), 7,45 (1H, dd), 7,59 (1H, dd), (1H, dd), 7.45 (1H, dd), 7.59 (1H, dd),

7,92 (1H, d), 8,20 (1H, s), 8,42 (1H, 7.92 (1H, d), 8.20 (1H, s), 8.42 (1H,

d) 9,08 (1H, sa) d) 9.08 (1H, sa)

3-32 3-32

0,3 (n-hexano:AcOEt = 1:1) DMSO-d6: 2,43 (s, 3H), 2,80-2,82 (m, 4H), 3,61-3,64 (m, 4H), 3,75 (s, 3H), 6,62 (dd, 1H), 6,93 (d, 1H), 7,46 (d, 1H), 7,54 (dd, 1H), 7,77 (dd, 2H), 8,14 (sa, 1H), 8,32 (s, 1H), 8,38-8,30 (m, 1H), 9,14 (sa, 1H) 0.3 (n-hexane: AcOEt = 1: 1) DMSO-d6: 2.43 (s, 3H), 2.80-2.82 (m, 4H), 3.61-3.64 (m, 4H), 3.75 (s, 3H), 6, 62 (dd, 1H), 6.93 (d, 1H), 7.46 (d, 1H), 7.54 (dd, 1H), 7.77 (dd, 2H), 8.14 (sa, 1H ), 8.32 (s, 1H), 8.38-8.30 (m, 1H), 9.14 (sa, 1H)

3-33 3-33

0,61 (MeOH:CH2Cl2 = 1:1) DMSO-d6: 1,59-1,68 (m, 2H), 1,881,98 (m, 2H), 2,13-2,25 (m, 2H), 2,19 (s, 3H), 2,43 (s, 3H), 2,60-2,70 (m, 2H), 3,75 (s, 3H), 4,32-4,40 (m, 1H), 6,51 (dd, 1H), 6,64 (d, 1H), 7,20 (dd, 1H), 7,39 (d, 1H), 7,75 (dd, 1H), 7,707,78 (s, 1H), 8,22 (s, 1H), 8,26 (s, 1H), 8,38-8,41 (m ,1H), 9,22 (s, 1H) 0.61 (MeOH: CH2Cl2 = 1: 1) DMSO-d6: 1.59-1.68 (m, 2H), 1,881.98 (m, 2H), 2.13-2.25 (m, 2H), 2.19 (s, 3H), 2, 43 (s, 3H), 2.60-2.70 (m, 2H), 3.75 (s, 3H), 4.32-4.40 (m, 1H), 6.51 (dd, 1H) , 6.64 (d, 1H), 7.20 (dd, 1H), 7.39 (d, 1H), 7.75 (dd, 1H), 7,707.78 (s, 1H), 8.22 ( s, 1H), 8.26 (s, 1H), 8.38-8.41 (m, 1H), 9.22 (s, 1H)

3-34* 3-34 *

0,17 (AcOEt) CDCl3: 2,11 (s, 3H), 2,68 (d, 3H), 2,76-2,83 (m, 2H), 2,89-2,97 (m, 2H), 3,47-3,55 (m, 2H), 3,58-3,66 (m ,2H), 3,86 (s, 3H), 4,70-4,78 (m, 1H), 6,53 (dd, 1H), 6,81 (d, 1H), 7,23 (dd, 1H), 7,54-7,62 (m, 2H), 7,97 (dd, 1H), 8,02-8,03 (m, 1H), 8,29 (s, 1H), 8,40 (d, 1H), 8,99 (sa, 1H) 0.17 (AcOEt) CDCl3: 2.11 (s, 3H), 2.68 (d, 3H), 2.76-2.83 (m, 2H), 2.89-2.97 (m, 2H), 3.47- 3.55 (m, 2H), 3.58-3.66 (m, 2H), 3.86 (s, 3H), 4.70-4.78 (m, 1H), 6.53 (dd, 1H), 6.81 (d, 1H), 7.23 (dd, 1H), 7.54-7.62 (m, 2H), 7.97 (dd, 1H), 8.02-8.03 (m, 1H), 8.29 (s, 1H), 8.40 (d, 1H), 8.99 (sa, 1H)

3-35 3-35

0,22 (AcOEt solo) DMSO-d6: 2,40-2,48 (m, 7H), 2,63 (t, 2H), 3,50-3,58 (m, 4H), 3,77 (s, 3H), 3,91 (t, 2H), 6,60 (dd, 1H), 6,93 (d, 1H), 7,28 (dd, 1H), 7,56 (d, 1H), 7,60 (dd, 1H), 7,75-7,80 (m, 1H), 7,80 (dd, 1H), 8,10 (s, 1H), 8,35 (s, 1H), 8,40 (d, 1H), 9,21 (s, 1H) 0.22 (AcOEt only) DMSO-d6: 2.40-2.48 (m, 7H), 2.63 (t, 2H), 3.50-3.58 (m, 4H), 3.77 (s, 3H), 3, 91 (t, 2H), 6.60 (dd, 1H), 6.93 (d, 1H), 7.28 (dd, 1H), 7.56 (d, 1H), 7.60 (dd, 1H ), 7.75-7.80 (m, 1H), 7.80 (dd, 1H), 8.10 (s, 1H), 8.35 (s, 1H), 8.40 (d, 1H) , 9.21 (s, 1H)

3-36 3-36

0,4 (n-hexano:AcOEt = 1:1) DMSO-d6: 2,43 (s, 3H), 7,03-7,08 (m, 1H), 7,21-7,23 (m, 1H), 7,25-7,36 (m, 1H), 7,47-7,57 (m, 2H), 7,74-7,77 (m, 2H), 8,28 (s, 1H), 8,35 (d, 1H), 9,09 (s, 1H), 9,24 (s, 1H) 0.4 (n-hexane: AcOEt = 1: 1) DMSO-d6: 2.43 (s, 3H), 7.03-7.08 (m, 1H), 7.21-7.23 (m, 1H), 7.25-7.36 (m, 1H ), 7.47-7.57 (m, 2H), 7.74-7.77 (m, 2H), 8.28 (s, 1H), 8.35 (d, 1H), 9.09 ( s, 1H), 9.24 (s, 1H)

3-37* 3-37 *

0,4 (n-hexano:AcOEt = 1:1) CDCl3: 2,64 (d, 3H), 4,53-4,54 (m, 1H), 6,88-6,93 (m, 1H), 7,14-7,28 (m, 3H), 7,54-7,58 (m, 1H), 7,95-7,98 (m, 1H), 8,16-8,21 (m, 1H), 8,24 (s, 1H), 8,33-8,36 (m, 1H), 9,05 (s, 1H) 0.4 (n-hexane: AcOEt = 1: 1) CDCl3: 2.64 (d, 3H), 4.53-4.54 (m, 1H), 6.88-6.93 (m, 1H), 7.14-7.28 (m, 3H), 7.54-7.58 (m, 1H), 7.95-7.98 (m, 1H), 8.16-8.21 (m, 1H), 8.24 (s, 1H), 8, 33-8.36 (m, 1H), 9.05 (s, 1H)

3-38* 3-38 *

0,42 (n-hexano:AcOEt = 1:1) CDCl3: 2,64 (d, 3H), 4,46-4,47 (m, 1H), 6,63-6,68 (m, 1H), 7,30-7,32 (m, 2H), 7,55 (s, 1H), 7,64-7,68 (m, 1H), 7,97-7,99 (m, 1H), 8,20-8,39 (m, 3H), 9,03 (s, 1H) 0.42 (n-hexane: AcOEt = 1: 1) CDCl3: 2.64 (d, 3H), 4.46-4.47 (m, 1H), 6.63-6.68 (m, 1H), 7.30-7.32 (m, 2H), 7.55 (s, 1H), 7.64-7.68 (m, 1H), 7.97-7.99 (m, 1H), 8.20-8.39 (m, 3H), 9, 03 (s, 1H)

3-39 3-39

562, 564 [M+1]+ CDCl3: 2,37 (s, 3H), 2,58-2,64 (m, 7H), 3,15-3,18 (m, 4H), 3,87 (s, 3H), 4,60-4,65 (m, 1H), 6,43 (dd, 1H), 6,44-6,54 (m, 1H), 7,22 (d, 1H), 7,30 (s, 1H), 7,57 (dd, 1H), 7,94-7,99 (m, 2H), 8,18 (s, 1H), 8,45 (d, 1H), 8,95 (s, 1H) 562, 564 [M + 1] + CDCl3: 2.37 (s, 3H), 2.58-2.64 (m, 7H), 3.15-3.18 (m, 4H), 3.87 (s, 3H), 4.60- 4.65 (m, 1H), 6.43 (dd, 1H), 6.44-6.54 (m, 1H), 7.22 (d, 1H), 7.30 (s, 1H), 7 , 57 (dd, 1H), 7.94-7.99 (m, 2H), 8.18 (s, 1H), 8.45 (d, 1H), 8.95 (s, 1H)

3-40* 3-40 *

572, 574 [M+1]+ DMSO-d6: 1,79-1,88 (m, 2H), 1,982,02 (m, 2H), 2,43 (s, 3H), 3,02-3,08 (m, 3H), 3,28-3,39 (m, 2H), 3,76 (s, 3H), 6,47 (dd, 1H), 6,65 (d, 1H), 7,22 (dd, 1H), 7,39 (d, 1H), 7,45-7,50 (m, 1H), 7,74-7,77 (m, 2H), 8,18 (s, 1H), 8,22 (s, 1H), 8,41-8,44 (m, 1H), 9,21 (sa, 1H) 572, 574 [M + 1] + DMSO-d6: 1.79-1.88 (m, 2H), 1,982.02 (m, 2H), 2.43 (s, 3H), 3.02-3.08 (m, 3H), 3, 28-3.39 (m, 2H), 3.76 (s, 3H), 6.47 (dd, 1H), 6.65 (d, 1H), 7.22 (dd, 1H), 7.39 (d, 1H), 7.45-7.50 (m, 1H), 7.74-7.77 (m, 2H), 8.18 (s, 1H), 8.22 (s, 1H), 8.41-8.44 (m, 1H), 9.21 (sa, 1H)

3-41* 3-41 *

565, 567 [M+1]+ DMSO-d6: 2,44 (d, 3H), 2,69-2,71 (m, 4H), 3,49-3,52 (m, 4H), 3,76 (s, 3H), 6,45 (dd, 1H), 6,62 (d, 1H), 7,23 (ddd, 1H), 7,38 (d, 1H), 7,46-7,50 (m, 1H), 7,72-7,77 (m, 2H), 8,19 (s, 1H), 8,22 (s, 1H), 8,42-8,45 (m, 1H), 9,22 (s, 1H) 565, 567 [M + 1] + DMSO-d6: 2.44 (d, 3H), 2.69-2.71 (m, 4H), 3.49-3.52 (m, 4H), 3.76 (s, 3H), 6, 45 (dd, 1H), 6.62 (d, 1H), 7.23 (ddd, 1H), 7.38 (d, 1H), 7.46-7.50 (m, 1H), 7.72 -7.77 (m, 2H), 8.19 (s, 1H), 8.22 (s, 1H), 8.42-8.45 (m, 1H), 9.22 (s, 1H)

3-42* 3-42 *

595, 597 [M+1]+ DMSO-d6: 2,44 (s, 3H), 3,31 (s, 6H), 3,48-3,53 (m, 8H), 3,72 (s, 3H), 6,24 (dd, 1H), 6,37 (d, 1H), 7,18-7,21 (m, 2H), 7,40-7,55 (m, 1H), 7,72-7,76 (m, 2H), 8,17-8,19 (m, 2H), 8,40-8,50 (m, 1H), 9,23 (s, 1H) 595, 597 [M + 1] + DMSO-d6: 2.44 (s, 3H), 3.31 (s, 6H), 3.48-3.53 (m, 8H), 3.72 (s, 3H), 6.24 (dd, 1H), 6.37 (d, 1H), 7.18-7.21 (m, 2H), 7.40-7.55 (m, 1H), 7.72-7.76 (m, 2H) , 8.17-8.19 (m, 2H), 8.40-8.50 (m, 1H), 9.23 (s, 1H)

3-43* 3-43 *

590, 592 [M+1]+ DMSO-d6: 1,64-1,71 (m, 2H), 1,751,82 (m, 2H), 2,21-2,28 (m, 1H), 2,43 (d, 3H), 2,62-2,67 (m, 2H), 3,68-3,74 (m, 2H), 3,76 (s, 3H), 6,45 (dd, 1H), 6,63 (d, 1H), 6,75-6,81 (m, 1H), 7,20 (ddd, 1H), 7,25-7,30 (m, 1H), 7,35 (d, 1H), 7,45-7,52 (m, 1H), 7,70-7,77 (m, 2H), 8,18 (s, 1H), 8,21 (s, 1H), 8,408,47 (m, 1H), 9,22 (s, 1H) 590, 592 [M + 1] + DMSO-d6: 1.64-1.71 (m, 2H), 1,751.82 (m, 2H), 2.21-2.28 (m, 1H), 2.43 (d, 3H), 2, 62-2.67 (m, 2H), 3.68-3.74 (m, 2H), 3.76 (s, 3H), 6.45 (dd, 1H), 6.63 (d, 1H) , 6.75-6.81 (m, 1H), 7.20 (ddd, 1H), 7.25-7.30 (m, 1H), 7.35 (d, 1H), 7.45-7 , 52 (m, 1H), 7.70-7.77 (m, 2H), 8.18 (s, 1H), 8.21 (s, 1H), 8,408.47 (m, 1H), 9, 22 (s, 1H)

3-44* 3-44 *

597, 599 [M+1]+ DMSO-d6: 2,44 (s, 3H), 3,12-3,17 (m, 4H), 3,68-3,85 (m, 4H), 3,79 (s, 3H), 6,55 (dd, 1H), 6,71 (d, 1H), 7,19-7,25 (m, 1H), 7,43 (d, 1H), 7,46-7,53 (m, 1H), 7,73-7,78 (m, 2H), 8,19-8,22 (m, 1H), 8,22 (s, 1H), 8,38-8,45 (m, 1H), 9,20 (sa, 1H) 597, 599 [M + 1] + DMSO-d6: 2.44 (s, 3H), 3.12-3.17 (m, 4H), 3.68-3.85 (m, 4H), 3.79 (s, 3H), 6, 55 (dd, 1H), 6.71 (d, 1H), 7.19-7.25 (m, 1H), 7.43 (d, 1H), 7.46-7.53 (m, 1H) , 7.73-7.78 (m, 2H), 8.19-8.22 (m, 1H), 8.22 (s, 1H), 8.38-8.45 (m, 1H), 9 , 20 (sa, 1H)

3-45* 3-45 *

600, 602 [M+1]+ DMSO-d6: 1,85-1,95 (m, 2H), 2,19 (t, 2H), 2,25-2,35 (m, 4H), 2,43 (s, 3H), 3,52-3,64 (m, 4H), 4,19 (t, 2H), 6,65 (d, 1H), 7,05 (dd, 1H), 7,20 (d, 1H), 7,23 (ddd, 1H), 7,27 (d, 1H), 7,407,46 (m, 1H), 7,42 (d, 1H), 7,70-7,75 (m, 1H), 7,76 (dd, 1H), 8,32 (s, 1H), 8,45 (d, 1H), 9,22 (s, 1H), 9,23 (s, 1H) 600, 602 [M + 1] + DMSO-d6: 1.85-1.95 (m, 2H), 2.19 (t, 2H), 2.25-2.35 (m, 4H), 2.43 (s, 3H), 3, 52-3.64 (m, 4H), 4.19 (t, 2H), 6.65 (d, 1H), 7.05 (dd, 1H), 7.20 (d, 1H), 7.23 (ddd, 1H), 7.27 (d, 1H), 7.407.46 (m, 1H), 7.42 (d, 1H), 7.70-7.75 (m, 1H), 7.76 ( dd, 1H), 8.32 (s, 1H), 8.45 (d, 1H), 9.22 (s, 1H), 9.23 (s, 1H)

3-46* 3-46 *

590, 592 [M+1]+ DMSO-d6: 2,05 (s, 3H), 2,44 (s, 3H), 3,08-3,17 (m, 4H), 3,55-3,63 (m, 4H), 3,77 (s, 3H), 6,48 (dd, 1H), 6,67 (d, 1H), 7,23 (dd, 1H), 7,41 (d, 1H), 7,457,52 (m, 1H), 7,76 (dd, 1H), 7,72-7,78 (m, 1H), 8,19 (s, 1H), 8,22 (s, 1H), 8,40-8,47 (m, 1H), 9,22 (sa, 1H) 590, 592 [M + 1] + DMSO-d6: 2.05 (s, 3H), 2.44 (s, 3H), 3.08-3.17 (m, 4H), 3.55-3.63 (m, 4H), 3, 77 (s, 3H), 6.48 (dd, 1H), 6.67 (d, 1H), 7.23 (dd, 1H), 7.41 (d, 1H), 7.457.52 (m, 1H ), 7.76 (dd, 1H), 7.72-7.78 (m, 1H), 8.19 (s, 1H), 8.22 (s, 1H), 8.40-8.47 ( m, 1H), 9.22 (sa, 1H)

3-47 3-47

548, 550 [M+1]+ DMSO-d6: 2,43 (s, 3H), 2,82-2,87 (m, 4H), 2,99-3,15 (m, 4H), 3,76 (s, 3H), 6,43 (dd, 1H), 6,61 (d, 1H), 7,22 (dd, 1H), 7,36 (d, 1H), 7,43-7,51 (m, 1H), 7,75 (dd, 1H), 8,17 (s, 1H), 8,21 (s, 1H), 8,38-8,45 (m, 1H), 9,12-9,28 (m, 1H) 548, 550 [M + 1] + DMSO-d6: 2.43 (s, 3H), 2.82-2.87 (m, 4H), 2.99-3.15 (m, 4H), 3.76 (s, 3H), 6, 43 (dd, 1H), 6.61 (d, 1H), 7.22 (dd, 1H), 7.36 (d, 1H), 7.43-7.51 (m, 1H), 7.75 (dd, 1H), 8.17 (s, 1H), 8.21 (s, 1H), 8.38-8.45 (m, 1H), 9.12-9.28 (m, 1H)

3-48 3-48

EM 530, 532 CDCl3: 2,65 (d, 3H), 3,96 (s, 3H), 4,40-4,48 (m, 1H), 6,85-6,88 (m, 2H), 7,22 (d, 1H), 7,25-7,31 (m, 1H), 7,567,65 (m, 3H), 7,79 (s, 1H), 8,00 (dd, 1H), 8,29 (s, 1H), 8,39 (dd, 1H), 9,00 (s, 1H) EM 530, 532 CDCl3: 2.65 (d, 3H), 3.96 (s, 3H), 4.40-4.48 (m, 1H), 6.85-6.88 (m, 2H), 7.22 ( d, 1H), 7.25-7.31 (m, 1H), 7,567.65 (m, 3H), 7.79 (s, 1H), 8.00 (dd, 1H), 8.29 (s , 1H), 8.39 (dd, 1H), 9.00 (s, 1H)

3-49* 3-49 *

Rf (AcOEt:MeOH = 9:1) 0,20 CDCl3: 2,18-2,50 (m, 4H), 2,28 (s, 3H), 2,65 (d, 3H), 3,10-3,75 (m, 4H), 3,93 (s, 3H), 4,50-4,61 (m, 1H), 6,89 (d, 1H), 7,06 (dd, 1H), 7,59-7,67 (m, 2H), 7,93-7,97 (m, 1H), 8,26 (s, 1H), 8,37-8,43 (m, 2H), 9,02 (s, 1H) Rf (AcOEt: MeOH = 9: 1) 0.20 CDCl3: 2.18-2.50 (m, 4H), 2.28 (s, 3H), 2.65 (d, 3H), 3.10-3.75 (m, 4H), 3.93 ( s, 3H), 4.50-4.61 (m, 1H), 6.89 (d, 1H), 7.06 (dd, 1H), 7.59-7.67 (m, 2H), 7 , 93-7.97 (m, 1H), 8.26 (s, 1H), 8.37-8.43 (m, 2H), 9.02 (s, 1H)

3-50* 3-50 *

Rf 0,4 (hexano/Ac OEt = 1/1) CDCl3: 2,63 (d, 3H), 3,90 (s, 3H), 4,00 (s, 3H), 4,39-4,47 (m, 1H), 6,23 (d, 1H), 7,00 (s, 1H), 7,22-7,25 (m, 1H), 7,57 (dd, 1H), 7,96 (dd, 1H), 8,22 (s, 1H), 8,25 (d, 1H), 8,37 (d, 1H), 8,96 (s, 1H) Rf 0.4 (hexane / Ac OEt = 1/1) CDCl3: 2.63 (d, 3H), 3.90 (s, 3H), 4.00 (s, 3H), 4.39-4.47 (m, 1H), 6.23 (d, 1H) , 7.00 (s, 1H), 7.22-7.25 (m, 1H), 7.57 (dd, 1H), 7.96 (dd, 1H), 8.22 (s, 1H), 8.25 (d, 1H), 8.37 (d, 1H), 8.96 (s, 1H)

3-51* 3-51 *

EM 535, 537 CDCl3: 1,17 (t, 3H), 1,71-1,79 (m, 1H), 2,28 (s, 3H), 2,62 (d, 3H), 3,41 (c, 2H), 3,46 (t, 2H), 3,79 (c, 2H), 4,41-4,48 (m, 1H), 6,43 (s, 1H), 6,106,18 (m, 2H), 7,15 (dd, 1H), 7,33 (d, 1H), 7,35-7,42 (m, 1H), 7,90 (dd, 1H), 8,16 (s, 1H), 8,45 (d, 1H), 9,07 (s, 1H) MS 535, 537 CDCl3: 1.17 (t, 3H), 1.71-1.79 (m, 1H), 2.28 (s, 3H), 2.62 (d, 3H), 3.41 (c, 2H) , 3.46 (t, 2H), 3.79 (c, 2H), 4.41-4.48 (m, 1H), 6.43 (s, 1H), 6,106.18 (m, 2H), 7.15 (dd, 1H), 7.33 (d, 1H), 7.35-7.42 (m, 1H), 7.90 (dd, 1H), 8.16 (s, 1H), 8 , 45 (d, 1H), 9.07 (s, 1H)

3-52* 3-52 *

Rf CDCl3: 2,66 (d, 3H), 3,91 (s, 3H), 4,41-4,47 (m, 1H), 6,80 (d, 1H), 6,92 (dd, 1H), 7,26-7,35 (m, 1H), 7,54 (s, 1H), 7,76 (dd, 1H), 8,00 (dd, 1H), 8,27-8,32 (m, 2H), 8,38 (dd, 1H), 8,97 (d, 1H). Rf CDCl3: 2.66 (d, 3H), 3.91 (s, 3H), 4.41-4.47 (m, 1H), 6.80 (d, 1H), 6.92 (dd, 1H) , 7.26-7.35 (m, 1H), 7.54 (s, 1H), 7.76 (dd, 1H), 8.00 (dd, 1H), 8.27-8.32 (m , 2H), 8.38 (dd, 1H), 8.97 (d, 1H).

3-53 3-53

EM 491, 493 CDCl3: 2,26 (s, 3H), 2,62 (d, 3H), 2,68 (s, 6H), 4,72 (c, 1H), 6,78 (s, 1H), 6,89 (d, 1H), 7,12 (d, 1H), 7,15 (d, 1H), 7,40-7,47 (m, 2H), 7,91 (dd, 1H), 8,40 (s, 1H), 8,41 (dd, 1H), 9,11 (s, 1H) MS 491, 493 CDCl3: 2.26 (s, 3H), 2.62 (d, 3H), 2.68 (s, 6H), 4.72 (c, 1H), 6.78 (s, 1H), 6.89 (d, 1H), 7.12 (d, 1H), 7.15 (d, 1H), 7.40-7.47 (m, 2H), 7.91 (dd, 1H), 8.40 ( s, 1H), 8.41 (dd, 1H), 9.11 (s, 1H)

3-54* 3-54 *

EM 525, 527 CDCl3: 2,04 (s, 3H), 2,65 (d, 3H), 4,42-4,48 (m, 1H), 6,79 (s, 1H), 6,967,00 (m, 2H), 7,28-7,34 (m, 4H), 7,877,91 (m, 1H), 8,18 (s, 1H), 8,23-8,26 (m, 2H), 8,53 (d, 2H), 9,07 (s, 1H). EM 525, 527 CDCl3: 2.04 (s, 3H), 2.65 (d, 3H), 4.42-4.48 (m, 1H), 6.79 (s, 1H), 6.967.00 (m, 2H) , 7.28-7.34 (m, 4H), 7.877.91 (m, 1H), 8.18 (s, 1H), 8.23-8.26 (m, 2H), 8.53 (d , 2H), 9.07 (s, 1H).

3-55 3-55

Rf (hexano:AcOEt = 3:1) 0,19 CDCl3: 1,34 (t, 3H), 1,44 (t, 3H), 2,63 (d, 3H), 3,81 (c, 2H), 4,06 (c, 2H), 4,46 (c, 1H), 6,43 (dd, 1H), 6,76 (d, 1H), 7,63-7,69 (m, 2H), 7,94 (d, 1H), 7,98 (dd, 1H), 8,42 (d, 1H), 8,93 (s, 1H) Rf (hexane: AcOEt = 3: 1) 0.19 CDCl3: 1.34 (t, 3H), 1.44 (t, 3H), 2.63 (d, 3H), 3.81 (c, 2H), 4.06 (c, 2H), 4.46 (c, 1H), 6.43 (dd, 1H), 6.76 (d, 1H), 7.63-7.69 (m, 2H), 7.94 (d, 1H), 7.98 ( dd, 1H), 8.42 (d, 1H), 8.93 (s, 1H)

3-56* 3-56 *

EM 570, 572 CDCl3: 2,63 (d, 3H), 3,85 (s, 3H), 3,93 (s, 3H), 4,52 (c, 1H), 6,78-6,83 (m, 2H), 6,93 (d, 2H), 6,90-7,02 (m, 1H), 7,11-7,15 (m, 1H), 7,21-7,27 (m, 1H), 7,61 (s, 1H), 7,87-7,92 (m, 1H), 8,26 (s, 1H), 8,20-8,30 (m, 1H), 8,388,41 (m, 1H), 8,92 (s, 1H) MS 570, 572 CDCl3: 2.63 (d, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.52 (c, 1H), 6.78-6.83 (m, 2H) , 6.93 (d, 2H), 6.90-7.02 (m, 1H), 7.11-7.15 (m, 1H), 7.21-7.27 (m, 1H), 7 , 61 (s, 1H), 7.87-7.92 (m, 1H), 8.26 (s, 1H), 8.20-8.30 (m, 1H), 8.388.41 (m, 1H ), 8.92 (s, 1 H)

3-57 3-57

Rf (hexano:AcOEt = 3:1) 0,16 CDCl3: 1,44 (t, 3H), 2,65 (d, 3H), 2,79-2,89 (m, 4H), 3,65-3,74 (m, 4H), 4,07 (c, 2H), 4,52 (c, 4H), 6,48 (dd, 1H), 6,80 (d, 1H), 7,20-7,25 (m, 1H), 7,55-7,67 (m, 2H), 7,92-7,98 (m, 2H), 8,29 (s, 1H), 8,43 (d, 1H), 8,95 (s, 1H) Rf (hexane: AcOEt = 3: 1) 0.16 CDCl3: 1.44 (t, 3H), 2.65 (d, 3H), 2.79-2.89 (m, 4H), 3.65-3.74 (m, 4H), 4.07 ( c, 2H), 4.52 (c, 4H), 6.48 (dd, 1H), 6.80 (d, 1H), 7.20-7.25 (m, 1H), 7.55-7 , 67 (m, 2H), 7.92-7.98 (m, 2H), 8.29 (s, 1H), 8.43 (d, 1H), 8.95 (s, 1H)

3-58 3-58

Rf 0,17 (hexano/AcOEt = 1/1) CDCl3: 1,46 (t, 3H), 2,63 (d, 3H), 3,08-3,13 (m, 4H), 3,83-3,90 (m, 4H), 4,09 (c, 2H), 4,46 (c, 1H), 6,39 (dd, 1H), 6,51 (d, 1H), 7,21-7,28 (m, 1H), 7,37 (s, 1H), 7,58 (dd, 1H), 7,97 (dd, 1H), 8,03 (d, 1H), 8,21 (s, 1H), 8,46 (d, 1H), 8,94 (s, 1H) Rf 0.17 (hexane / AcOEt = 1/1) CDCl3: 1.46 (t, 3H), 2.63 (d, 3H), 3.08-3.13 (m, 4H), 3.83-3.90 (m, 4H), 4.09 ( c, 2H), 4.46 (c, 1H), 6.39 (dd, 1H), 6.51 (d, 1H), 7.21-7.28 (m, 1H), 7.37 (s , 1H), 7.58 (dd, 1H), 7.97 (dd, 1H), 8.03 (d, 1H), 8.21 (s, 1H), 8.46 (d, 1H), 8 , 94 (s, 1H)

3-59* 3-59 *

EM 538, 540 CDCl3: 2,63 (d, 3H), 3,44 (s, 3H), 3,65 (s, 3H), 3,69-3,73 (m, 2H), 4,104,15 (m, 2H), 4,40 (c, 1H), 6,45 (dd, 1H), 6,85 (d, 1H), 7,19-7,25 (m, 1H), 7,61 (dd, 1H), 7,88 (s, 1H), 7,93-7,97 (m, 2H), 8,27 (s, 1H), 8,46 (d, 1H), 8,95 (s, 1H) MS 538, 540 CDCl3: 2.63 (d, 3H), 3.44 (s, 3H), 3.65 (s, 3H), 3.69-3.73 (m, 2H), 4,104.15 (m, 2H) , 4.40 (c, 1H), 6.45 (dd, 1H), 6.85 (d, 1H), 7.19-7.25 (m, 1H), 7.61 (dd, 1H), 7.88 (s, 1H), 7.93-7.97 (m, 2H), 8.27 (s, 1H), 8.46 (d, 1H), 8.95 (s, 1H)

3-60* 3-60 *

Rf (AcOEt) 0,54 CDCl3: 2,63 (d, 3H), 3,67 (s, 3H), 4,18 (t, 2H), 4,38-4,49 (m, 3H), 6,46 (dd, 1H), 6,81 (d, 1H), 7,60-7,69 (m, 2H), 7,92-7,99 (m, 2H), 8,27 (s, 1H), 8,49 (d, 1H), 9,00 (s, 1H) Rf (AcOEt) 0.54 CDCl3: 2.63 (d, 3H), 3.67 (s, 3H), 4.18 (t, 2H), 4.38-4.49 (m, 3H), 6.46 (dd, 1H) , 6.81 (d, 1H), 7.60-7.69 (m, 2H), 7.92-7.99 (m, 2H), 8.27 (s, 1H), 8.49 (d , 1H), 9.00 (s, 1H)

3-61 3-61

Rf (hexano:AcOEt = 2:1) 0,46 CDCl3: 1,44 (t, 3H), 2,63 (d, 3H), 3,64 (s, 3H), 4,07 (c, 2H), 4,47 (c, 1H), 6,45 (dd, 1H), 6,78 (d, 1H), 7,21-7,28 (m, 1H), 7,40-7,48 (m, 2H), 7,93-7,99 (m, 2H), 8,26 (s, 1H), 8,44 (d, 1H), 8,96 (s, 1H) Rf (hexane: AcOEt = 2: 1) 0.46 CDCl3: 1.44 (t, 3H), 2.63 (d, 3H), 3.64 (s, 3H), 4.07 (c, 2H), 4.47 (c, 1H), 6.45 (dd, 1H), 6.78 (d, 1H), 7.21-7.28 (m, 1H), 7.40-7.48 (m, 2H), 7.93-7.99 (m , 2H), 8.26 (s, 1H), 8.44 (d, 1H), 8.96 (s, 1H)

3-62* 3-62 *

Rf (hexano:AcOEt = 3:1) 0,31 CDCl3: 1,36 (d, 6H), 2,63 (d, 3H), 3,63 (s, 3H), 4,41-4,52 (m, 2H), 6,45 (dd, 1H), 6,81 (d, 1H), 7,21-7,26 (m, 1H), 7,59-7,68 (m, 2H), 7,91-7,98 (m, 2H), 8,26 (s, 1H), 8,45 (d, 1H), 8,96 (s, 1H) Rf (hexane: AcOEt = 3: 1) 0.31 CDCl3: 1.36 (d, 6H), 2.63 (d, 3H), 3.63 (s, 3H), 4.41-4.52 (m, 2H), 6.45 (dd, 1H) , 6.81 (d, 1H), 7.21-7.26 (m, 1H), 7.59-7.68 (m, 2H), 7.91-7.98 (m, 2H), 8 , 26 (s, 1H), 8.45 (d, 1H), 8.96 (s, 1H)

3-63* 3-63 *

Rf (hexano:AcOEt = 3:1) 0,40 CDCl3: 1,07 (t, 3H), 1,84 (m, 2H), 6,63 (d, 3H), 3,64 (s, 3H), 3,96 (t, 2H), 4,40-4,49 (m, 1H), 6,46 (dd, 1H), 6,79 (d, 1H), 7,20-7,27 (m, 1H), 7,587,66 (m, 2H), 7,94-7,97 (m, 2H), 8,26 (s, 1H), 8,45 (d, 1H), 8,97 (s, 1H). 2,62 6,68 3,84 4,41 Rf (hexane: AcOEt = 3: 1) 0.40 CDCl3: 1.07 (t, 3H), 1.84 (m, 2H), 6.63 (d, 3H), 3.64 (s, 3H), 3.96 (t, 2H), 4.40 -4.49 (m, 1H), 6.46 (dd, 1H), 6.79 (d, 1H), 7.20-7.27 (m, 1H), 7.587.66 (m, 2H), 7.94-7.97 (m, 2H), 8.26 (s, 1H), 8.45 (d, 1H), 8.97 (s, 1H). 2.62 6.68 3.84 4.41

3-64 3-64

Rf (hexano:AcOEt = 3:1) 0,19 CDCl3: (d, 3H), (s, 6H), s, 3H), 4,48 (m, 1H), 6,36 (dd, 1H), 6,80 (d, 1H), 7,17-7,24 (m, 1H), 7,51-7,62 (m, 2H), 7,83 (s, 1H), 7,95 (dd, 1H), 8,27 (s, 1H), 8,3*9-8,45 (m, 1H), 8,91 (s, 1H) Rf (hexane: AcOEt = 3: 1) 0.19 CDCl3: (d, 3H), (s, 6H), s, 3H), 4.48 (m, 1H), 6.36 (dd, 1H), 6.80 (d, 1H), 7.17- 7.24 (m, 1H), 7.51-7.62 (m, 2H), 7.83 (s, 1H), 7.95 (dd, 1H), 8.27 (s, 1H), 8 , 3 * 9-8.45 (m, 1H), 8.91 (s, 1H)

3-65* 3-65 *

Rf (hexano:AcOEt = 1:1) 0,12 CDCl3: 2,66 (d, 3H), 3,97 (s, 3H), 4,47-4,55 (m, 1H), 6,96-7,10 (m, 3H), 7,21-7,24 (m, 1H), 7,66 (s, 1H), 7,93 (dd, 1H), 8,25 (d, 1H), 8,31 (s, 1H), 8,47 (d, 2H), 8,59 (s, 1H), 8,96 (s, 1H) Rf (hexane: AcOEt = 1: 1) 0.12 CDCl3: 2.66 (d, 3H), 3.97 (s, 3H), 4.47-4.55 (m, 1H), 6.96-7.10 (m, 3H), 7.21- 7.24 (m, 1H), 7.66 (s, 1H), 7.93 (dd, 1H), 8.25 (d, 1H), 8.31 (s, 1H), 8.47 (d , 2H), 8.59 (s, 1H), 8.96 (s, 1H)

3-66* 3-66 *

EM 541, 543 CDCl3: 2,65 (d, 3H), 3,96 (s, 3H), 4,61-4,71 (m, 1H), 6,89-7,05 (m, 3H), 7,16 (dd, 1H), 7,15-7,23 (m, 1H), 7,60 (d, 1H), 7,65 (s, 1H), 7,89 (d, 1H), 8,21 (d, 1H), 8,28 (d, 1H), 8,51 (sa, 2H), 8,57 (s, 1H), 8,93 (s, 1H) MS 541, 543 CDCl3: 2.65 (d, 3H), 3.96 (s, 3H), 4.61-4.71 (m, 1H), 6.89-7.05 (m, 3H), 7.16 ( dd, 1H), 7.15-7.23 (m, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 7.89 (d, 1H), 8.21 (d , 1H), 8.28 (d, 1H), 8.51 (sa, 2H), 8.57 (s, 1H), 8.93 (s, 1H)

3-67* 3-67 *

EM 541, 543 CDCl3: 2,65 (d, 3H), 3,96 (s, 3H), 4,51 (c, 1H), 6,90-7,06 (m, 3H), 7,117,16 (m, 1H), 7,38 (d, 1H), 7,50-7,61 (m, 2H), 7,62-7,67 (m, 1H), 7,89 (dd, 1H), 8,29 (s, 1H), 8,34 (d, 1H), 8,53 (d, 1H), 8,79 (sa, 1H), 8,94 (s, 1H) MS 541, 543 CDCl3: 2.65 (d, 3H), 3.96 (s, 3H), 4.51 (c, 1H), 6.90-7.06 (m, 3H), 7.117.16 (m, 1H) , 7.38 (d, 1H), 7.50-7.61 (m, 2H), 7.62-7.67 (m, 1H), 7.89 (dd, 1H), 8.29 (s , 1H), 8.34 (d, 1H), 8.53 (d, 1H), 8.79 (sa, 1H), 8.94 (s, 1H)

3-68* 3-68 *

EM-CL 590 CDCl3: 1,45-1,59 (m, 2H), 1,70-1,78 (m, 1H), 1,82-1,90 (m, 1H), 2,38-2,50 (m, 1H), 2,43 (s, 3H), 2,62-2,77 (m, 2H), 3,56-3,70 (m, 2H), 3,76 (s, 3H), 6,46 (dd, 1H), 6,63 (d, 1H), 6,82-6,88 (a, 1H), 7,22 (dd, 1H), 7,31-7,40 (m, 2H), 7,43-7,51 (m, 1H), 7,50-7,80 (m, 2H), 8,14-8,20 (a, 1H), 8,21 (s, 1H), 8,39-8,48 (m, 1H), 9,16-9,26 (a, 1H) EM-CL 590 CDCl3: 1.45-1.59 (m, 2H), 1.70-1.78 (m, 1H), 1.82-1.90 (m, 1H), 2.38-2.50 (m , 1H), 2.43 (s, 3H), 2.62-2.77 (m, 2H), 3.56-3.70 (m, 2H), 3.76 (s, 3H), 6, 46 (dd, 1H), 6.63 (d, 1H), 6.82-6.88 (a, 1H), 7.22 (dd, 1H), 7.31-7.40 (m, 2H) , 7.43-7.51 (m, 1H), 7.50-7.80 (m, 2H), 8.14-8.20 (a, 1H), 8.21 (s, 1H), 8 , 39-8.48 (m, 1H), 9.16-9.26 (a, 1H)

3-69* 3-69 *

0,34 (CH2Cl2:MeOH = 9,1) CDCl3: 1,58-1,82 (a, 7H), 1,88-2,03 (a, 3H), 2,44-2,45 (m, 5H), 3,42-3,52 (m, 3H), 3,75 (s, 3H), 6,66 (dd, 1H), 6,92 (d, 1H), 7,28 (dd, 1H), 7,44 (a, 1H), 7,51 (dd, 1H), 7,79-7,81 (m, 2H), 8,18 (s, 1H), 8,32 (s, 1H), 8,35-8,37 (m, 1H), 9,17 (s, 1H) 0.34 (CH2Cl2: MeOH = 9.1) CDCl3: 1.58-1.82 (a, 7H), 1.88-2.03 (a, 3H), 2.44-2.45 (m, 5H), 3.42-3.52 (m , 3H), 3.75 (s, 3H), 6.66 (dd, 1H), 6.92 (d, 1H), 7.28 (dd, 1H), 7.44 (a, 1H), 7 , 51 (dd, 1H), 7.79-7.81 (m, 2H), 8.18 (s, 1H), 8.32 (s, 1H), 8.35-8.37 (m, 1H ), 9.17 (s, 1H)

3-70 3-70

EM. 607, 609 DMSO-d6: 1,84-1,92 (m, 2H), 2,342,41 (m, 4H), 2,41-2,45 (m, 3H), 2,44 (t, 2H), 3,58 (t, 4H), 3,75 (s, 3H), 4,02 (t, 2H), 6,48 (dd, 1H), 6,63 (d, 1H), 7,21 (dd, 1H), 7,41 (d, 1H), 7,46 (dd, 1H), 7,72-7,78 (m, 1H), 7,76 (dd, 1H), 8,22 (s, 1H), 8,25 (s, 1H), 8,40 (d, 1H), 9,22 (s, 1H) EM. 607, 609 DMSO-d6: 1.84-1.92 (m, 2H), 2,342.41 (m, 4H), 2.41-2.45 (m, 3H), 2.44 (t, 2H), 3, 58 (t, 4H), 3.75 (s, 3H), 4.02 (t, 2H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.21 (dd, 1H ), 7.41 (d, 1H), 7.46 (dd, 1H), 7.72-7.78 (m, 1H), 7.76 (dd, 1H), 8.22 (s, 1H) , 8.25 (s, 1H), 8.40 (d, 1H), 9.22 (s, 1H)

3-71 3-71

EM: 591, 593 DMSO-d6: 1,84-1,92 (m, 2H), 2,14 (s, 3H), 2,35-2,4 (m, 4H), 2,43 (t, 2H), 2,44 (d, 3H), 3,58 (t, 4H), 4,01 (t, 2H), 6,77 (dd, 1H), 6,82 (d, 1H), 7,17 (dd, 1H), 7,20 (d, 1H), 7,3-7,39 (m, 1H), 7,71-7,77 (m, 2H), 8,2 (s, 1H), 8,358,44 (m, 1H), 8,71 (s, 1H), 9,27 (s, 1H) MS: 591, 593 DMSO-d6: 1.84-1.92 (m, 2H), 2.14 (s, 3H), 2.35-2.4 (m, 4H), 2.43 (t, 2H), 2, 44 (d, 3H), 3.58 (t, 4H), 4.01 (t, 2H), 6.77 (dd, 1H), 6.82 (d, 1H), 7.17 (dd, 1H ), 7.20 (d, 1H), 7.3-7.39 (m, 1H), 7.71-7.77 (m, 2H), 8.2 (s, 1H), 8.358.44 ( m, 1H), 8.71 (s, 1H), 9.27 (s, 1H)

3-72 3-72

EM: 620, 622 DMSO-d6: 1,82-1,9 (m, 2H), 2,132,17 (m, 3H), 2,25-2,47 (m, 13H), 3,75 (s, 3H), 4,01 (t, 2H), 6,47 (dd, 1H), 6,63 (d, 1H), 7,19-7,24 (m, 1H), 7,41 (d, 1H), 7,43-7,5 (m, 1H), 7,707,79 (m, 2H), 8,22 (s, 1H), 8,25 (sa, 1H), 8,37-8,44 (m, 1H), 9,22 (s, 1H) MS: 620, 622 DMSO-d6: 1.82-1.9 (m, 2H), 2,132.17 (m, 3H), 2.25-2.47 (m, 13H), 3.75 (s, 3H), 4, 01 (t, 2H), 6.47 (dd, 1H), 6.63 (d, 1H), 7.19-7.24 (m, 1H), 7.41 (d, 1H), 7.43 -7.5 (m, 1H), 7,707.79 (m, 2H), 8.22 (s, 1H), 8.25 (sa, 1H), 8.37-8.44 (m, 1H), 9.22 (s, 1 H)

3-73 3-73

EM: 607, 609 DMSO-d6: 1,78 (t, 2H), 2,32-2,36 (m, 4H), 2,35-2,38 (m, 3H), 3,54-3,59 (m, 4H), 3,74 (t, 3H), 3,78 (s, 3H), 6,386,42 (m, 1H), 6,85 (d, 1H), 6,86-6,95 (m, 1H), 7,33-7,43 (m, 2H), 7,63-7,68 (m, 1H), 7,85-8,15 (m, 3H), 8,64-8,8 (m, 1H) MS: 607, 609 DMSO-d6: 1.78 (t, 2H), 2.32-2.36 (m, 4H), 2.35-2.38 (m, 3H), 3.54-3.59 (m, 4H ), 3.74 (t, 3H), 3.78 (s, 3H), 6.386.42 (m, 1H), 6.85 (d, 1H), 6.86-6.95 (m, 1H) , 7.33-7.43 (m, 2H), 7.63-7.68 (m, 1H), 7.85-8.15 (m, 3H), 8.64-8.8 (m, 1 HOUR)

3-74* 3-74 *

EM: 605, 607 DMSO-d6: 1,47-1,67 (m, 2H), 1,842,01 (m, 2H), 2,03 (s, 3H), 2,41-2,46 (m, 3H), 3,23-3,39 (m, 2H), 3,65-3,73 (m, 1H), 3,81 (s, 3H), 3,8-3,88 (m, 1H), 4,58-4,65 (m, 1H), 6,55 (dd, 1H), 6,68 (d, 1H), 7,2-7,26 (m, 1H), 7,43 (d, 1H), 7,42-7,51 (m, 1H), 7,7-7,8 (m, 2H), 8,23 (s, 1H), 8,26 (sa, 1H), 8,37-8,44 (m, 1H), 9,22 (sa, 1H) MS: 605, 607 DMSO-d6: 1.47-1.67 (m, 2H), 1,842.01 (m, 2H), 2.03 (s, 3H), 2.41-2.46 (m, 3H), 3, 23-3.39 (m, 2H), 3.65-3.73 (m, 1H), 3.81 (s, 3H), 3.8-3.88 (m, 1H), 4.58- 4.65 (m, 1H), 6.55 (dd, 1H), 6.68 (d, 1H), 7.2-7.26 (m, 1H), 7.43 (d, 1H), 7 , 42-7.51 (m, 1H), 7.7-7.8 (m, 2H), 8.23 (s, 1H), 8.26 (sa, 1H), 8.37-8.44 (m, 1H), 9.22 (sa, 1H)

3-75* 3-75 *

EM: 605, 607 DMSO-d6: 1,38-1,6 (m, 2H), 1,74-1,9 (m, 2H), 2,0 (s, 3H), 2,42-2,47 (m, 3H), 3,12-3,3 (m, 2H), 3,55-3,65 (m, 1H), 3,7-3,8 (m, 1H), 3,78 (s, 3H), 4,27-4,34 (m, 1H), 6,65 (dd, 1H), 6,94 (d, 1H), 7,24-7,3 (m, 1H), 7,53-7,63 (m, 2H), 7,74-7,83 (m, 2H), 8,09 (sa, 1H), 8,35 (s, 1H), 8,38 (d, 1H), 9,19(sa, 1H) MS: 605, 607 DMSO-d6: 1.38-1.6 (m, 2H), 1.74-1.9 (m, 2H), 2.0 (s, 3H), 2.42-2.47 (m, 3H ), 3.12-3.3 (m, 2H), 3.55-3.65 (m, 1H), 3.7-3.8 (m, 1H), 3.78 (s, 3H), 4.27-4.34 (m, 1H), 6.65 (dd, 1H), 6.94 (d, 1H), 7.24-7.3 (m, 1H), 7.53-7, 63 (m, 2H), 7.74-7.83 (m, 2H), 8.09 (sa, 1H), 8.35 (s, 1H), 8.38 (d, 1H), 9.19 (sa, 1H)

3-76* 3-76 *

EM: 577, 579 DMSO-d6: 1,51-1,61 (m, 2H), 1,791,87 (m, 2H), 2,03-2,11 (m, 2H), 2,14 (s, 3H), 2,42-2,47 (m, 3H), 2,52-2,6 (m, 2H), 3,77 (s, 3H), 4,02-4,09 (m, 1H), 6,6 (dd, 1H), 6,92 (d, 1H), 7,247,3 (m, 1H), 7,52-7,6 (m, 2H), 7,747,82 (m, 2H), 8,08 (sa, 1H), 8,34 (s, 1H), 8,4 (d, 1H), 9,2 (sa, 1H) MS: 577, 579 DMSO-d6: 1.51-1.61 (m, 2H), 1,791.87 (m, 2H), 2.03-2.11 (m, 2H), 2.14 (s, 3H), 2, 42-2.47 (m, 3H), 2.52-2.6 (m, 2H), 3.77 (s, 3H), 4.02-4.09 (m, 1H), 6.6 ( dd, 1H), 6.92 (d, 1H), 7.247.3 (m, 1H), 7.52-7.6 (m, 2H), 7.747.82 (m, 2H), 8.08 (sa , 1H), 8.34 (s, 1H), 8.4 (d, 1H), 9.2 (sa, 1H)

3-77 3-77

Rf: 0,4 (n-hexano:AcOEt = 7:3) DMSO-d6: 2,41-2,45 (m, 3H), 6,896,96 (m, 1H), 6,69 (sa, 1H), 7,24-7,33 (m, 2H), 7,51-7,57 (m, 1H), 7,63-7,7 (m, 1H), 7,73-7,78 (m, 1H), 7,79 (dd, 1H), 8,37 (s, 1H), 8,41 (d, 1H), 9,21 (sa, 1H), 9,24 (sa, 1H) Rf: 0.4 (n-hexane: AcOEt = 7: 3) DMSO-d6: 2.41-2.45 (m, 3H), 6,896.96 (m, 1H), 6.69 (sa, 1H), 7.24-7.33 (m, 2H), 7, 51-7.57 (m, 1H), 7.63-7.7 (m, 1H), 7.73-7.78 (m, 1H), 7.79 (dd, 1H), 8.37 ( s, 1H), 8.41 (d, 1H), 9.21 (sa, 1H), 9.24 (sa, 1H)

3-78 3-78

EM: 563, 565 DMSO-d6: 1,33-1,43 (m, 2H), 1,791,86 (m, 2H), 2,43-2,46 (m, 3H), 2,462,53 (m, 2H), 2,87-2,94 (m, 2H), 3,77 (s, 3H), 4,07-4,14 (m, 1H), 6,59 (dd, 1H), 6,91 (d, 1H), 7,23-7,28 (m, 1H), 7,53-7,59 (m, 2H), 7,79 (dd, 1H), 8,03 (sa, 1H), 8,32 (s, 1H), 8,38 (d, 1H), 8,7-9,5 (sa, 1H) MS: 563, 565 DMSO-d6: 1.33-1.43 (m, 2H), 1,791.86 (m, 2H), 2.43-2.46 (m, 3H), 2,462.53 (m, 2H), 2, 87-2.94 (m, 2H), 3.77 (s, 3H), 4.07-4.14 (m, 1H), 6.59 (dd, 1H), 6.91 (d, 1H) , 7.23-7.28 (m, 1H), 7.53-7.59 (m, 2H), 7.79 (dd, 1H), 8.03 (sa, 1H), 8.32 (s , 1H), 8.38 (d, 1H), 8.7-9.5 (sa, 1H)

3-79* 3-79 *

EM: 563, 565 DMSO-d6: 1,41-1,51 (m, 2H), 1,881,95 (m, 2H), 2,41-2,45 (m, 3H), 2,542,63 (m, 2H), 2,92-3,0 (m, 2H), 3,75 (s, 3H), 4,35-4,43 (m, 1H), 6,50 (dd, 1H), 6,63 (d, 1H), 7,18-7,23 (m, 1H), 7,40 (d, 1H), 7,42-7,48 (m, 1H), 7,75 (dd, 1H), 8,21 (s, 1H), 8,22-8,25 (m, 1H), 8,37-8,42 (m, 1H), 8,9-9,5 (sa, 1H) MS: 563, 565 DMSO-d6: 1.41-1.51 (m, 2H), 1,881.95 (m, 2H), 2.41-2.45 (m, 3H), 2,542.63 (m, 2H), 2, 92-3.0 (m, 2H), 3.75 (s, 3H), 4.35-4.43 (m, 1H), 6.50 (dd, 1H), 6.63 (d, 1H) , 7.18-7.23 (m, 1H), 7.40 (d, 1H), 7.42-7.48 (m, 1H), 7.75 (dd, 1H), 8.21 (s , 1H), 8.22-8.25 (m, 1H), 8.37-8.42 (m, 1H), 8.9-9.5 (sa, 1H)

3-80 3-80

EM: 482, 484 DMSO-d6: 2,4-2,46 (m, 3H), 3,79 (s, 3H), 6,72 (ddd, 1H), 6,99 (dd, 1H), 7,21-7,26 (m, 1H), 7,47-7,53 (m, 1H), 7,59-7,64 (m, 1H), 7,76 (dd, 1H), 8,25 (s, 1H), 8,29-8,37 (m, 2H), 8,8-9,6 (m, 1H) MS: 482, 484 DMSO-d6: 2.4-2.46 (m, 3H), 3.79 (s, 3H), 6.72 (ddd, 1H), 6.99 (dd, 1H), 7.21-7, 26 (m, 1H), 7.47-7.53 (m, 1H), 7.59-7.64 (m, 1H), 7.76 (dd, 1H), 8.25 (s, 1H) , 8.29-8.37 (m, 2H), 8.8-9.6 (m, 1H)

3-81 3-81

EM: 482, 484 DMSO-d6: 2,41-2,49 (m, 3H), 3,82 (s, 3H), 6,80 (ddd, 1H), 7,01 (dd, 1H), 7,3-7,35 (m, 1H), 7,56-7,63 (m, 1H), 7,7-7,8 (m, 1H), 7,82 (dd, 1H), 7,85 (dd, 1H), 8,16 (s, 1H), 8,35 (dd, 1H), 9,18 (m, 1H) MS: 482, 484 DMSO-d6: 2.41-2.49 (m, 3H), 3.82 (s, 3H), 6.80 (ddd, 1H), 7.01 (dd, 1H), 7.3-7, 35 (m, 1H), 7.56-7.63 (m, 1H), 7.7-7.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1H) , 8.16 (s, 1H), 8.35 (dd, 1H), 9.18 (m, 1H)

3-82* 3-82 *

EM: 563, 565 DMSO-d6: 1,73-1,82 (m, 1H), 2,232,34 (m, 4H), 2,34-2,42 (m, 3H), 2,422,46 (m, 3H), 2,59 (dd, 1H), 2,62-2,68 (m, 1H), 2,80 (dd, 1H), 3,75 (s, 1H), 4,85-4,91 (m, 1H), 6,42 (dd, 1H), 6,57 (d, 1H), 7,19-7,24 (m, 1H), 7,41 (d, 1H), 7,43-7,51 (m, 1H), 7,68-7,79 (m, 2H), 8,22 (s, 1H), 8,23 (s, 1H), 8,378,43 (m, 1H), 9,21 (sa, 1H) MS: 563, 565 DMSO-d6: 1.73-1.82 (m, 1H), 2,232.34 (m, 4H), 2.34-2.42 (m, 3H), 2,422.46 (m, 3H), 2, 59 (dd, 1H), 2.62-2.68 (m, 1H), 2.80 (dd, 1H), 3.75 (s, 1H), 4.85-4.91 (m, 1H) , 6.42 (dd, 1H), 6.57 (d, 1H), 7.19-7.24 (m, 1H), 7.41 (d, 1H), 7.43-7.51 (m , 1H), 7.68-7.79 (m, 2H), 8.22 (s, 1H), 8.23 (s, 1H), 8.378.43 (m, 1H), 9.21 (sa, 1 HOUR)

3,83* 3.83 *

EM 2,36 (s, 3H), 2,65 (d, 3H), 3,93 (s, EM 2.36 (s, 3H), 2.65 (d, 3H), 3.93 (s,

544, 546 544, 546

3H), 4,46-4,51 (m, 1H), 6,75-6,80 (m, 3H), 4.46-4.51 (m, 1H), 6.75-6.80 (m,

2H), 6,97-7,04 (m, 2H), 7,25-7,30 (m, 2H), 6.97-7.04 (m, 2H), 7.25-7.30 (m,

1H), 7,56-7,66 (m, 2H), 7,98 (dd, 1H), 1H), 7.56-7.66 (m, 2H), 7.98 (dd, 1H),

8,29 (s, 1H), 8,36-8,44 (m, 2H), 9,01 8.29 (s, 1H), 8.36-8.44 (m, 2H), 9.01

(s, 1H) (s, 1H)

3-84 3-84

EM 582, 564 DMSO-d6: 2,32 (s, 3H), 2,39-2,47 (m, 4H), 2,64 (d, 3H), 2,89-2,97 (m, 4H), 3,85 (s, 3H), 4,54-4,52 (m, 1H), 6,52 (dd, 1H), 6,79 (d, 1H), 7,22 (m, 1H), 7,52-7,64 (m, 2H), 7,94-7,99 (m, 2H), 8,28 (s, 1H), 8,42 (d, 1H), 8,93 (s, 1H) MS 582, 564 DMSO-d6: 2.32 (s, 3H), 2.39-2.47 (m, 4H), 2.64 (d, 3H), 2.89-2.97 (m, 4H), 3, 85 (s, 3H), 4.54-4.52 (m, 1H), 6.52 (dd, 1H), 6.79 (d, 1H), 7.22 (m, 1H), 7.52 -7.64 (m, 2H), 7.94-7.99 (m, 2H), 8.28 (s, 1H), 8.42 (d, 1H), 8.93 (s, 1H)

Ejemplo 4: 2-[5-Bromo-2-(fenilamino sust.)-pirimidin-4-il-amino-N-propil-bencenosulfonamidas Example 4: 2- [5-Bromo-2- (substituted phenylamino) - pyrimidin-4-yl-amino-N-propyl-benzenesulfonamides

[0092] Estos compuestos de manera análoga al ejemplo 2 usando 2-(5-bromo-2-cloro-pirimidin-4-ilamino)-N5 propil-bencenosulfonamida y la anilina correspondiente para proporcionar los compuestos nº 4-1 a 4-31, que tienen los sustituyentes Rx expuestos en el ejemplo 3 para los compuestos nº 3-1 a 3-31. [0092] These compounds analogously to Example 2 using 2- (5-bromo-2-chloro-pyrimidin-4-ylamino) -N5 propylbenzenesulfonamide and the corresponding aniline to provide compounds 4-1 to 4-31 , which have the Rx substituents set forth in Example 3 for compounds No. 3-1 to 3-31.

Preparación de 2-(5-bromo-2-cloro-pirimidin-4-ilamino)-N-propil-bencenosulfonamida Preparation of 2- (5-Bromo-2-chloro-pyrimidin-4-ylamino) -N-propyl-benzenesulfonamide

10 [0093] A una disolución de 5-bromo-2,4-dicloropirimidina (90 μl, 0,70 mmoles) y 2-amino-N-propilbencenosulfonamida (100 mg, 0,47 mmoles) se añade hidruro sódico (54,2 mg, 0,56 mmoles) en DMSO (1,0 ml) y la disolución resultante se agita durante 3,0 h a 80ºC. La mezcla se vierte en agua y se extrae tres veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato sódico y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) [0093] To a solution of 5-bromo-2,4-dichloropyrimidine (90 μl, 0.70 mmol) and 2-amino-N-propylbenzenesulfonamide (100 mg, 0.47 mmol) sodium hydride (54, 2 mg, 0.56 mmol) in DMSO (1.0 ml) and the resulting solution is stirred for 3.0 h at 80 ° C. The mixture is poured into water and extracted three times with ethyl acetate. The organic phase is washed with water and then with brine, dried over sodium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1)

15 para proporcionar el compuesto del título en forma de un sólido ligeramente amarillento. 15 to provide the title compound as a slightly yellowish solid.

1H-RMN (δ, ppm): 0,89 (t, 3H), 1,41 (c, 2H), 3,56 (t, 2H), 4,92 (sa, 2H), 6,71 (dd, 1H), 6,77 (dd, 1H), 7,33 (dd, 1H), 7,54 (dd, 1H), 8,79 (s, 1H). Rf (hexano: acetato de etilo = 1:1): 0,64. 1H-NMR (δ, ppm): 0.89 (t, 3H), 1.41 (c, 2H), 3.56 (t, 2H), 4.92 (sa, 2H), 6.71 (dd , 1H), 6.77 (dd, 1H), 7.33 (dd, 1H), 7.54 (dd, 1H), 8.79 (s, 1H). Rf (hexane: ethyl acetate = 1: 1): 0.64.

20 Ejemplo 5: 2-[5-Trifluorometil-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-metil-bencenosulfonamidas Example 5: 2- [5-Trifluoromethyl-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-methyl-benzenesulfonamides

[0094] Estos compuestos de manera análoga al ejemplo 2 usando 2-(2-cloro-5-trifluorometil-pirimidin-4ilamino)-N-metil-bencenosulfonamida y la anilina correspondiente para proporcionar los compuestos nº 5-1 a 5-31, que presentan los sustituyentes Rx expuestos en el ejemplo 3 para los compuestos nº 3-1 a 3-31. [0094] These compounds analogously to Example 2 using 2- (2-chloro-5-trifluoromethyl-pyrimidin-4 -lamino) -N-methyl-benzenesulfonamide and the corresponding aniline to provide compounds 5-1 to 5-31 presenting the Rx substituents set forth in Example 3 for compounds No. 3-1 to 3-31.

5 Preparación de 2-(2-cloro-5-trifluorometil-pirimidin-4-ilamino-N-metil-bencenosulfonamida 5 Preparation of 2- (2-Chloro-5-trifluoromethyl-pyrimidin-4-ylamino-N-methyl-benzenesulfonamide

[0095] A una disolución de 2,4-dicloro-5-trifluorometil-pirimidina (386 mg, 1,79 mmoles) en acetonitrilo (10 ml) se añaden sucesivamente a temperatura ambiente 2-amino-N-metil-bencenosulfonamida (333 mg, 1,79 mmoles) y [0095] To a solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (386 mg, 1.79 mmol) in acetonitrile (10 ml) are added successively at room temperature 2-amino-N-methyl-benzenesulfonamide (333 mg, 1.79 mmol) and

10 1,8-diaza[5.4.0]-biciclo-7-undeceno (280 μl, 1,88 mmoles). Tras agitar durante 15 h a temperatura ambiente se añade dicloromoetano (30 ml) a la mezcla, y la disolución se lava con hidrogenocarbonato sódico acuoso saturado y cloruro sódico acuoso saturado, se seca mediante sulfato de magnesio y se evapora al vacío. El sólido resultante se purifica mediante cromatografía ultrarrápida. 10 1,8-diaza [5.4.0] -bicyclo-7-undecene (280 μl, 1.88 mmol). After stirring for 15 h at room temperature, dichloromoethane (30 ml) is added to the mixture, and the solution is washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting solid is purified by flash chromatography.

15 1H-RMN (CDCl3) δ: 3,73 (s, 3H), 6,67-6,69 (m, 1H), 6,72-6,73 (m, 1H), 7,27-7,31 (m, 1H), 7,78 (dd, 1H), 8,60 (s, 1H). Rf (hexano: acetato de etilo = 1:1): 0,28. 1 H-NMR (CDCl3) δ: 3.73 (s, 3H), 6.67-6.69 (m, 1H), 6.72-6.73 (m, 1H), 7.27-7, 31 (m, 1H), 7.78 (dd, 1H), 8.60 (s, 1H). Rf (hexane: ethyl acetate = 1: 1): 0.28.

Ejemplo 6: 2-[5-Bromo-2-(2,3-[difluorometilendioxi]fenil-amino)-pirimidin-4-ilamino]-bencenosulfonamida Example 6: 2- [5-Bromo-2- (2,3- [difluoromethylenedioxy] phenyl-amino) -pyrimidin-4-ylamino] -benzenesulfonamide

20 [0096] 20 [0096]

imagen1image 1

[0097] Este compuesto se obtiene como producto secundario por N-desmetilación en la reacción de 2-(5bromo-2-cloro-pirimidin-4-ilamino)-N-metil-bencenosulfonamida con 2,3-(difluorometilendioxi)anilina según el [0097] This compound is obtained as a by-product by N-demethylation in the reaction of 2- (5-bromo-2-chloro-pyrimidin-4-ylamino) -N-methyl-benzenesulfonamide with 2,3- (difluoromethylenedioxy) aniline according to

25 procedimiento del ejemplo 2. También se puede preparar por reacción de 2-(5-bromo-2-cloro-pirimidin-4-ilamino)bencenosulfonamida con 2,3-(difluorometilendioxi)anilina. Rf (n-hexano: acetato de etilo = 1:1): 0,46. The procedure of Example 2. It can also be prepared by reacting 2- (5-bromo-2-chloro-pyrimidin-4-ylamino) benzenesulfonamide with 2,3- (difluoromethylenedioxy) aniline. Rf (n-hexane: ethyl acetate = 1: 1): 0.46.

1H-RMN (CDCl3) 4,83 (sa, 2H), 6,77 (dd, 1H), 6,86 (s, 1H), 6,97 (dd, 1H), 7,31-7,24 (m, 1H), 7,57 (dd, 1H), 7,81 (d, 30 1H), 8,02 (dd, 1H), 8,28 (d, 1H), 8,29 (s, 1H), 8,88 (s, 1H). 1H-NMR (CDCl3) 4.83 (sa, 2H), 6.77 (dd, 1H), 6.86 (s, 1H), 6.97 (dd, 1H), 7.31-7.24 ( m, 1H), 7.57 (dd, 1H), 7.81 (d, 30 1H), 8.02 (dd, 1H), 8.28 (d, 1H), 8.29 (s, 1H) , 8.88 (s, 1 H).

[0098] Preparación de 2-(5-bromo-2-cloropirimidin-4-il-amino)bencenosulfonamida: A una disolución de 5bromo-2,4-dicloropirimidina (300 mg, 1,32 mmoles) y 2-amino-bencenosulfonamida (340 mg, 1,97 mmoles) en 2propanol (3 ml) se añade ácido clorhídrico concentrado (0,06 ml) y la mezcla se agita durante 4,5 horas a 90ºC. La [0098] Preparation of 2- (5-bromo-2-chloropyrimidin-4-yl-amino) benzenesulfonamide: To a solution of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) and 2-amino-benzenesulfonamide (340 mg, 1.97 mmol) in 2-propanol (3 ml), concentrated hydrochloric acid (0.06 ml) is added and the mixture is stirred for 4.5 hours at 90 ° C. The

35 mezcla se vierte en hidrogenocarbonato sódico acuoso y se extrae tres veces con acetato de etilo. La fase orgánica se lava con agua, se seca mediante sulfato sódico y se evapora al vacío. El residuo se purifica por cromatografía en columna (hexano: acetato de etilo = 2:1) para proporcionar el compuesto del título. The mixture is poured into aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography (hexane: ethyl acetate = 2: 1) to provide the title compound.

Rf (hexano: acetato de etilo = 1:1): 0,55. 1H-RMN (400 MHz, CDCl3) δ: 4,78 (sa, 2H), 7,22 (dd, 1H), 7,61 (ddd, 1H), 40 7,95 (dd, 1H), 8,35 (s, 1H), 8,35 (d, 1H), 9,18 (s, 1H). Rf (hexane: ethyl acetate = 1: 1): 0.55. 1H-NMR (400 MHz, CDCl3) δ: 4.78 (sa, 2H), 7.22 (dd, 1H), 7.61 (ddd, 1H), 40 7.95 (dd, 1H), 8, 35 (s, 1H), 8.35 (d, 1H), 9.18 (s, 1H).

Ejemplo de referencia 7A: 2-[5-Cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)pirimidin-4-ilamino]-N-metil-benzamida Reference Example 7A: 2- [5-Chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) pyrimidin-4-ylamino] -N-methyl-benzamide

[0099] [0099]

imagen1image 1

[0100] A una suspensión de 2-(2,5-dicloro-pirimidin-4-il-amino)-N-metilbenzamida (5,05 g, 17,0 mmoles) en 90 ml de 2-metoxietanol se añaden dihidrocloruro de 2-metoxi-4-morfolinoanilina (4,56 g, 16,2 mmoles) y 17,0 ml de una 5 disolución etanólica de cloruro de hidrógeno 1N (17,0 mmoles). Tras agitar la mezcla de reacción durante 4 horas a 110ºC y enfriarla a temperatura ambiente, la mezcla se neutraliza con una disolución acuosa de NaOH 1N y se extrae con EtOAc (100 ml x 3). La fase orgánica se lava con salmuera, se seca mediante Na2SO4 y se concentra a presión reducida. El sólido negro resultante se lava con EtOH (90 ml) y después se purifica mediante cromatografía en columna de gel de sílice (CH2Cl2 a CH2Cl2:AcOEt = 1:2) para dar 2-[5-cloro-2-(2-metoxi-4-morfolin-4-ilfenilamino)[0100] To a suspension of 2- (2,5-dichloro-pyrimidin-4-yl-amino) -N-methylbenzamide (5.05 g, 17.0 mmol) in 90 ml of 2-methoxyethanol are added dihydrochloride of 2-methoxy-4-morpholinoaniline (4.56 g, 16.2 mmol) and 17.0 ml of an ethanolic solution of 1N hydrogen chloride (17.0 mmol). After stirring the reaction mixture for 4 hours at 110 ° C and cooling it to room temperature, the mixture is neutralized with a 1N aqueous NaOH solution and extracted with EtOAc (100 ml x 3). The organic phase is washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting black solid is washed with EtOH (90 ml) and then purified by silica gel column chromatography (CH2Cl2 to CH2Cl2: AcOEt = 1: 2) to give 2- [5-chloro-2- (2-methoxy -4-morpholin-4-ylphenylamino)

10 pirimidin-4-il-amino]-N-metil-benzamida en forma de un sólido amarillo pálido. 1H-RMN (400 MHz, DMSO-d6, δ): 2,80 (d, 3H, J = 4,52 Hz), 3,10-3,20 (m, 4H), 3,78 (s, 3H), 3,70-3,80 (m, 4H), 6,49 (dd, 1H, J = 8,56, 2,52 Hz), 6,66 (d, 1H, J = 2,52 Hz), 7,08 (dd, 1H, J = 8,04, 8,04 Hz), 7,44 (d, 1H, J = 8,56 Hz), 7,71 (dd, 1H, J = 8,04, 1,48 Hz), 8,10 (s, 1H), 8,13 (s, 1H), 8,59 (d, 1H, J = 8,04 Hz), 8,68-8,75 (m, 1H), 11,59 (s, 1H). EM m/z 469, 471 (M+1)+. 10 pyrimidin-4-yl-amino] -N-methyl-benzamide in the form of a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6, δ): 2.80 (d, 3H, J = 4.52 Hz), 3.10-3.20 (m, 4H), 3.78 (s, 3H ), 3.70-3.80 (m, 4H), 6.49 (dd, 1H, J = 8.56, 2.52 Hz), 6.66 (d, 1H, J = 2.52 Hz) , 7.08 (dd, 1H, J = 8.04, 8.04 Hz), 7.44 (d, 1H, J = 8.56 Hz), 7.71 (dd, 1H, J = 8.04 , 1.48 Hz), 8.10 (s, 1H), 8.13 (s, 1H), 8.59 (d, 1H, J = 8.04 Hz), 8.68-8.75 (m , 1H), 11.59 (s, 1H). MS m / z 469, 471 (M + 1) +.

15 [0101] Las siguientes 2-[5-cloro-2-(fenilamino sustituido)-pirimidin-4-ilamino-N-metil-benzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(2,5-dicloro-pirimidin-4-ilamino)-N[0101] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino-N-methyl-benzamides, which are all reference examples (marked with a (*)), are prepared at from 2- (2,5-dichloro-pyrimidin-4-ylamino) -N

imagen8image8

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

7-1* 7-1 *

EM: m/z 550, 552 (M+1) DMSO-d6: 1,44-1,33 (m, 2H), 1,641,45 (m, 6H), 1,73-1,89 (m, 2H), 2,342,44 (m, 1H), 2,43-2,55 (m, 4H), 2,65 (t, 2H), 2,80 (d, 3H), 3,75 (s, 3H), 3,72-3,75 (m, 2H), 6,48 (dd, 1H), 6,62 (d, 1H), 7,06 (dd, 1H), 7,32 (dd, 1H), 7,39 (d, 1H), 7,71 (dd, 1H), 8,09 (s, 1H), 8,60 (d, 1H), 8,70 (d, 1H), 11,58 (s, 1H) MS: m / z 550, 552 (M + 1) DMSO-d6: 1.44-1.33 (m, 2H), 1,641.45 (m, 6H), 1.73-1.89 (m, 2H), 2,342.44 (m, 1H), 2, 43-2.55 (m, 4H), 2.65 (t, 2H), 2.80 (d, 3H), 3.75 (s, 3H), 3.72-3.75 (m, 2H) , 6.48 (dd, 1H), 6.62 (d, 1H), 7.06 (dd, 1H), 7.32 (dd, 1H), 7.39 (d, 1H), 7.71 ( dd, 1H), 8.09 (s, 1H), 8.60 (d, 1H), 8.70 (d, 1H), 11.58 (s, 1H)

7-2* 7-2 *

0,3 (MeOH:AcOEt = 5:95) CDCl3: 1,70-1,97 (m, 4H), 2,62-2,79 (m, 1H), 3,04 (d, 3H), 3,02-3,18 (m, 2H), 3,23-3,33 (m, 2H), 3,88 (s, 3H), 5,39-5,47 (m, 1H), 6,15-6,24 (m, 1H), 6,55-6,62 (m, 2H), 6,74-6,82 (m, 1H), 7,09 (dd, 1H), 7,23-7,32 (m, 1H), 7,46-7,52 (m, 2H), 8,09 (s, 1H), 8,15 (d, 1H), 8,68 (d, 1H), 11,0 (sa, 1H) 0.3 (MeOH: AcOEt = 5:95) CDCl3: 1.70-1.97 (m, 4H), 2.62-2.79 (m, 1H), 3.04 (d, 3H), 3.02-3.18 (m, 2H), 3.23-3.33 (m, 2H), 3.88 (s, 3H), 5.39-5.47 (m, 1H), 6.15-6.24 (m, 1H), 6, 55-6.62 (m, 2H), 6.74-6.82 (m, 1H), 7.09 (dd, 1H), 7.23-7.32 (m, 1H), 7.46- 7.52 (m, 2H), 8.09 (s, 1H), 8.15 (d, 1H), 8.68 (d, 1H), 11.0 (sa, 1H)

7-3* 7-3 *

EM (ESI) m/z 482, 484 (M+1)+ DMSO-d6: 2,24 (s, 3H), 2,45-2,55 (m, 4H), 2,80 (d, 3H, J=4,52 Hz), 3,123,17 (m, 4H), 3,76 (s, 3H), 6,48 (dd, 1H, J=8,56, 2,52 Hz), 6,63 (d, 1H, J=2,52 Hz), 7,05-7,10 (m, 1H), 7,277,35 (m, 1H), 7,40 (d, 1H, J=8,56 Hz), 7,69-7,72 (m, 1H), 8,09 (s, 1H), 8,12 (s, 1H), 8,55-8,65 (m, 1H), 8,67-8,75 (m, 1H), 11,59 (s, 1H) MS (ESI) m / z 482, 484 (M + 1) + DMSO-d6: 2.24 (s, 3H), 2.45-2.55 (m, 4H), 2.80 (d, 3H, J = 4.52 Hz), 3,123.17 (m, 4H) , 3.76 (s, 3H), 6.48 (dd, 1H, J = 8.56, 2.52 Hz), 6.63 (d, 1H, J = 2.52 Hz), 7.05- 7.10 (m, 1H), 7.277.35 (m, 1H), 7.40 (d, 1H, J = 8.56 Hz), 7.69-7.72 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.65 (m, 1H), 8.67-8.75 (m, 1H), 11.59 (s, 1H)

7-4* 7-4 *

0,46 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 2,48-2,55 (m, 4H), 2,71 (t, 2H), 2,80 (d, 3H), 3,58-3,61 (m, 4H), 3,76 (s, 3H), 4,11 (t, 2H), 6,52 (dd, 1H), 6,66 (d, 1H), 7,06 (dd, 1H), 7,32 (dd, 1H), 7,46 (d, 1H), 7,71 (dd, 1H), 8,11 (s, 1H), 8,19 (s, 1H), 8,54-8,60 (m, 1H), 8,60-8,75 (m, 1H), 11,6 (s, 1H) 0.46 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 2.48-2.55 (m, 4H), 2.71 (t, 2H), 2.80 (d, 3H), 3.58-3.61 (m, 4H), 3, 76 (s, 3H), 4.11 (t, 2H), 6.52 (dd, 1H), 6.66 (d, 1H), 7.06 (dd, 1H), 7.32 (dd, 1H ), 7.46 (d, 1H), 7.71 (dd, 1H), 8.11 (s, 1H), 8.19 (s, 1H), 8.54-8.60 (m, 1H) , 8.60-8.75 (m, 1H), 11.6 (s, 1H)

7-5* 7-5 *

m/z 497, 499 (M+1)+ DMSO-d6: 1,60-1,70 (m, 2H), 1,901,98 (m, 2H), 2,13-2,25 (m, 2H), 2,19 (s, 3H), 2,60-2,67 (m, 2H), 2,80 (d, 3H, J=4,52 Hz), 3,75 (s, 3H), 4,304,40 (m, 1H), 6,54 (dd, 1H, J=8,56, 2,0 Hz), 6,65 (d, 1H, J=2,0 Hz), 7,047,09 (m, 1H), 7,25-7,35 (m, 1H), 7,43 (d, 1H, J=8,56 Hz), 7,68-7,73 (m, 1H), 8,10 (s, 1H), 8,18 (s, 1H), 8,52-8,59 (m, 1H), 8,68-8,75 (m, 1H), 11, 57 (s, 1H) m / z 497, 499 (M + 1) + DMSO-d6: 1.60-1.70 (m, 2H), 1.901.98 (m, 2H), 2.13-2.25 (m, 2H), 2.19 (s, 3H), 2, 60-2.67 (m, 2H), 2.80 (d, 3H, J = 4.52 Hz), 3.75 (s, 3H), 4.304.40 (m, 1H), 6.54 (dd , 1H, J = 8.56, 2.0 Hz), 6.65 (d, 1H, J = 2.0 Hz), 7.047.09 (m, 1H), 7.25-7.35 (m, 1H), 7.43 (d, 1H, J = 8.56 Hz), 7.68-7.73 (m, 1H), 8.10 (s, 1H), 8.18 (s, 1H), 8.52-8.59 (m, 1H), 8.68-8.75 (m, 1H), 11, 57 (s, 1H)

7-6* 7-6 *

0,25 (n-hexano:AcOEt = 1:2) CDCl3: 2,95 (m, 4H), 3,03 (d, 3H), 3,75 (m, 4H), 3,86 (s, 3H), 6,21-6,19 (a, 1H), 6,49 (dd, 1H), 6,80 (d, 1H), 7,09-7,05 (m, 1H), 7,50 (dd, 1H), 8,08 (d, 1H), 8,13 (s, 1H), 8,68 (d, 1H), 11,07 (s, 1H) 0.25 (n-hexane: AcOEt = 1: 2) CDCl3: 2.95 (m, 4H), 3.03 (d, 3H), 3.75 (m, 4H), 3.86 (s, 3H), 6.21-6.19 (a, 1H) , 6.49 (dd, 1H), 6.80 (d, 1H), 7.09-7.05 (m, 1H), 7.50 (dd, 1H), 8.08 (d, 1H), 8.13 (s, 1H), 8.68 (d, 1H), 11.07 (s, 1H)

7-7* 7-7 *

EM m/z 510, 512 (M+1) DMSO-d6: 2,06 (s, 3H), 2,80 (d, 3H), 3,11 (t, 2H), 3,16 (t, 2H), 3,60 (dd, 4H), 3,77 (s, 3H), 6,51 (dd, 1H), 6,68 (d, 1H), 7,08 (dd, 1H), 7,33 (dd, 1H), 7,46 (d, 1H), 7,71 (d, 1H), 8,10 (s, 1H), 8,12 (s, 1H), 8,59-8,61 (m, 1H), 8,70-8,71 (m, 1H), 11,59 (s, 1H) MS m / z 510, 512 (M + 1) DMSO-d6: 2.06 (s, 3H), 2.80 (d, 3H), 3.11 (t, 2H), 3.16 (t, 2H), 3.60 (dd, 4H), 3 , 77 (s, 3H), 6.51 (dd, 1H), 6.68 (d, 1H), 7.08 (dd, 1H), 7.33 (dd, 1H), 7.46 (d, 1H), 7.71 (d, 1H), 8.10 (s, 1H), 8.12 (s, 1H), 8.59-8.61 (m, 1H), 8.70-8.71 (m, 1H), 11.59 (s, 1H)

7-8* 7-8 *

0,48 (MeOH:AcOEt = 5:95) CDCl3: 1,46 (d, 1H), 1,68-1,82 (m, 2H), 2,02-2,09 (m, 2H), 2,83-2,96 (m, 2H), 3,03 (d, 3H), 3,44-3,53 (m, 2H), 3,82-3,92 (m, 1H), 3,87 (s, 3H), 6,156,23 (m, 1H), 6,51 (d, 1H), 6,56 (sa, 1H), 7,07 (dd, 1H), 7,48 (d, 2H), 8,08 (s, 1H), 8,08-8,10 (m, 1H), 8,69 (d, 1H), 11,0 (sa, 1H) 0.48 (MeOH: AcOEt = 5:95) CDCl3: 1.46 (d, 1H), 1.68-1.82 (m, 2H), 2.02-2.09 (m, 2H), 2.83-2.96 (m, 2H), 3.03 (d, 3H), 3.44-3.53 (m, 2H), 3.82-3.92 (m, 1H), 3.87 (s, 3H), 6.156.23 (m, 1H), 6.51 (d, 1H), 6.56 (sa, 1H), 7.07 (dd, 1H), 7.48 (d, 2H), 8.08 (s, 1H), 8, 08-8.10 (m, 1H), 8.69 (d, 1H), 11.0 (sa, 1H)

7-9* 7-9 *

0,4 (n-hexano:AcOEt = 1:1) CDCl3: 1,22 (t, 3H), 1,73-1,85 (m, 2H), 2,00-2,09 (m, 2H), 2,81-2,90 (m, 2H), 3,03 (d, 3H), 3,41-3,56 (m, 3H), 3,56 (dd, 2H), 3,58-3,62 (m, 2H), 3,64-3,68 (m, 2H), 3,86 (s, 3H), 6,15-6,24 (m, 1H), 6,50 (dd, 1H), 6,56 (d, 1H), 7,07 (dd, 1H), 7,24-7,30 (m, 1H), 7,45-7,52 (m, 2H), 8,08 (s, 1H), 8,06-8,08 (m, 1H), 8,69 (d, 1H), 11,0 (sa, 1H) 0.4 (n-hexane: AcOEt = 1: 1) CDCl3: 1.22 (t, 3H), 1.73-1.85 (m, 2H), 2.00-2.09 (m, 2H), 2.81-2.90 (m, 2H), 3.03 (d, 3H), 3.41-3.56 (m, 3H), 3.56 (dd, 2H), 3.58-3.62 (m, 2H), 3.64-3, 68 (m, 2H), 3.86 (s, 3H), 6.15-6.24 (m, 1H), 6.50 (dd, 1H), 6.56 (d, 1H), 7.07 (dd, 1H), 7.24-7.30 (m, 1H), 7.45-7.52 (m, 2H), 8.08 (s, 1H), 8.06-8.08 (m , 1H), 8.69 (d, 1H), 11.0 (sa, 1H)

7-10* 7-10 *

0,4 (n-hexano:AcOEt = 1:1) CDCl3: 1,73-1,85 (m, 2H), 2,01-2,10 (m, 2H), 2,82-2,90 (m, 2H), 3,03 (d, 3H), 3,41 (s, 3H), 3,45-3,51 (m, 2H), 3,56-3,58 (m, 2H), 3,65-3,68 (m, 2H), 3,86 (s, 3H), 6,14-6,22 (m, 1H), 6,50 (dd, 1H), 6,56 (d, 1H), 7,07 (dd, 1H), 7,23-7,30 (m, 1H), 7,44-7,52 (m, 2H), 8,08 (s, 1H), 8,06-8,08 (m, 1H), 8,69 (d, 1H), 11,0 (sa, 1H) 0.4 (n-hexane: AcOEt = 1: 1) CDCl3: 1.73-1.85 (m, 2H), 2.01-2.10 (m, 2H), 2.82-2.90 (m, 2H), 3.03 (d, 3H), 3.41 (s, 3H), 3.45-3.51 (m, 2H), 3.56-3.58 (m, 2H), 3.65-3.68 (m, 2H), 3, 86 (s, 3H), 6.14-6.22 (m, 1H), 6.50 (dd, 1H), 6.56 (d, 1H), 7.07 (dd, 1H), 7.23 -7.30 (m, 1H), 7.44-7.52 (m, 2H), 8.08 (s, 1H), 8.06-8.08 (m, 1H), 8.69 (d , 1H), 11.0 (sa, 1H)

7-11* 7-11 *

0,54 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 1,78-1,89 (m, 1H), 2,132,22 (m, 1H), 2,22 (s, 6H), 2,77-2,87 (m, 1H), 2,79 (d, 3H), 3,04-3,10 (m, 1H), 3,23-3,50 (m, 3H), 3,75 (s, 3H), 6,11 (dd, 1H), 6,22 (d, 1H), 7,05 (dd, 1H), 7,21-7,32 (m, 1H), 7,26 (d, 1H), 7,70 (d, 1H), 8,06 (s, 1H), 8,08 (s, 1H), 8,57-8,66 (m, 1H), 8,66-8,73 (m, 1H), 11,6 (s, 1H), 0.54 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 1.78-1.89 (m, 1H), 2,132.22 (m, 1H), 2.22 (s, 6H), 2.77-2.87 (m, 1H), 2, 79 (d, 3H), 3.04-3.10 (m, 1H), 3.23-3.50 (m, 3H), 3.75 (s, 3H), 6.11 (dd, 1H) , 6.22 (d, 1H), 7.05 (dd, 1H), 7.21-7.32 (m, 1H), 7.26 (d, 1H), 7.70 (d, 1H), 8.06 (s, 1H), 8.08 (s, 1H), 8.57-8.66 (m, 1H), 8.66-8.73 (m, 1H), 11.6 (s, 1 HOUR),

7-12* 7-12 *

0,27 (MeOH:CH2Cl2 = 1:1) DMSO-d6: 1,77-1,87 (m, 1H), 2,092,18 (m, 1H), 2,35 (s, 3H), 2,79 (d, 3H), 3,02-3,07 (m, 1H), 3,23-3,50 (m, 4H), 3,74 (s, 3H), 6,09 (dd, 1H), 6,20 (d, 1H), 7,04 (dd, 1H), 7,22-7,32 (m, 1H), 7,26 (d, 1H), 7,70 (d, 1H), 8,05 (s, 1H), 8,08 (s, 1H), 8,57-8,67 (m, 1H), 8,67-8,73 (m, 1H), 11,6 (s, 1H), 0.27 (MeOH: CH2Cl2 = 1: 1) DMSO-d6: 1.77-1.87 (m, 1H), 2,092.18 (m, 1H), 2.35 (s, 3H), 2.79 (d, 3H), 3.02-3, 07 (m, 1H), 3.23-3.50 (m, 4H), 3.74 (s, 3H), 6.09 (dd, 1H), 6.20 (d, 1H), 7.04 (dd, 1H), 7.22-7.32 (m, 1H), 7.26 (d, 1H), 7.70 (d, 1H), 8.05 (s, 1H), 8.08 ( s, 1H), 8.57-8.67 (m, 1H), 8.67-8.73 (m, 1H), 11.6 (s, 1H),

7-13* 7-13 *

0,23 (MeOH:AcOEt = 5:95) CDCl3: 1,62-1,74 (m, 3H), 1,76-1,85 (m, 2H), 2,00-2,09 (m, 2H), 2,20-2,31 (m, 1H), 2,64-2,69 (m, 2H), 2,79 (d, 3H), 3,56-4,04 (m, 2H), 4,04 (s, 3H), 6,49 (dd, 1H), 6,63 (d, 1H), 6,78 (sa, 1H), 7,07 (dd, 1H), 7,28-7,38 (m, 1H), 7,39 (d, 1H), 7,71 (d, 1H), 8,09-8,11 (m, 2H), 8,09 (s, 1H), 8,60 (d, 1H), 8,71 (d, 1H), 11,6 (sa, 1H) 0.23 (MeOH: AcOEt = 5:95) CDCl3: 1.62-1.74 (m, 3H), 1.76-1.85 (m, 2H), 2.00-2.09 (m, 2H), 2.20-2.31 (m , 1H), 2.64-2.69 (m, 2H), 2.79 (d, 3H), 3.56-4.04 (m, 2H), 4.04 (s, 3H), 6, 49 (dd, 1H), 6.63 (d, 1H), 6.78 (sa, 1H), 7.07 (dd, 1H), 7.28-7.38 (m, 1H), 7.39 (d, 1H), 7.71 (d, 1H), 8.09-8.11 (m, 2H), 8.09 (s, 1H), 8.60 (d, 1H), 8.71 ( d, 1H), 11.6 (sa, 1H)

7-14* 7-14 *

0,30 (MeOH:CH2Cl2 = 4:1) DMSO-d6: 1,61-1,46 (m, 2H), 1,921,82 (m, 2H), 2,14 (s, 3H), 2,41-2,23 (m, 5H), 2,60-2,45 (m, 4H), 2,67 (t, 2H), 2,79 (d, 3H), 3,75 (s, 3H), 3,713,75 (m, 2H), 6,48 (dd, 1H), 6,63 (d, 1H), 7,10-7,03 (m, 1H), 7,34-7,27 (m, 1H), 7,43-7,35 (m, 1H), 7,71 (dd, 1H), 8,09 (s, 1H), 8,11 (sa, 1H), 8,65-8,56 (m, 1H), 8,75-8,67 (m,, 1H), 11,6 (s, 1H) 0.30 (MeOH: CH2Cl2 = 4: 1) DMSO-d6: 1.61-1.46 (m, 2H), 1,921.82 (m, 2H), 2.14 (s, 3H), 2.41-2.23 (m, 5H), 2, 60-2.45 (m, 4H), 2.67 (t, 2H), 2.79 (d, 3H), 3.75 (s, 3H), 3,713.75 (m, 2H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.10-7.03 (m, 1H), 7.34-7.27 (m, 1H), 7.43-7.35 (m , 1H), 7.71 (dd, 1H), 8.09 (s, 1H), 8.11 (sa, 1H), 8.65-8.56 (m, 1H), 8.75-8, 67 (m ,, 1H), 11.6 (s, 1H)

7-15* 7-15 *

EM (ESI) m/z 524, 526 (M+1)+ DMSO-d6: 2,19-2,37 (m, 4H), 2,652,85 (m, 3H), 2,80 (d, 3H, J=4,5 Hz), 3,15-3,21 (m, 1H), 3,48-3,59 (m, 2H), 3,61-3,67 (m, 1H), 3,72-3,81 (m, 1H), 3,76 (s, 3H), 6,47 (dd, 1H, J=8,6, 2,5 Hz), 6,65 (d, 1H, J=2,5 Hz), 7,04-7,10 (m, 1H), 7,28-7,35 (m, 1H), 7,42 (d, 1H, J=8,6 Hz), 7,69-7,74 (m, 1H), 8,09 (s, 1H), 8,12 (s, 1H), 8,55-8,63 (m, 1H), 8,68-8,73 (m, 1H), 11,60 (s, 1H) MS (ESI) m / z 524, 526 (M + 1) + DMSO-d6: 2.19-2.37 (m, 4H), 2,652.85 (m, 3H), 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 ( m, 1H), 3.48-3.59 (m, 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s, 3H), 6.47 (dd, 1H, J = 8.6, 2.5 Hz), 6.65 (d, 1H, J = 2.5 Hz), 7.04-7.10 (m, 1H ), 7.28-7.35 (m, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.69-7.74 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H)

7-16* 7-16 *

EM (ESI) m/z 524, 526 (M+1)+ DMSO-d6: 2,19-2,37 (m, 4H), 2,652,85 (m, 3H), 2,80 (d, 3H, J=4,5 Hz), 3,15-3,21 (m, 1H), 3,48-3,59 (m, 2H), 3,61-3,67 (m, 1H), 3,72-3,81 (m, 1H), 3,76 (s, 3H), 6,47 (dd, 1H, J=8,6, 2,5 Hz), 6,65 (d, 1H, J=2,5 Hz), 7,04-7,10 (m, 1H), 7,28-7,35 (m, 1H), 7,42 (d, 1H, J=8,6 Hz), 7,69-7,74 (m, 1H), 8,09 (s, 1H), 8,12 (s, 1H), 8,55-8,63 (m, 1H), 8,68-8,73 (m, 1H), 11,60 (s, 1H) MS (ESI) m / z 524, 526 (M + 1) + DMSO-d6: 2.19-2.37 (m, 4H), 2,652.85 (m, 3H), 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 ( m, 1H), 3.48-3.59 (m, 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s, 3H), 6.47 (dd, 1H, J = 8.6, 2.5 Hz), 6.65 (d, 1H, J = 2.5 Hz), 7.04-7.10 (m, 1H ), 7.28-7.35 (m, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.69-7.74 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H)

7-17* 7-17 *

EM 510 DMSO-d6: 0,98 (t, 3H), 1,81-1,71 (m, 3H), 1,95-1,84 (m, 3H), 2,68-2,63 (m, 1H), 2,80 (d, 3H), 3,12-3,08 (m, 4H), 3,28 (d, 2H), 3,76 (s, 3H), 6,50 (dd, 1H), 6,64 (d, 1H), 6,86 (sa, 1H), 7,07 (dd, 1H), 7,46-7,19 (m, 3H), 7,71 (d, 1H), 8,09 (s, 1H), 8,15-8,10 (m, 1H), 8,66-8,58 (m, 1H), 8,77-8,70 (m, 1H), 11,6 (s, 1H) EM 510 DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63 (m, 1H ), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28 (d, 2H), 3.76 (s, 3H), 6.50 (dd, 1H) , 6.64 (d, 1H), 6.86 (sa, 1H), 7.07 (dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1H), 8.09 (s, 1H), 8.15-8.10 (m, 1H), 8.66-8.58 (m, 1H), 8.77-8.70 (m, 1H), 11, 6 (s, 1H)

7-18* 7-18 *

EM 510 DMSO-d6: 0,98 (t, 3H), 1,81-1,71 (m, 3H), 1,95-1,84 (m, 3H), 2,68-2,63 (m, 1H), 2,80 (d, 3H), 3,12-3,08 (m, 4H), 3,28 (d, 2H), 3,76 (s, 3H), 6,50 (dd, 1H), 6,64 (d, 1H), 6,86 (sa, 1H), 7,07 (dd, 1H), 7,46-7,19 (m, 3H), 7,71 (d, 1H), 8,09 (s, 1H), 8,15-8,10 (m, 1H), 8,66-8,58 (m, 1H), 8,77-8,70 (m, 1H), 11,6 (s, 1H) EM 510 DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63 (m, 1H ), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28 (d, 2H), 3.76 (s, 3H), 6.50 (dd, 1H) , 6.64 (d, 1H), 6.86 (sa, 1H), 7.07 (dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1H), 8.09 (s, 1H), 8.15-8.10 (m, 1H), 8.66-8.58 (m, 1H), 8.77-8.70 (m, 1H), 11, 6 (s, 1H)

7-19* 7-19 *

0,16 1,40-1,53 (m, 2H), 1,72-1,80 (m, 2H), 0.16 1.40-1.53 (m, 2H), 1.72-1.80 (m, 2H),

(CH2Cl2:MeOH = 9:1) (CH2Cl2: MeOH = 9: 1)

2,18 (s, 3H), 2,19-2,44 (m, 5H), 2,80 2.18 (s, 3H), 2.19-2.44 (m, 5H), 2.80

(d, 3H), 3,46 (m, 2H), 3,74 (s, 3H), (d, 3H), 3.46 (m, 2H), 3.74 (s, 3H),

6,65 (dd, 1H), 6,91 (d, 1H), 7,07-7,10 6.65 (dd, 1H), 6.91 (d, 1H), 7.07-7.10

(m, 1H), 7,36-7,40 (m, 1H), 7,45-7,49 (m, 1H), 7.36-7.40 (m, 1H), 7.45-7.49

(m, 1H), 7,73 (dd, 1H), 8,12 (s, 1H), (m, 1H), 7.73 (dd, 1H), 8.12 (s, 1H),

8,18 (s, 1H), 8,61 (d, 1H), 8,72-8,77 8.18 (s, 1H), 8.61 (d, 1H), 8.72-8.77

(m, 1H), 11,68 (s, 1H) (m, 1H), 11.68 (s, 1H)

7-20* 7-20 *

EM: 519 1,25-1,37 (m, 2H), 1,62-1,79 (m, 3H), MS: 519 1.25-1.37 (m, 2H), 1.62-1.79 (m, 3H),

1,81-1,9 (m, 2H), 2,16 (s, 3H), 2,751.81-1.9 (m, 2H), 2.16 (s, 3H), 2.75

2,85 (m, 5H), 3,76 (s, 3H), 3,8-3,88 2.85 (m, 5H), 3.76 (s, 3H), 3.8-3.88

(m, 2H), 6,45-6,55 (m, 1H), 6,6-6,67 (m, 2H), 6.45-6.55 (m, 1H), 6.6-6.67

(m, 1H), 7,02-7,12 (m, 1H), 7,25-7,35 (m, 1H), 7.02-7.12 (m, 1H), 7.25-7.35

(m, 1H), 7,4-7,5 (m, 1H), 7,67-7,78 (m, 1H), 7.4-7.5 (m, 1H), 7.67-7.78

(m, 1H), 8,1 (s, 1H), 8,19 (sa, 1H), (m, 1H), 8.1 (s, 1H), 8.19 (sa, 1H),

8,5-8,62 (m, 1H), 8,66-8,8 (m, 1H), 8.5-8.62 (m, 1H), 8.66-8.8 (m, 1H),

11,6 (s, 1H) 11.6 (s, 1 H)

7-21* 7-21 *

EM: 526 2,17 (s, 3H), 2,29-2,39 (m, 3H), 2,45 MS: 526 2.17 (s, 3H), 2.29-2.39 (m, 3H), 2.45

2,56 (m, 4H), 2,7 (t, 2H), 3,76 (s, 3H), 2.56 (m, 4H), 2.7 (t, 2H), 3.76 (s, 3H),

4,09 (t, 2H), 6,52 (dd, 1H), 6,66 (d, 4.09 (t, 2H), 6.52 (dd, 1H), 6.66 (d,

1H), 7,06 (dd, 1H), 7,31 (dd, 1H), 7,45 1H), 7.06 (dd, 1H), 7.31 (dd, 1H), 7.45

(d, 1H), 7,71 (dd, 1H), 8,1 (s, 1H), (d, 1H), 7.71 (dd, 1H), 8.1 (s, 1H),

8,19 (s, 1H), 8,5-8,6 (m, 1H), 8,678.19 (s, 1 H), 8.5-8.6 (m, 1 H), 8.67

8,75 (m, 1H), 11,6 (s, 1H) 8.75 (m, 1H), 11.6 (s, 1H)

7-22* 7-22 *

EM: 482 2,24 (s, 3H), 2,42-2,5 (m, 4H), 2,8 (d, MS: 482 2.24 (s, 3H), 2.42-2.5 (m, 4H), 2.8 (d,

3H), 2,94-3,0 (m, 4H), 3,74 (s, 3H), 3H), 2.94-3.0 (m, 4H), 3.74 (s, 3H),

6,65 (dd, 1H), 6,93 (d, 1H), 7,07-7,14 6.65 (dd, 1H), 6.93 (d, 1H), 7.07-7.14

(m, 1H), 7,34-7,4 (m, 1H), 7,45 (d, (m, 1H), 7.34-7.4 (m, 1H), 7.45 (d,

1H), 7,73 (dd, 1H), 8,14 (s, 1H), 8,18 1H), 7.73 (dd, 1H), 8.14 (s, 1H), 8.18

(s, 1H), 8,61 (dd, 1H), 8,7-8,77 (m, (s, 1H), 8.61 (dd, 1H), 8.7-8.77 (m,

1H), 11,7 (s, 1H) 1H), 11.7 (s, 1H)

7-23* 7-23 *

EM: 482 1,67-1,76 (m, 1H), 2,0-2,1 (m, 1H), MS: 482 1.67-1.76 (m, 1H), 2.0-2.1 (m, 1H),

2,25-2,31 (m, 3H), 2,8 (d, 3H), 2,852.25-2.31 (m, 3H), 2.8 (d, 3H), 2.85

2,91 (m, 1H), 3,04-3,12 (m, 1H), 3,142.91 (m, 1H), 3.04-3.12 (m, 1H), 3.14

3,3 (m, 3H), 3,7 (s, 3H), 6,26 (dd, 1H), 3.3 (m, 3H), 3.7 (s, 3H), 6.26 (dd, 1H),

6,91 (d, 1H), 7,01-7,04 (m, 1H), 7,07 6.91 (d, 1H), 7.01-7.04 (m, 1H), 7.07

(dd, 1H), 7,32 (dd, 1H), 7,72 (d, 1H), (dd, 1H), 7.32 (dd, 1H), 7.72 (d, 1H),

8,14 (s, 1H), 8,17 (s, 1H), 8,63 (d, 8.14 (s, 1H), 8.17 (s, 1H), 8.63 (d,

1H), 8,7-8,78 (m, 1H), 11,6 (s, 1H) 1H), 8.7-8.78 (m, 1H), 11.6 (s, 1H)

7-24* 7-24 *

EM: 550 1,35-1,57 (m, 8H), 1,7-1,78 (m, 2H), MS: 550 1.35-1.57 (m, 8H), 1.7-1.78 (m, 2H),

2,81 (d, 3H), 3,46-3,52 (m, 2H), 3,74 2.81 (d, 3H), 3.46-3.52 (m, 2H), 3.74

(s, 3H), 6,65 (dd, 1H), 6,91 (d, 1H), (s, 3H), 6.65 (dd, 1H), 6.91 (d, 1H),

7,05-7,12 (m, 1H), 7,34-7,42 (m, 1H), 7.05-7.12 (m, 1H), 7.34-7.42 (m, 1H),

7,46 (d, 1H), 7,73 (dd, 1H), 8,11 (s, 7.46 (d, 1H), 7.73 (dd, 1H), 8.11 (s,

1H), 8,18 (s, 1H), 8,62 (dd, 1H), 8,711H), 8.18 (s, 1H), 8.62 (dd, 1H), 8.71

8,78 (m, 1H), 11,7 (s, 1H) 8.78 (m, 1H), 11.7 (s, 1H)

7-25* 7-25 *

36 [M+1]+ DMSO-d6: 1,48-1,58 (m, 2H), 1,651,72 (m, 4H), 1,90-1,97 (m, 2H), 2,072,14 (m, 1H), 2,49-2,55 (m, 4H), 2,702,77 (m, 2H), 2,79 (d, 3H), 3,60-3,65 (m, 2H), 3,75 (s, 3H), 6,48 (dd, 1H), 6,63 (d, 1H), 7,03-7,09 (m, 1H), 7,287,34 (m, 1H), 7,39 (d, 1H), 7,71 (dd, 1H), 8,09 (s, 1H), 8,11 (s, 1H), 8,558,65 (m, 1H), 8,69-8,73 (m, 1H), 11,59 (s, 1H) 36 [M + 1] + DMSO-d6: 1.48-1.58 (m, 2H), 1,651.72 (m, 4H), 1.90-1.97 (m, 2H), 2,072.14 (m, 1H), 2, 49-2.55 (m, 4H), 2,702.77 (m, 2H), 2.79 (d, 3H), 3.60-3.65 (m, 2H), 3.75 (s, 3H) , 6.48 (dd, 1H), 6.63 (d, 1H), 7.03-7.09 (m, 1H), 7.287.34 (m, 1H), 7.39 (d, 1H), 7.71 (dd, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.558.65 (m, 1H), 8.69-8.73 (m, 1H), 11 , 59 (s, 1H)

7-26* 7-26 *

468 [M+1]+ DMSO-d6: 2,80 (d, 3H), 2,84-2,89 (m, 4H), 3,04-3,08 (m, 4H), 3,76 (s, 3H), 6,47 (dd, 1H), 6,62 (dd, 1H), 7,047,10 (m, 1H), 7,28-7,35 (m, 1H), 7,40 (d, 1H), 7,69-7,73 (m, 1H), 8,09 (s, 1H), 8,12 (s, 1H), 8,55-8,63 (m, 1H), 8,68-8,73 (m, 1H), 11,59 (s, 1H) (un NH alifático oculto) 468 [M + 1] + DMSO-d6: 2.80 (d, 3H), 2.84-2.89 (m, 4H), 3.04-3.08 (m, 4H), 3.76 (s, 3H), 6, 47 (dd, 1H), 6.62 (dd, 1H), 7.047.10 (m, 1H), 7.28-7.35 (m, 1H), 7.40 (d, 1H), 7.69 -7.73 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m , 1H), 11.59 (s, 1H) (a hidden aliphatic NH)

7-27* 7-27 *

393 [M+1]+ DMSO-d6: 2,80 (d, 3H), 6,64-6,67 (m, 1H), 7,01-7,08 (m, 2H), 7,15 (d, 1H), 7,24-7,29 (m, 2H), 7,44 (d, 1H), 7,697,73 (m, 1H), 8,20 (s, 1H), 8,65-8,73 (m, 2H), 9,15 (m, 1H), 11,06 (s, 1H), 11,63 (s, 1H) 393 [M + 1] + DMSO-d6: 2.80 (d, 3H), 6.64-6.67 (m, 1H), 7.01-7.08 (m, 2H), 7.15 (d, 1H), 7, 24-7.29 (m, 2H), 7.44 (d, 1H), 7.697.73 (m, 1H), 8.20 (s, 1H), 8.65-8.73 (m, 2H) , 9.15 (m, 1H), 11.06 (s, 1H), 11.63 (s, 1H)

7-28* 7-28 *

407 [M+1]+ DMSO-d6: 2,81 (d, 3H), 3,79 (s, 3H), 6,67 (d, 1H), 7,05-7,10 (m, 1H), 7,12 (d, 1H), 7,17 (d, 1H), 7,23 (d, 1H), 7,25-7,30 (m, 1H), 7,50 (d, 1H), 7,707,73 (m, 1H), 8,20 (s, 1H), 8,67 (d, 1H), 8,70-8,75 (m, 1H), 9,17 (s, 1H), 11,64 (s, 1H) 407 [M + 1] + DMSO-d6: 2.81 (d, 3H), 3.79 (s, 3H), 6.67 (d, 1H), 7.05-7.10 (m, 1H), 7.12 (d, 1H), 7.17 (d, 1H), 7.23 (d, 1H), 7.25-7.30 (m, 1H), 7.50 (d, 1H), 7,707.73 (m, 1H ), 8.20 (s, 1H), 8.67 (d, 1H), 8.70-8.75 (m, 1H), 9.17 (s, 1H), 11.64 (s, 1H)

7-29* 7-29 *

492 [M+1]+ DMSO-d6: 2,80 (d, 3H), 2,91-2,99 (m, 4H), 3,65-3,81 (m, 2H), 3,82-3,95 (m, 2H), 4,12 (s, 3H), 6,58 (d, 1H), 6,90 (d, 1H), 7,05-7,09 (m, 1H), 7,14 (d, 1H), 7,22-7,28 (m, 1H), 7,30 (d, 1H), 7,70 (dd, 1H), 8,16 (s, 1H), 8,63-8,67 (m, 1H), 8,68-8,72 (m, 1H), 9,06 (s, 1H), 11,64 (s, 1H) 492 [M + 1] + DMSO-d6: 2.80 (d, 3H), 2.91-2.99 (m, 4H), 3.65-3.81 (m, 2H), 3.82-3.95 (m, 2H ), 4.12 (s, 3H), 6.58 (d, 1H), 6.90 (d, 1H), 7.05-7.09 (m, 1H), 7.14 (d, 1H) , 7.22-7.28 (m, 1H), 7.30 (d, 1H), 7.70 (dd, 1H), 8.16 (s, 1H), 8.63-8.67 (m , 1H), 8.68-8.72 (m, 1H), 9.06 (s, 1H), 11.64 (s, 1H)

7-30* 7-30 *

EM m/z 510 DMSO-d6: 2,02 (s, 3H), 2,80 (d, 3H), 2,82-2,92 (m, 2H), 2,92-3,01 (m, 2H), 3,44-3,53 (m, 4H), 3,76 (s, 3H), 6,68 (dd, 1H), 6,95 (d, 1H), 7,09 (dd, 1H), 7,35-7,40 (m, 1H), 7,50 (sa, 1H), 7,73 (d, 1H), 8,15 (s, 1H), 8,19 (s, 1H), 8,59 (d, 1H), 8,69-8,76 (m, 1H), 11,66 (s, 1H) MS m / z 510 DMSO-d6: 2.02 (s, 3H), 2.80 (d, 3H), 2.82-2.92 (m, 2H), 2.92-3.01 (m, 2H), 3, 44-3.53 (m, 4H), 3.76 (s, 3H), 6.68 (dd, 1H), 6.95 (d, 1H), 7.09 (dd, 1H), 7.35 -7.40 (m, 1H), 7.50 (sa, 1H), 7.73 (d, 1H), 8.15 (s, 1H), 8.19 (s, 1H), 8.59 ( d, 1H), 8.69-8.76 (m, 1H), 11.66 (s, 1H)

[0102] Las siguientes 2-[5-bromo-2-(fenilamino sustituido)-pirimidin-4-ilamino]-N-etil-benzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(5-bromo-2-cloro-pirimidin-4-ilamino)N-etil-benzamida y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A. [0102] The following 2- [5-bromo-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-ethyl-benzamides, which are all reference examples (marked with a (*)), are prepared at from 2- (5-Bromo-2-chloro-pyrimidin-4-ylamino) N-ethyl-benzamide and the corresponding aniline according to the procedure of reference example 7A.

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN Rx Rf (solvent) or MS NMR

8-1* 8-1 *

0,27 (n-hexano:AcOEt = 1:2) DMSO-d6: 2,80 (d, 3H), 2,88 (t, 4H), 3,65 (m, 4H), 3,75 (s, 3H), 6,64 (dd, 1H), 6,94 (d, 1H), 7,11-7,08 (m, 1H), 7,38-7,34 (m, 1H), 7,47-7,46 (m, 1H), 7,70 (dd, 1H), 8,11 (s, 1H), 8,26 (s, 1H), 8,51-8,49 (m, 1H), 8,72-8,71 (m, 1H), 11,41 (s, 1H) 0.27 (n-hexane: AcOEt = 1: 2) DMSO-d6: 2.80 (d, 3H), 2.88 (t, 4H), 3.65 (m, 4H), 3.75 (s, 3H), 6.64 (dd, 1H), 6 , 94 (d, 1H), 7.11-7.08 (m, 1H), 7.38-7.34 (m, 1H), 7.47-7.46 (m, 1H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.26 (s, 1H), 8.51-8.49 (m, 1H), 8.72-8.71 (m, 1H), 11.41 (s, 1 H)

8-2* 8-2 *

m/z 513, 515 (M+1) DMSO-d6: 2,79 (d, 3H, J=4,04 Hz), 3,103,20 (m, 4H), 3,77 (s, 3H), 3,70-3,80 (m, 4H), 6,45-6,55 (m, 1H), 6,63-6,69 (m, 1H), 7,05-7,10 (m, 1H), 7,28-7,34 (m, 1H), 7,40-7,45 (m, 1H), 7,65-7,70 (m, 1H), 8,13 (s, 1H), 8,16 (s, 1H), 8,50-8,56 (m, 1H), 8,65-8,72 (m, 1H), 11,40 (s, 1H) m / z 513, 515 (M + 1) DMSO-d6: 2.79 (d, 3H, J = 4.04 Hz), 3.103.20 (m, 4H), 3.77 (s, 3H), 3.70-3.80 (m, 4H) , 6.45-6.55 (m, 1H), 6.63-6.69 (m, 1H), 7.05-7.10 (m, 1H), 7.28-7.34 (m, 1H), 7.40-7.45 (m, 1H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 8.16 (s, 1H), 8.50 -8.56 (m, 1H), 8.65-8.72 (m, 1H), 11.40 (s, 1H)

8-3* 8-3 *

0,48 (n-hexano:AcOEt = 4:1) DMSO-d6: 2,80 (d, 3H), 3,83 (s, 3H), 4,11 (t, 2H), 6,82 (ddd, 1H), 7,03 (dd, 1H), 7,15 (dd, 1H), 7,44 (dd, 1H), 7,73 (d, 1H), 7,93 (dd, 1H), 8,13 (s, 1H), 8,33 (s, 1H), 8,50 (d, 1H), 8,70-8,77 (m, 1H), 11,3 (s, 1H) 0.48 (n-hexane: AcOEt = 4: 1) DMSO-d6: 2.80 (d, 3H), 3.83 (s, 3H), 4.11 (t, 2H), 6.82 (ddd, 1H), 7.03 (dd, 1H), 7 , 15 (dd, 1H), 7.44 (dd, 1H), 7.73 (d, 1H), 7.93 (dd, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.50 (d, 1H), 8.70-8.77 (m, 1H), 11.3 (s, 1H)

8-4* 8-4 *

EM 446, 448 2,79 (d, 3H), 3,79 (s, 3H), 6,75 (ddd, 1H), 7,0 (dd, 1H), 7,05-7,12 (m, 1H), 7,3-7,36 (m, 1H), 7,62 (dd, 1H), 7,69 (dd, 1H), 8,2 (s, 1H), 8,29 (s, 1H), 8,45 (d, 1H), 8,668,73 (m, 1H), 11,4 (sa, 1H) MS 446, 448 2.79 (d, 3H), 3.79 (s, 3H), 6.75 (ddd, 1H), 7.0 (dd, 1H), 7.05-7.12 (m, 1H), 7 , 3-7.36 (m, 1H), 7.62 (dd, 1H), 7.69 (dd, 1H), 8.2 (s, 1H), 8.29 (s, 1H), 8, 45 (d, 1H), 8,668.73 (m, 1H), 11.4 (sa, 1H)

[0103] Las siguientes 2-[5-cloro-2-(fenilamino sustituido)-pirimidin-4-ilamino]-N-etil-benzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(2,5-dicloro-pirimidin-4-ilamino)-N-etil10 benzamida y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A. [0103] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-ethyl-benzamides, which are all reference examples (marked with a (*)), are prepared at from 2- (2,5-dichloro-pyrimidin-4-ylamino) -N-ethyl10 benzamide and the corresponding aniline according to the procedure of reference example 7A.

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

9-1* 9-1 *

0,35 (n-hexano:AcOEt = 1:2) CDCl3: 1,27 (t, 3H), 3,10-3,15 (m, 4H), 3,47-3,58 (m, 2H), 3,85-3,93 (m, 4H), 3,89 (s, 3H), 6,08-6,17 (m, 1H), 6,48 (dd, 1H), 6,53 (d, 1H), 7,05-7,11 (m, 1H), 7,42-7,53 (m, 2H), 8,08 (s, 1H), 8,12 (d, 1H), 8,67 (d, 1H), 10,94 (sa, 1H). 0.35 (n-hexane: AcOEt = 1: 2) CDCl3: 1.27 (t, 3H), 3.10-3.15 (m, 4H), 3.47-3.58 (m, 2H), 3.85-3.93 (m, 4H), 3.89 (s, 3H), 6.08-6.17 (m, 1H), 6.48 (dd, 1H), 6.53 (d, 1H), 7.05-7.11 (m, 1H), 7.42-7.53 (m, 2H), 8.08 (s, 1H), 8.12 (d, 1H), 8.67 (d, 1H), 10.94 (sa, 1H ).

9-2* 9-2 *

EM (ESI) m/z 497, 499 (M+1)+ CDCl3: 1,26 (t, 3H, J=7,56 Hz), 2,37 (s, 3H), 2,57-2,62 (m, 4H), 3,15-3,20 (m, 4H), 3,49 (dc, 2H, J=7,56, 1,52 Hz), 3,87 (s, 3H), 6,11-6,16 (m, 1H), 6,49 (dd, 1H, J=8,56, 2,52 Hz), 6,55 (d, 1H, J=2,52 Hz), 7,05-7,10 (m, 1H), 7,23 (s, 1H), 7,41-7,50 (m, 2H), 8,07 (s, 1H), 8,08 (d, 1H, J=8,56 Hz), 8,65-8,69 (m, 1H), 10,93 (s, 1H) MS (ESI) m / z 497, 499 (M + 1) + CDCl3: 1.26 (t, 3H, J = 7.56 Hz), 2.37 (s, 3H), 2.57-2.62 (m, 4H), 3.15-3.20 (m, 4H), 3.49 (dc, 2H, J = 7.56, 1.52 Hz), 3.87 (s, 3H), 6.11-6.16 (m, 1H), 6.49 (dd , 1H, J = 8.56, 2.52 Hz), 6.55 (d, 1H, J = 2.52 Hz), 7.05-7.10 (m, 1H), 7.23 (s, 1H), 7.41-7.50 (m, 2H), 8.07 (s, 1H), 8.08 (d, 1H, J = 8.56 Hz), 8.65-8.69 (m , 1H), 10.93 (s, 1H)

9-3* 9-3 *

m/z 564, 566 (M+1)+ DMSO-d6: 1,26 (t, 3H, J=7,56 Hz), 1,40-1,50 (m, 2H), 1,56-1,64 (m, 4H), 1,67-1,82 (m, 2H), 1,88-1,97 (m, 2H), 2,33-2,44 (m, 1H), 2,52-2,57 (m, 4H), 2,63-2,73 (m, 2H), 3,51 (dc, 2H, J=7,56, 1,52 Hz), 3,62-3,69 (m, 2H), 3,86 (s, 3H), 6,10-6,15 (m, 1H), 6,49 (dd, 1H, J=8,56, 2,52 Hz), 6,55 (d, 1H, J=2,52 Hz), 7,05-7,10 (m, 1H), 7,23 (s, 1H), 7,43-7,50 (m, 2H), 8,05-8,11 (m, 1H), 8,07 (s, 1H), 8,65-8,69 (m, 1H), 10,91 (s, 1H) m / z 564, 566 (M + 1) + DMSO-d6: 1.26 (t, 3H, J = 7.56 Hz), 1.40-1.50 (m, 2H), 1.56-1.64 (m, 4H), 1.67- 1.82 (m, 2H), 1.88-1.97 (m, 2H), 2.33-2.44 (m, 1H), 2.52-2.57 (m, 4H), 2, 63-2.73 (m, 2H), 3.51 (dc, 2H, J = 7.56, 1.52 Hz), 3.62-3.69 (m, 2H), 3.86 (s, 3H), 6.10-6.15 (m, 1H), 6.49 (dd, 1H, J = 8.56, 2.52 Hz), 6.55 (d, 1H, J = 2.52 Hz ), 7.05-7.10 (m, 1H), 7.23 (s, 1H), 7.43-7.50 (m, 2H), 8.05-8.11 (m, 1H), 8.07 (s, 1H), 8.65-8.69 (m, 1H), 10.91 (s, 1H)

9-4* 9-4 *

0,39 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 1,19 (t, 3H), 1,52-1,68 (m, 2H), 1,71-1,79 (m, 4H), 1,92-2,05 (m, 2H), 2,12-2,23 (m, 1H), 2,76-2,85 (m, 2H), 3,65-3,73 (m, 2H), 3,82 (s, 3H), 6,54 (dd, 1H), 6,69 (d, 1H), 7,13 (m, 1H), 7,45 (d, 1H), 7,79 (dd, 1H), 8,15 (s, 1H), 8,15-8,18 (m, 1H), 8,60-8,68 (m, 1H), 8,74-8,83 (m, 1H) 0.39 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 1.19 (t, 3H), 1.52-1.68 (m, 2H), 1.71-1.79 (m, 4H), 1.92-2.05 (m, 2H ), 2.12-2.23 (m, 1H), 2.76-2.85 (m, 2H), 3.65-3.73 (m, 2H), 3.82 (s, 3H), 6.54 (dd, 1H), 6.69 (d, 1H), 7.13 (m, 1H), 7.45 (d, 1H), 7.79 (dd, 1H), 8.15 (s , 1H), 8.15-8.18 (m, 1H), 8.60-8.68 (m, 1H), 8.74-8.83 (m, 1H)

9-5* 9-5 *

Rf (hexano:AcOEt = 1:2): 0,30 CDCl3: 1,27 (t, 3H), 3,08-3,14 (m, 4H), 3,52 (c, 2H), 3,71-3,90 (m, 7H), 6,056,18 (m, 1H), 6,47 (dd, 1H), 6,53 (dd, 1H), 7,08 (dd, 1H), 7,41-7,53 (m, 2H), 8,08 (s, 1H), 8,12 (d, 1H), 8,67 (d, 1H), 10,94 (s, 1H) Rf (hexane: AcOEt = 1: 2): 0.30 CDCl3: 1.27 (t, 3H), 3.08-3.14 (m, 4H), 3.52 (c, 2H), 3.71-3.90 (m, 7H), 6.056.18 ( m, 1H), 6.47 (dd, 1H), 6.53 (dd, 1H), 7.08 (dd, 1H), 7.41-7.53 (m, 2H), 8.08 (s , 1H), 8.12 (d, 1H), 8.67 (d, 1H), 10.94 (s, 1H)

9-6* 9-6 *

Rf (AcOEt:MeOH = 4:1) 0,050 DMSO-d6: 1,11 (t, 3H), 1,60-1,69 (m, 1H), 1,88-1,96 (m, 2H), 2,19 (s, 3H), 2,55-2,68 (m, 2H), 3,30-3,45 (m, 2H), 3,75 (s, 3H), 4,33-4,43 (m, 1H), 6,54 (dd, 1H), 6,65 (d, 1H), 7,07 (dd, 1H), 7,30 (dd, 1H), 7,43 (d, 1H), 7,71 (dd, 1H), 8,11 (s, 1H), 8,20 (s, 1H), 8,54 (da, 1H), 8,75 (dd, 1H), 11,49 (s, 1H) Rf (AcOEt: MeOH = 4: 1) 0.050 DMSO-d6: 1.11 (t, 3H), 1.60-1.69 (m, 1H), 1.88-1.96 (m, 2H), 2.19 (s, 3H), 2, 55-2.68 (m, 2H), 3.30-3.45 (m, 2H), 3.75 (s, 3H), 4.33-4.43 (m, 1H), 6.54 ( dd, 1H), 6.65 (d, 1H), 7.07 (dd, 1H), 7.30 (dd, 1H), 7.43 (d, 1H), 7.71 (dd, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.54 (da, 1H), 8.75 (dd, 1H), 11.49 (s, 1H)

9-7* 9-7 *

0,44 (CH2Cl2:MeOH = 8:2) CDCl3: 1,34 (t, 3H), 1,82-1,68 (m, 2H), 1,93-2,18 (m, 8H), 2,37-2,40 (a, 2H), 2,74-2,86 (a, 3H), 3,20-3,23 (m, 2H), 3,34 (a, 2H), 3,53 (c, 2H), 3,85 (s, 3H), 6,47 (dd, 1H), 6,76 (d, 1H), 7,04-7,08 (m, 1H), 7,30 (dd, 1H), 7,53 (s, 1H), 8,00 (d, 1H), 8,13-8,17 (m, 1H), 8,22 (d, 1H), 8,42-8,53 (a, 1H), 10,91 (s, 1H), 11,59-11,75 (a, 1H) 0.44 (CH2Cl2: MeOH = 8: 2) CDCl3: 1.34 (t, 3H), 1.82-1.68 (m, 2H), 1.93-2.18 (m, 8H), 2.37-2.40 (a, 2H), 2.74-2.86 (a, 3H), 3.20-3.23 (m, 2H), 3.34 (a, 2H), 3.53 (c, 2H), 3.85 (s, 3H), 6.47 (dd, 1H), 6.76 (d, 1H), 7.04-7.08 (m, 1H), 7.30 (dd, 1H), 7.53 (s, 1H ), 8.00 (d, 1H), 8.13-8.17 (m, 1H), 8.22 (d, 1H), 8.42-8.53 (a, 1H), 10.91 ( s, 1H), 11.59-11.75 (a, 1H)

[0104] Las siguientes 2-[5-cloro-2-(fenilamino sustituido)-pirimidin-4-ilamino]-6,N-dimetil-benzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(2,5-dicloro-pirimidin-4-ilamino)-6,Ndimetil-benzamida y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A. [0104] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -6, N-dimethyl-benzamides, which are all reference examples (marked with a (*)), are they prepare from 2- (2,5-dichloro-pyrimidin-4-ylamino) -6, N-dimethyl-benzamide and the corresponding aniline according to the procedure of reference example 7A.

5 5

imagen1image 1

Ej. nº Ex. Nº

Rx Identificación Rx ID

10-1* 10-1 *

RMN (400 MHz, DMSO-d6, δ): 1,58-1,68 (m, 2H), 1,87-1,96 (m, 2H), 2,13-2,22 (m, 2H), 2,18 (s, 3H), 2,18 (s, 3H), 2,29 (s, 3H), 2,57-2,65 (m, 2H), 2,76 (d, 3H), 3,75 (s, 3H), 4,29-4,37 (m, 1H), 6,45 (dd, 1H), 6,61 (d, 1H), 6,98 (d, 1H), 7,18 (dd, 1H), 7,47 (d, 1H), 7,89 (d, 1H), 8,02 (s, 1H), 8,07 (s, 1H), 8,37-8,43 (m, 1H), 8,49 (s, 1H). Rf: 0,39 (MeOH:CH2Cl2=1:4) NMR (400 MHz, DMSO-d6, δ): 1.58-1.68 (m, 2H), 1.87-1.96 (m, 2H), 2.13-2.22 (m, 2H) , 2.18 (s, 3H), 2.18 (s, 3H), 2.29 (s, 3H), 2.57-2.65 (m, 2H), 2.76 (d, 3H), 3.75 (s, 3H), 4.29-4.37 (m, 1H), 6.45 (dd, 1H), 6.61 (d, 1H), 6.98 (d, 1H), 7 , 18 (dd, 1H), 7.47 (d, 1H), 7.89 (d, 1H), 8.02 (s, 1H), 8.07 (s, 1H), 8.37-8, 43 (m, 1H), 8.49 (s, 1H). Rf: 0.39 (MeOH: CH2Cl2 = 1: 4)

10-2* 10-2 *

RMN (400 MHz, DMSO-d6, δ): 1,35-1,42 (m, 2H), 1,45-1,60 (m, 6H), 1,75-1,85 (m, 2H), 2,29 (s, 3H), 2,30-2,35 (m, 1H), 2,43-2,50 (m, 4H), 2,57-2,66 (m, 2H), 2,76 (d, 3H, J=5,0 Hz), 3,65-3,74 (m, 2H), 3,76 (s, 3H), 6,40 (dd, 1H, J=9,0, 2,0 Hz), 6,59 (d, 1H, J=2,0 Hz), 6,98 (d, 1H, J=7,6 Hz), 7,20 (dd, 1H, J=7,6, 7,6 Hz), 7,43 (d, 1H, J=9,0 Hz), 7,917,94 (m, 1H), 7,93 (s, 1H), 8,06 (s, 1H), 8,36-8,42 (m, 1H), 8,47 (s, 1H). EM (ESI) m/z 564, 566 (M+1)+ NMR (400 MHz, DMSO-d6, δ): 1.35-1.42 (m, 2H), 1.45-1.60 (m, 6H), 1.75-1.85 (m, 2H) , 2.29 (s, 3H), 2.30-2.35 (m, 1H), 2.43-2.50 (m, 4H), 2.57-2.66 (m, 2H), 2 , 76 (d, 3H, J = 5.0 Hz), 3.65-3.74 (m, 2H), 3.76 (s, 3H), 6.40 (dd, 1H, J = 9.0 , 2.0 Hz), 6.59 (d, 1H, J = 2.0 Hz), 6.98 (d, 1H, J = 7.6 Hz), 7.20 (dd, 1H, J = 7 , 6, 7.6 Hz), 7.43 (d, 1H, J = 9.0 Hz), 7,917.94 (m, 1H), 7.93 (s, 1H), 8.06 (s, 1H ), 8.36-8.42 (m, 1H), 8.47 (s, 1H). MS (ESI) m / z 564, 566 (M + 1) +

10-3* 10-3 *

DMSO-d6: 2,29 (s, 3H), 2,77 (d, 3H), 3,07-3,11 (m, 4H), 3,73-3,76 (m, 4H), 3,77 (s, 3H), 6,41 (dd, 1H), 6,63 (d, 1H), 7,00 (d, 1H), 7,21 (dd, 1H), 7,49 (d, 1H), 7,93 (d, 1H), 7,96 (s, 1H), 8,07 (s, 1H), 8,37-8,42 (m, 1H), 8,49 (s, 1H). EM m/z 483 [M+1]+ DMSO-d6: 2.29 (s, 3H), 2.77 (d, 3H), 3.07-3.11 (m, 4H), 3.73-3.76 (m, 4H), 3, 77 (s, 3H), 6.41 (dd, 1H), 6.63 (d, 1H), 7.00 (d, 1H), 7.21 (dd, 1H), 7.49 (d, 1H ), 7.93 (d, 1H), 7.96 (s, 1H), 8.07 (s, 1H), 8.37-8.42 (m, 1H), 8.49 (s, 1H) . MS m / z 483 [M + 1] +

5 [0105] Las siguientes 2-[5-cloro-2-(fenilamino sustituido)-pirimidin-4-ilamino]-5-fluoro-N-metil-benzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(2,5-dicloro-pirimidin-4-ilamino)-5fluoro-N-metil-benzamida y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A. 5 [0105] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -5-fluoro-N-methyl-benzamides, which are all reference examples (marked with a (*) ), are prepared from 2- (2,5-dichloro-pyrimidin-4-ylamino) -5fluoro-N-methyl-benzamide and the corresponding aniline according to the procedure of reference example 7A.

imagen1image 1

Ej. nº Ex. Nº

Rx Identificación Rx ID

11-1* 11-1 *

RMN (400 MHz, DMSO-d6, δ): 2,79 (d, 3H), 3,10-3,15 (m, 4H), 3,74-3,78 (m, 7H), 6,50 (dd, 1H), 6,66 (d, 1H), 7,13-7,20 (m, 1H), 7,41 (d, 1H), 7,57 (dd, 1H), 8,09 (s, 1H), 8,14 (s, 1H), 8,55-8,65 (m, 1H), 8,75-8,82 (m, 1H), 11,39 (s, 1H). EM (ESI): m/z 487, 489 (M+1). NMR (400 MHz, DMSO-d6, δ): 2.79 (d, 3H), 3.10-3.15 (m, 4H), 3.74-3.78 (m, 7H), 6.50 (dd, 1H), 6.66 (d, 1H), 7.13-7.20 (m, 1H), 7.41 (d, 1H), 7.57 (dd, 1H), 8.09 ( s, 1H), 8.14 (s, 1H), 8.55-8.65 (m, 1H), 8.75-8.82 (m, 1H), 11.39 (s, 1H). MS (ESI): m / z 487, 489 (M + 1).

11-2* 11-2 *

RMN (400 MHz, DMSO-d6, δ): 1,68-1,33 (m, 8H), 1,93-1,73 (m, 2H), 2,352,60 (m, 1H), 2,62-2,74 (m, 2H), 2,67 (t, 2H), 2,74 (d, 3H), 3,25-3,38 (m, 4H), 3,76 (s, 3H), 3,83-3,71 (m, 2H), 6,48 (dd, 1H), 6,49 (dd, 1H), 6,63 (d, 1H), 7,15 (dd, 1H), 7,36 (d, 1H), 7,57 (dd, 1H), 8,09 (s, 1H), 8,12 (s, 1H), 8,65-8,55 (m, 1H), 8,78 (d, 1H), 11,39 (s, 1H). EM (ESI) m/z 568, 570 (M+1) NMR (400 MHz, DMSO-d6, δ): 1.68-1.33 (m, 8H), 1.93-1.73 (m, 2H), 2,352.60 (m, 1H), 2.62 -2.74 (m, 2H), 2.67 (t, 2H), 2.74 (d, 3H), 3.25-3.38 (m, 4H), 3.76 (s, 3H), 3.83-3.71 (m, 2H), 6.48 (dd, 1H), 6.49 (dd, 1H), 6.63 (d, 1H), 7.15 (dd, 1H), 7 , 36 (d, 1H), 7.57 (dd, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.65-8.55 (m, 1H), 8, 78 (d, 1H), 11.39 (s, 1H). MS (ESI) m / z 568, 570 (M + 1)

11-3* 11-3 *

DMSO-d6: 2,80 (d, 3H), 3,79 (s, 3H), 6,64 (d, 1H), 7,05-7,20 (m, 3H), 7,23 (d, 1H), 7,42-7,49 (d, 1H), 7,57 (dd, 1H), 8,20 (s, 1H), 8,62-8,69 (m, 1H), 8,75-8,82 (m, 1H), 9,17 (s, 1H), 11,43 (s, 1H). EM m/z 425 [M+1]+ DMSO-d6: 2.80 (d, 3H), 3.79 (s, 3H), 6.64 (d, 1H), 7.05-7.20 (m, 3H), 7.23 (d, 1H), 7.42-7.49 (d, 1H), 7.57 (dd, 1H), 8.20 (s, 1H), 8.62-8.69 (m, 1H), 8.75 -8.82 (m, 1H), 9.17 (s, 1H), 11.43 (s, 1H). MS m / z 425 [M + 1] +

11-4* 11-4 *

DMSO-d6: 2,06 (s, 3H), 2,79 (d, 3H), 3,10-3,14 (m, 2H), 3,15-3,19 (m, 2H), 3,55-3,62 (m, 4H), 3,77 (s, 3H), 6,52 (dd, 1H), 6,69 (d, 1H), 7,15-7,23 (m, 1H), 7,43 (d, 1H), 7,58 (dd, 1H), 8,10 (s, 1H), 8,14 (s, 1H), 8,56-8,65 (m, 1H), 8,75-8,81 (m, 1H), 11,39 (s, 1H). EM m/z 528 [M+1]+ DMSO-d6: 2.06 (s, 3H), 2.79 (d, 3H), 3.10-3.14 (m, 2H), 3.15-3.19 (m, 2H), 3, 55-3.62 (m, 4H), 3.77 (s, 3H), 6.52 (dd, 1H), 6.69 (d, 1H), 7.15-7.23 (m, 1H) , 7.43 (d, 1H), 7.58 (dd, 1H), 8.10 (s, 1H), 8.14 (s, 1H), 8.56-8.65 (m, 1H), 8.75-8.81 (m, 1H), 11.39 (s, 1H). MS m / z 528 [M + 1] +

12-1 Preparación de 7-[5-cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-2-metil-2,3-dihidro-isoindol1-ona 12-1 Preparation of 7- [5-Chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -2-methyl-2,3-dihydro-isoindole-1-one

5 [0106] N-Metil-7-nitro-2,3-dihidroisoindol-1-ona. Una disolución de 2-bromometil-6-nitrobenzoato de metilo (1,26 g, 4,63 mmoles) en THF (13 ml) se trata a temperatura ambiente con una disolución de metilamina 2 M en THF (14 ml), se agita durante 5 h, se diluye con EtOAc (100 ml), se lava con una disolución acuosa saturada de NaHCO3 (15 ml) y salmuera (15 ml), se seca (MgSO4) y se evapora. La cromatografía ultrarrápida (30 g de gel de sílice; 5 [0106] N-Methyl-7-nitro-2,3-dihydroisoindole-1-one. A solution of methyl 2-bromomethyl-6-nitrobenzoate (1.26 g, 4.63 mmol) in THF (13 ml) is treated at room temperature with a solution of 2M methylamine in THF (14 ml), stirred for 5 h, it is diluted with EtOAc (100 ml), washed with a saturated aqueous solution of NaHCO3 (15 ml) and brine (15 ml), dried (MgSO4) and evaporated. Flash chromatography (30 g of silica gel;

10 CH2Cl2/EtOAc 1:1) proporciona N-metil-7-nitro-2,3-dihidroisoindol-1-ona (0,561 g, 2,92 mmoles) al 63%. Sólido amarillo. Rf(CH2Cl2/EtOAc 1:1) 0,46.1H-RMN (400 MHz, CDCl3) 3,21 (s), 4,44 (s), 7,63-7,69 (m, 2H), 7,70-7,75 (m, 1H). 7-Amino-N-metil-2,3-dihidroisoindol-1-ona. Una disolución de N-metil-7-nitro-2,3-dihidroisoindol-1-ona (561,0 mg, 2,92 mmoles) en EtOAc (8,4 ml) se trata a temperatura ambiente con SnCl2·2H2O (2,68 g), se agita a 80ºC a reflujo 1: 1 CH2Cl2 / EtOAc) provides 63% N-methyl-7-nitro-2,3-dihydroisoindole-1-one (0.561 g, 2.92 mmol). Solid yellow. Rf (CH2Cl2 / EtOAc 1: 1) 0.46.1H-NMR (400 MHz, CDCl3) 3.21 (s), 4.44 (s), 7.63-7.69 (m, 2H), 7, 70-7.75 (m, 1 H). 7-Amino-N-methyl-2,3-dihydroisoindole-1-one. A solution of N-methyl-7-nitro-2,3-dihydroisoindole-1-one (561.0 mg, 2.92 mmol) in EtOAc (8.4 mL) is treated at room temperature with SnCl2 · 2H2O (2 , 68 g), stirred at 80 ° C at reflux

15 durante 5 h y se trata con 30 ml de NaOH 5 N a 0ºC. Tras separarse las dos fases, la fase acuosa se extrae con EtOAc (2 x 8 ml), los extractos combinados se lavan con salmuera (5 ml), se secan (MgSO4) y se evaporan para dar 7-amino-N-metil-2,3-dihidroisoindol-1-ona (455,9 g, 2,81 mmoles) al 96%. Sólido amarillo. Rf(CH2Cl2/EtOAc 1:1) 0,53. 1H-RMN (400 MHz, CDCl3) 3,12 (s), 4,28 (s), 5,20 (sa), 6,56 (d, J = 8,0), 6,68 (d, J = 8,0), 7,21 (dd, J = 8,0, 8,0). 15 for 5 h and treated with 30 ml of 5 N NaOH at 0 ° C. After separating the two phases, the aqueous phase is extracted with EtOAc (2 x 8 ml), the combined extracts are washed with brine (5 ml), dried (MgSO4) and evaporated to give 7-amino-N-methyl- 2,3% dihydroisoindole-1-one (455.9 g, 2.81 mmol) at 96%. Solid yellow. Rf (CH2Cl2 / EtOAc 1: 1) 0.53. 1 H-NMR (400 MHz, CDCl 3) 3.12 (s), 4.28 (s), 5.20 (sa), 6.56 (d, J = 8.0), 6.68 (d, J = 8.0), 7.21 (dd, J = 8.0, 8.0).

7-(4-Amino-2,5-dicloropirimidin-4-il)amino-N-metil-2,3-dihidroisoindol-1-ona. Una disolución de 7-amino-N-metil-2,3dihidroisoindol-1-ona (232,6 mg, 1,43 mmoles) en DMF (2,0 ml) se trata a 0ºC con NaH al 60% (89,8 mg), se agita a la misma temperatura durante 1,5 h, se trata con una disolución de 2,4,5-tricloropirimidina (0,557 g) en DMF (3,5 ml), se agita durante 1 h y se calienta a temperatura ambiente. Tras agitar durante otras 13 h, la mezcla se trata con 7- (4-Amino-2,5-dichloropyrimidin-4-yl) amino-N-methyl-2,3-dihydroisoindole-1-one. A solution of 7-amino-N-methyl-2,3-dihydroisoindole-1-one (232.6 mg, 1.43 mmol) in DMF (2.0 ml) is treated at 0 ° C with 60% NaH (89.8 mg), stirred at the same temperature for 1.5 h, treated with a solution of 2,4,5-trichloropyrimidine (0.557 g) in DMF (3.5 ml), stirred for 1 h and heated to temperature ambient. After stirring for another 13 h, the mixture is treated with

5 NH4Cl acuoso sat. (6 ml) y los precipitados pardos resultantes se recogen por filtración y seguidamente se lavan con H2O, hexano y CH3CN para proporcionar 7-(4-amino-2,5-dicloropirimidin-4-il)amino-N-metil-2,3-dihidroisoindol-1-ona (130,2 g, 0,416 mmoles) al 26%. Sólido pardo. Rf (CH2Cl2/EtOAc 1:1) 0,50. 1H-RMN (400 MHz, CDCl3): 3,22 (s), 4,43 (s), 7,15 (d, J = 8,0), 7,59 (dd, J = 8,0, 8,0), 8,24 (s), 8,71 (d, J = 8,0), 11,05 (sa). 5 NH4Cl aqueous sat. (6 ml) and the resulting brown precipitates are collected by filtration and then washed with H2O, hexane and CH3CN to provide 7- (4-amino-2,5-dichloropyrimidin-4-yl) amino-N-methyl-2, 26% 3-dihydroisoindole-1-one (130.2 g, 0.416 mmol). Solid brown. Rf (CH2Cl2 / EtOAc 1: 1) 0.50. 1 H-NMR (400 MHz, CDCl 3): 3.22 (s), 4.43 (s), 7.15 (d, J = 8.0), 7.59 (dd, J = 8.0, 8 , 0), 8.24 (s), 8.71 (d, J = 8.0), 11.05 (sa).

imagen1image 1

10 [0107] Las siguientes 7-[5-cloro-2-(fenilamino sustituido)-pirimidin-4-ilamino]-2-metil-2,3-dihidro-isoindol-1onas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 7-(2,5-dicloro-pirimidin-4ilamino)-2-metil-2,3-dihidro-isoindol-1-ona y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A. [0107] The following 7- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -2-methyl-2,3-dihydro-isoindole-1ones, which are all reference examples (labeled with one (*)), are prepared from 7- (2,5-dichloro-pyrimidin-4-ylamino) -2-methyl-2,3-dihydro-isoindole-1-one and the corresponding aniline according to the procedure of the example of reference 7A.

15 7-[5-Cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-2-metil-2,3-dihidroisoindol-1-ona* 15 7- [5-Chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -2-methyl-2,3-dihydroisoindole-1-one *

[0108] [0108]

20 (dd, 1H, J = 8,6, 2,5 Hz), 6,67 (d, 1H, J = 2,5 Hz), 7,15 (d, 1H, J = 7,6 Hz), 7,25-7,34 (m, 1H), 7,36 (d, 1H, J = 8,6 Hz), 8,13 (s, 1H), 8,36 (s, 1H), 8,37-8,50 (m, 1H), 10,57 (s, 1H). EM (ESI) m/z 481, 483 (M+1)+ 20 (dd, 1H, J = 8.6, 2.5 Hz), 6.67 (d, 1H, J = 2.5 Hz), 7.15 (d, 1H, J = 7.6 Hz), 7.25-7.34 (m, 1H), 7.36 (d, 1H, J = 8.6 Hz), 8.13 (s, 1H), 8.36 (s, 1H), 8.37 -8.50 (m, 1H), 10.57 (s, 1H). MS (ESI) m / z 481, 483 (M + 1) +

[0109] Las siguientes 7-(5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino)-2-metil-2,3-dihidro-isoindol-1-onas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 7-(2,5-dicloro-pirimidin-425 ilamino)-2-metil-2,3-dihidro-isoindol-1-ona y la anilina correspondiente según el procedimiento del ejemplo 2: [0109] The following 7- (5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino) -2-methyl-2,3-dihydro-isoindole-1-ones, which are all reference examples ( marked with a (*)), they are prepared from 7- (2,5-dichloro-pyrimidin-425 ylamino) -2-methyl-2,3-dihydro-isoindole-1-one and the corresponding aniline according to the procedure from example 2:

imagen9image9

imagen1image 1

Ej. nº Ex. Nº

Rx Masa (m/z) RMN (400 MHz) δ (ppm) Rx Mass (m / z) NMR (400 MHz) δ (ppm)

12-2* 12-2 *

494 [M+1]+ DMSO-d6: 2,24 (s, 3H), 2,45-2,50 (m, 4H), 3,07 (s, 3H), 3,15-3,19 (m, 4H), 3,74 (s, 3H), 4,46 (s, 2H), 6,52 (dd, 1H), 6,66 (d, 1H), 7,15 (d, 1H), 7,25-7,36 (m, 2H), 8,12 (s, 1H), 8,35 (s, 1H), 8,35-8,45 (m, 1H), 10,57 (s, 1H) 494 [M + 1] + DMSO-d6: 2.24 (s, 3H), 2.45-2.50 (m, 4H), 3.07 (s, 3H), 3.15-3.19 (m, 4H), 3, 74 (s, 3H), 4.46 (s, 2H), 6.52 (dd, 1H), 6.66 (d, 1H), 7.15 (d, 1H), 7.25-7.36 (m, 2H), 8.12 (s, 1H), 8.35 (s, 1H), 8.35-8.45 (m, 1H), 10.57 (s, 1H)

12-3* 12-3 *

495 [M+1]+ DMSO-d6: 1,48-1,57 (m, 2H), 1,83-1,88 (m, 2H), 2,83-2,90 (m, 2H), 3,07 (s, 3H), 3,51-3,60 (m, 2H), 3,61-3,70 (m, 2H), 3,73 (s, 3H), 4,46 (s, 2H), 4,69 (d, 1H), 6,52 (dd, 1H), 6,64 (d, 1H), 7,14 (d, 1H), 7,25-7,35 (m, 2H), 8,12 (s, 1H), 8,33 (s, 1H), 8,35-8,45 (m, 1H), 10,57 (s, 1H) 495 [M + 1] + DMSO-d6: 1.48-1.57 (m, 2H), 1.83-1.88 (m, 2H), 2.83-2.90 (m, 2H), 3.07 (s, 3H ), 3.51-3.60 (m, 2H), 3.61-3.70 (m, 2H), 3.73 (s, 3H), 4.46 (s, 2H), 4.69 ( d, 1H), 6.52 (dd, 1H), 6.64 (d, 1H), 7.14 (d, 1H), 7.25-7.35 (m, 2H), 8.12 (s , 1H), 8.33 (s, 1H), 8.35-8.45 (m, 1H), 10.57 (s, 1H)

12-4* 12-4 *

577 [M+1]+ DMSO-d6: 1,48-1,59 (m, 2H), 9,83-1,88 (m, 2H), 2,14 (s, 3H), 2,25-2,39 (m, 4H), 2,42-2,60 (m, 5H), 2,66-2,73 (m, 2H), 3,07 (s, 3H), 3,73-3,77 (m, 2H), 3,74 (s, 3H), 4,46 (s, 2H), 6,52 (dd, 1H), 6,64 (d, 1H), 7,14 (d, 1H), 7,25-7,34 (m, 2H), 8,12 (s, 1H), 8,34 (s, 1H), 8,35-8,45 (m, 1H), 10,57 (s, 1H) 577 [M + 1] + DMSO-d6: 1.48-1.59 (m, 2H), 9.83-1.88 (m, 2H), 2.14 (s, 3H), 2.25-2.39 (m, 4H ), 2.42-2.60 (m, 5H), 2.66-2.73 (m, 2H), 3.07 (s, 3H), 3.73-3.77 (m, 2H), 3.74 (s, 3H), 4.46 (s, 2H), 6.52 (dd, 1H), 6.64 (d, 1H), 7.14 (d, 1H), 7.25-7 , 34 (m, 2H), 8.12 (s, 1H), 8.34 (s, 1H), 8.35-8.45 (m, 1H), 10.57 (s, 1H)

12-5* 12-5 *

562 [M+1]+ DMSO-d6: 1,35-1,65 (m, 8H), 1,73-1,85 (m, 2H), 2,40-2,59 (m, 7H), 3,08 (s, 3H), 3,52-3,61 (m, 2H), 3,73 (s, 3H), 4,47 (s, 2H), 6,72 (dd, 1H), 6,94 (d, 1H), 7,17 (d, 1H), 7,34-7,39 (m, 2H), 8,21 (s, 1H), 8,37 (s, 1H), 8,45-8,53 (m, 1H), 10,64 (s, 1H) 562 [M + 1] + DMSO-d6: 1.35-1.65 (m, 8H), 1.73-1.85 (m, 2H), 2.40-2.59 (m, 7H), 3.08 (s, 3H ), 3.52-3.61 (m, 2H), 3.73 (s, 3H), 4.47 (s, 2H), 6.72 (dd, 1H), 6.94 (d, 1H) , 7.17 (d, 1H), 7.34-7.39 (m, 2H), 8.21 (s, 1H), 8.37 (s, 1H), 8.45-8.53 (m , 1H), 10.64 (s, 1H)

12-6* 12-6 *

EM m/z 536 DMSO-d6: 2,19-2,42 (m, 4H), 2,65-2,89 (m, 3H), 3,07 (s, 3H), 3,11-3,30 (m, 1H), 3,48-3,61 (m, 2H), 3,62-3,71 (m, 1H), 3,75 (s, 3H), 3,75-3,83 (m, 2H), 4,47 (s, 2H), 6,48-6,52 (m, 1H), 6,66 (d, 1H), 7,15 (d, 1H), 7,26-7,37 (m, 2H), 8,13 (s, 1H), 8,35 (s, 1H), 8,42 (sa, 1H), 10,57 (s, 1H) MS m / z 536 DMSO-d6: 2.19-2.42 (m, 4H), 2.65-2.89 (m, 3H), 3.07 (s, 3H), 3.11-3.30 (m, 1H ), 3.48-3.61 (m, 2H), 3.62-3.71 (m, 1H), 3.75 (s, 3H), 3.75-3.83 (m, 2H), 4.47 (s, 2H), 6.48-6.52 (m, 1H), 6.66 (d, 1H), 7.15 (d, 1H), 7.26-7.37 (m, 2H), 8.13 (s, 1H), 8.35 (s, 1H), 8.42 (sa, 1H), 10.57 (s, 1H)

[0110] Las siguientes 7-(5-cloro-2-(fenilamino sust.)-pirimidin-1-ilamino)-2-etil-2,3-dihidro-isoindol-1-onas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 7-(2,5-dicloro-pirimidin-4-ilamino)-2etil-2,3-dihidro-isoindol-1-ona y la anilina correspondiente según el procedimiento del ejemplo 2: [0110] The following 7- (5-chloro-2- (phenylamino substitu) - pyrimidin-1-ylamino) -2-ethyl-2,3-dihydro-isoindole-1-ones, which are all reference examples ( marked with a (*)), they are prepared from 7- (2,5-dichloro-pyrimidin-4-ylamino) -2ethyl-2,3-dihydro-isoindole-1-one and the corresponding aniline according to the procedure of example 2:

imagen1image 1

Ej. nº Ex. Nº

Rx Masa (m/z) RMN (400 MHz) δ (ppm) Rx Mass (m / z) NMR (400 MHz) δ (ppm)

13-1* 13-1 *

508 [M+1]+ DMSO-d6: 1,19 (t, 3H), 2,24 (s, 3H), 2,47-2,51 (m, 4H), 3,15-3,21 (m, 4H), 3,54 (c, 2H), 3,74 (s, 3H), 4,48 (s, 2H), 6,54 (dd, 1H), 6,65 (d, 1H), 7,15 (d, 1H), 7,267,36 (m, 2H), 8,12 (s, 1H), 8,34 (s, 1H), 8,37-8,48 (m, 1H), 10,58 (s, 1H) 508 [M + 1] + DMSO-d6: 1.19 (t, 3H), 2.24 (s, 3H), 2.47-2.51 (m, 4H), 3.15-3.21 (m, 4H), 3, 54 (c, 2H), 3.74 (s, 3H), 4.48 (s, 2H), 6.54 (dd, 1H), 6.65 (d, 1H), 7.15 (d, 1H ), 7,267.36 (m, 2H), 8.12 (s, 1H), 8.34 (s, 1H), 8.37-8.48 (m, 1H), 10.58 (s, 1H)

Ejemplo de referencia 7B: 2-[5-Cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)-4-pirimidin-4-ilamino]-N-metil-benzamida (síntesis alternativa al ejemplo de referencia 7A) Reference Example 7B: 2- [5-Chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -4-pyrimidin-4-ylamino] -N-methyl-benzamide (alternative synthesis to the example of reference 7A)

10 [0111] A una suspensión de ácido 2-[5-cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)pirimidin-4-ilamino]benzoico (5,5 g, 12,1 mmoles) en 100 ml de THF se añaden Et3N (2,06 ml, 14,8 mmoles) y cloroformiato de isobutilo (1,7 ml, 12,8 mmoles) a -5ºC. Tras agitar durante 30 min a la misma temperatura, la mezcla de reacción se sigue agitando durante 1 hora a temperatura ambiente y después se añade H2O a la mezcla de reacción. El precipitado 10 [0111] To a suspension of 2- [5-chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) pyrimidin-4-ylamino] benzoic acid (5.5 g, 12.1 mmol ) in 100 ml of THF Et3N (2.06 ml, 14.8 mmol) and isobutyl chloroformate (1.7 ml, 12.8 mmol) are added at -5 ° C. After stirring for 30 min at the same temperature, the reaction mixture is further stirred for 1 hour at room temperature and then H2O is added to the reaction mixture. The precipitate

15 resultante se recoge por filtración, se lava con H2O y se seca a presión reducida para proporcionar un producto intermedio (4,80 g) (10,96 mmoles, 91%) en forma de un sólido amarillo. The resulting is collected by filtration, washed with H2O and dried under reduced pressure to provide an intermediate (4.80 g) (10.96 mmol, 91%) as a yellow solid.

RMN (400 MHz, DMSO-d6, δ): 3,10-3,20 (m, 4H), 3,70-3,80 (m, 4H), 3,93 (s, 3H), 6,53 (dd, 1H, J = 9,08, 2,0 Hz), 6,70 (d, 1H, J = 2,0 Hz), 7,49-7,54 (m, 1H), 7,67 (d, 1H, J = 8,56 Hz), 7,89 (s, 1H), 7,85-7,95 (m, 1H), 8,23 (d, 1H, J = 20 9,08 Hz), 8,26 (d, 1H, J = 8,56 Hz), 12,60 (s, 1H). NMR (400 MHz, DMSO-d6, δ): 3.10-3.20 (m, 4H), 3.70-3.80 (m, 4H), 3.93 (s, 3H), 6.53 (dd, 1H, J = 9.08, 2.0 Hz), 6.70 (d, 1H, J = 2.0 Hz), 7.49-7.54 (m, 1H), 7.67 ( d, 1H, J = 8.56 Hz), 7.89 (s, 1H), 7.85-7.95 (m, 1H), 8.23 (d, 1H, J = 20 9.08 Hz) , 8.26 (d, 1H, J = 8.56 Hz), 12.60 (s, 1H).

[0112] A una disolución de metilamina 1 M en THF (560 μl, 0,56 mmoles) se añaden 82 mg del producto intermedio obtenido (0,187 mmoles) y, seguidamente, gota a gota una disolución de NaHMDS 1 M en THF (560 μl, 0,56 mmoles). Después de agitar la mezcla de reacción durante 10 minutos se añaden 5 ml de H2O y se realiza una [0112] To a solution of 1 M methylamine in THF (560 μl, 0.56 mmol) 82 mg of the intermediate obtained (0.187 mmol) are added and then dropwise a solution of 1 M NaHMDS in THF (560 μl, 0.56 mmol). After stirring the reaction mixture for 10 minutes, 5 ml of H2O are added and a

25 extracción con AcOEt. La fase orgánica se lava con salmuera, se seca mediante Na2SO4, se concentra a presión reducida y se purifica mediante cromatografía en columna de gel de sílice (hexano: AcOEt = 1:1 hasta AcOEt) para dar el compuesto del título en forma de un sólido amarillo pálido. Los datos se proporcionan en el ejemplo de referencia 7A. 25 extraction with AcOEt. The organic phase is washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: AcOEt = 1: 1 to AcOEt) to give the title compound as a pale yellow solid. The data is provided in reference example 7A.

[0113] Por repetición de los procedimientos antes descritos usando materiales de partida y condiciones apropiados se obtienen los compuestos siguientes identificados a continuación, que son todos ejemplos de referencia (marcados con un (*)). [0113] By repeating the procedures described above using appropriate starting materials and conditions, the following compounds identified below are obtained, which are all reference examples (marked with a (*)).

imagen1image 1

Ej. nº Ex. Nº

Ry Rf (disolvente) o EM RMN (400 MHz) δ (ppm) Ry Rf (solvent) or MS NMR (400 MHz) δ (ppm)

14-1* 14-1 *

0,10 (n-hexano:AcOEt = 1:1) CDCl3: 3,02-3,19 (m, 10H), 3,833,91 (m, 4H), 3,87 (s, 3H), 6,45 (dd, 1H), 6,52 (d, 1H), 7,09-7,14 (m, 1H), 7,29 (m, 1H), 7,31 (dd, 1H), 7,38-7,45 (m, 1H), 8,06 (s, 1H), 8,14 (d, 1H), 8,39 (d, 1H), 8,97 (s, 1H) 0.10 (n-hexane: AcOEt = 1: 1) CDCl3: 3.02-3.19 (m, 10H), 3.833.91 (m, 4H), 3.87 (s, 3H), 6.45 (dd, 1H), 6.52 (d, 1H) , 7.09-7.14 (m, 1H), 7.29 (m, 1H), 7.31 (dd, 1H), 7.38-7.45 (m, 1H), 8.06 (s , 1H), 8.14 (d, 1H), 8.39 (d, 1H), 8.97 (s, 1H)

14-2* 14-2 *

0,36 (n-hexano:AcOEt = 1:2) CDCl3: 1,27 (d, 6H), 3,09-3,16 (m, 4H), 3,81-3,92 (m, 4H), 3,89 (s, 3H), 4,26-4,37 (m, 1H), 5,93-5,98 (m, 1H), 6,48 (dd, 1H), 6,53 (d, 1H), 7,05-7,11 (m, 1H), 7,42-7,49 (m, 2H), 8,08 (s, 1H), 8,12 (d, 1H), 8,65 (d, 1H), 10,88 (sa, 1H) 0.36 (n-hexane: AcOEt = 1: 2) CDCl3: 1.27 (d, 6H), 3.09-3.16 (m, 4H), 3.81-3.92 (m, 4H), 3.89 (s, 3H), 4.26- 4.37 (m, 1H), 5.93-5.98 (m, 1H), 6.48 (dd, 1H), 6.53 (d, 1H), 7.05-7.11 (m, 1H), 7.42-7.49 (m, 2H), 8.08 (s, 1H), 8.12 (d, 1H), 8.65 (d, 1H), 10.88 (sa, 1H )

14-3* 14-3 *

505 [M+1]+ DMSO-d6: 2,79 (d, 3H), 3,09-3,14 (m, 4H), 3,74-3,77 (m, 4H), 3,75 (s, 3H), 6,49 (dd, 1H), 6,65 (d, 1H), 7,30 (d, 1H), 7,84 (dd, 1H), 8,12 (s, 1H), 8,40 (s, 1H), 8,658,79 (m, 2H), 11,39 (s, 1H) 505 [M + 1] + DMSO-d6: 2.79 (d, 3H), 3.09-3.14 (m, 4H), 3.74-3.77 (m, 4H), 3.75 (s, 3H), 6, 49 (dd, 1H), 6.65 (d, 1H), 7.30 (d, 1H), 7.84 (dd, 1H), 8.12 (s, 1H), 8.40 (s, 1H ), 8,658.79 (m, 2H), 11.39 (s, 1H)

14-4* 14-4 *

466 [M+1]+ DMSO-d6: 2,70-2,75 (m, 2H), 3,043,09 (m, 2H), 3,12-3,18 (m, 4H), 3,74-3,80 (m, 4H), 3,75 (s, 3H), 6,54 (dd, 1H), 6,67 (d, 1H), 7,14 (d, 1H), 7,34 (d, 1H), 7,37-7,44 (m, 1H), 8,17 (s, 1H), 8,35-8,50 (m, 1H), 8,44 (s, 1H), 10,59 (s, 1H) 466 [M + 1] + DMSO-d6: 2.70-2.75 (m, 2H), 3.043.09 (m, 2H), 3.12-3.18 (m, 4H), 3.74-3.80 (m, 4H ), 3.75 (s, 3H), 6.54 (dd, 1H), 6.67 (d, 1H), 7.14 (d, 1H), 7.34 (d, 1H), 7.37 -7.44 (m, 1H), 8.17 (s, 1H), 8.35-8.50 (m, 1H), 8.44 (s, 1H), 10.59 (s, 1H)

14-5* 14-5 *

Rf (hexano:AcOEt = 1:2): 0,31 DMSO: 1,18 (t, 3H), 3,11-3,21 (4, 4H), 3,30-3,60 (m, 2H), 3,71-3,85 (m, 7H), 6,50-6,58 (m, 1H), 6,71 (d, 1H), 7,17-7,26 (m, 1H), 7,46 (d, 1H), 7,64 (dd, 1H), 8,14 (s, 1H), 8,19 (s, 1H), 8,57-8,68 (m, 1H), 8,80-8,87 (m, 1H), 11,36 (s, 1H). Rf (hexane: AcOEt = 1: 2): 0.31 DMSO: 1.18 (t, 3H), 3.11-3.21 (4, 4H), 3.30-3.60 (m, 2H), 3.71-3.85 (m, 7H), 6.50-6.58 (m, 1H), 6.71 (d, 1H), 7.17-7.26 (m, 1H), 7.46 (d, 1H), 7.64 (dd, 1H), 8.14 (s, 1H), 8.19 (s, 1H), 8.57-8.68 (m, 1H), 8.80-8.87 (m, 1H), 11.36 (s, 1H).

14-6* 14-6 *

Rf (hexano:AcOEt = 1:1): DMSO: 1,71-1,92 (m, 2H), 1,92 Rf (hexane: AcOEt = 1: 1): DMSO: 1.71-1.92 (m, 2H), 1.92

0,051 0.051

2,06 (m, 2H), 3,08-3,14 (m, 4H), 2.06 (m, 2H), 3.08-3.14 (m, 4H),

3,48-3,57 (m, 2H), 3,63-3,75 (m, 3.48-3.57 (m, 2H), 3.63-3.75 (m,

2H), 3,84-3,90 (m, 7H), 6,47 (dd, 2H), 3.84-3.90 (m, 7H), 6.47 (dd,

1H), 6,53 (d, 1H), 7,09 (ddd, 1H), 1H), 6.53 (d, 1H), 7.09 (ddd, 1H),

7,25-7,29 (m, 1H), 7,38-7,44 (m, 7.25-7.29 (m, 1H), 7.38-7.44 (m,

1H), 8,06 (s, 1H), 8,15 (d, 1H), 1H), 8.06 (s, 1H), 8.15 (d, 1H),

8,45 (dd, 1H), 9,60 (s, 1H). 8.45 (dd, 1H), 9.60 (s, 1H).

14-7* 14-7 *

1H-RMN (400 MHz, δ ppm, CDCl3): 3,04-3,10 (m, 4H), 3,103,16 (m, 4H), 3,63-3,68 (m, 4H), 3,85-3,90 (m, 7H), 6,46 (dd, 1H), 6,53 (d, 1H), 7,20-7,25 (m, 1H), 7,33 (sa, 1H), 7,56-7,62 (m, 1H), 7,85 (dd, 1H), 8,03 (d, 1H), 8,12 (s, 1H), 8,57-8,61 (m, 1H), 9,30 (s, 1H). 1 H-NMR (400 MHz, δ ppm, CDCl 3): 3.04-3.10 (m, 4H), 3.103.16 (m, 4H), 3.63-3.68 (m, 4H), 3, 85-3.90 (m, 7H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.20-7.25 (m, 1H), 7.33 (sa, 1H) , 7.56-7.62 (m, 1H), 7.85 (dd, 1H), 8.03 (d, 1H), 8.12 (s, 1H), 8.57-8.61 (m , 1H), 9.30 (s, 1H).

[0114] Las siguientes 2-(5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino)-N-metil-5-pirrolidin-1-il-benzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(5-cloro-2-metil-pirimidin-4ilamino)-N-metil-5-pirrolidin-1-ilbenzamida y la anilina correspondiente según el procedimiento del ejemplo 2: [0114] The following 2- (5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino) -N-methyl-5-pyrrolidin-1-yl-benzamides, which are all reference examples (labeled with a (*)), are prepared from 2- (5-chloro-2-methyl-pyrimidin-4-ylamino) -N-methyl-5-pyrrolidin-1-ylbenzamide and the corresponding aniline according to the procedure of Example 2:

imagen1image 1

Ej. nº Ex. Nº

Rx Masa (m/z) RMN (400 MHz) δ (ppm) Rx Mass (m / z) NMR (400 MHz) δ (ppm)

15-1* 15-1 *

551 [M+1]+ DMSO-d6: 1,94-1,99 (m, 4H), 2,23 (s, 3H), 2,43-2,48 (m, 4H), 2,78 (d, 3H), 3,11-3,17 (m, 4H), 3,22-3,29 (m, 4H), 3,76 (s, 3H), 6,46 (dd, 1H), 6,48-6,53 (m, 1H), 6,63 (d, 1H), 6,79 (d, 1H), 7,44 (d, 1H), 7,89 (s, 1H), 7,99 (s, 1H), 8,24 (d, 1H), 8,60 (d, 1H), 10,88 (s, 1H) 551 [M + 1] + DMSO-d6: 1.94-1.99 (m, 4H), 2.23 (s, 3H), 2.43-2.48 (m, 4H), 2.78 (d, 3H), 3, 11-3.17 (m, 4H), 3.22-3.29 (m, 4H), 3.76 (s, 3H), 6.46 (dd, 1H), 6.48-6.53 ( m, 1H), 6.63 (d, 1H), 6.79 (d, 1H), 7.44 (d, 1H), 7.89 (s, 1H), 7.99 (s, 1H), 8.24 (d, 1H), 8.60 (d, 1H), 10.88 (s, 1H)

15-2* 15-2 *

566 [M+1]+ DMSO-d6: 1,60-1,70 (m, 2H), 1,90-2,00 (m, 6H), 2,12-2,20 (m, 2H), 2,18 (s, 3H), 2,60-2,65 (m, 2H), 2,78 (d, 3H), 3,22-3,28 (m, 4H), 3,75 (s, 3H), 4,254,37 (m, 1H), 6,49-6,55 (m, 2H), 6,62 (d, 1H), 6,80 (d, 1H), 7,53 (d, 1H), 7,90 (s, 1H), 8,00 (s, 1H), 8,24 (d, 1H), 8,58-8,63 (m, 1H), 10,88 (s, 1H) 566 [M + 1] + DMSO-d6: 1.60-1.70 (m, 2H), 1.90-2.00 (m, 6H), 2.12-2.20 (m, 2H), 2.18 (s, 3H ), 2.60-2.65 (m, 2H), 2.78 (d, 3H), 3.22-3.28 (m, 4H), 3.75 (s, 3H), 4,254.37 ( m, 1H), 6.49-6.55 (m, 2H), 6.62 (d, 1H), 6.80 (d, 1H), 7.53 (d, 1H), 7.90 (s , 1H), 8.00 (s, 1H), 8.24 (d, 1H), 8.58-8.63 (m, 1H), 10.88 (s, 1H)

15-3* 15-3 *

538 [M+1]+ DMSO-d6: 1,94-1,99 (m, 4H), 2,78 (d, 3H), 3,09-3,15 (m, 4H), 3,22-3,27 (m, 4H), 3,73-3,77 (m, 4H), 3,76 (s, 3H), 6,47 (dd, 1H), 6,47-6,53 (m, 1H), 6,65 (d, 1H), 6,79 (d, 1H), 7,47 (d, 1H), 7,90 (s, 1H), 7,99 (s, 1H), 8,24 (d, 1H), 8,60 (d, 1H), 10,88 (s, 1H) 538 [M + 1] + DMSO-d6: 1.94-1.99 (m, 4H), 2.78 (d, 3H), 3.09-3.15 (m, 4H), 3.22-3.27 (m, 4H ), 3.73-3.77 (m, 4H), 3.76 (s, 3H), 6.47 (dd, 1H), 6.47-6.53 (m, 1H), 6.65 ( d, 1H), 6.79 (d, 1H), 7.47 (d, 1H), 7.90 (s, 1H), 7.99 (s, 1H), 8.24 (d, 1H), 8.60 (d, 1H), 10.88 (s, 1H)

[0115] Las siguientes 2-(5-cloro-2-(4-fluoro-2-metoxi-fenilamino)-pirimidin-4-ilamino)-5-sust.-N-metilbenzamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de la anilina correspondiente según el procedimiento del ejemplo 2: [0115] The following 2- (5-chloro-2- (4-fluoro-2-methoxy-phenylamino) -pyrimidin-4-ylamino) -5-noun-N-methylbenzamides, which are all reference examples (labeled with a (*)), they are prepared from the corresponding aniline according to the procedure of example 2:

imagen1image 1

Ej. nº Ex. Nº

Ry Masa (m/z) RMN (400 MHz) δ (ppm) Ry Mass (m / z) NMR (400 MHz) δ (ppm)

16-1* 16-1 *

487 [M+1]+ DMSO-d6: 2,79 (d, 3H), 3,11-3,15 (m, 4H), 3,74-3,81 (m, 4H), 3,81 (s, 3H), 6,76 (ddd, 1H), 6,95-7,05 (m, 2H), 7,21 (d, 1H), 7,72 (dd, 1H), 8,08 (s, 1H), 8,09 (s, 1H), 8,33 (d, 1H), 8,63-8,73 (m, 1H), 11,17 (s, 1H) 487 [M + 1] + DMSO-d6: 2.79 (d, 3H), 3.11-3.15 (m, 4H), 3.74-3.81 (m, 4H), 3.81 (s, 3H), 6, 76 (ddd, 1H), 6.95-7.05 (m, 2H), 7.21 (d, 1H), 7.72 (dd, 1H), 8.08 (s, 1H), 8.09 (s, 1H), 8.33 (d, 1H), 8.63-8.73 (m, 1H), 11.17 (s, 1H)

16-2* 16-2 *

500 [M+1]+ DMSO-d6: 2,24 (s, 3H), 2,45-2,52 (m, 4H), 2,79 (d, 3H), 3,13-3,18 (m, 4H), 3,81 (s, 3H), 6,75 (ddd, 1H), 6,94-7,02 (m, 2H), 7,20 (d, 1H), 7,73 (dd, 1H), 8,03-8,11 (m, 2H), 8,30 (d, 1H), 8,60-8,70 (m, 1H), 11,14 (s, 1H) 500 [M + 1] + DMSO-d6: 2.24 (s, 3H), 2.45-2.52 (m, 4H), 2.79 (d, 3H), 3.13-3.18 (m, 4H), 3, 81 (s, 3H), 6.75 (ddd, 1H), 6.94-7.02 (m, 2H), 7.20 (d, 1H), 7.73 (dd, 1H), 8.03 -8.11 (m, 2H), 8.30 (d, 1H), 8.60-8.70 (m, 1H), 11.14 (s, 1H)

16-3* 16-3 *

432 [M+1]+ DMSO-d6: 2,79 (d, 3H), 3,80-3,81 (m, 6H), 6,75 (ddd, 1H), 6,90-7,02 (m, 2H), 7,27 (d, 1H), 7,67 (dd, 1H), 8,10 (s, 1H), 8,16 (s, 1H), 8,39 (d, 1H), 8,70-8,76 (m, 1H), 11,20 (s, 1H) 432 [M + 1] + DMSO-d6: 2.79 (d, 3H), 3.80-3.81 (m, 6H), 6.75 (ddd, 1H), 6.90-7.02 (m, 2H), 7, 27 (d, 1H), 7.67 (dd, 1H), 8.10 (s, 1H), 8.16 (s, 1H), 8.39 (d, 1H), 8.70-8.76 (m, 1H), 11.20 (s, 1H)

16-4* 16-4 *

568 [M+1]+ DMSO-d6: 1,35-1,62 (m, 8H), 1,78-1,85 (m, 2H), 2,30-2,40 (m, 1H), 2,41-2,52 (m, 4H), 2,60-2,70 (m, 2H), 2,78 (d, 3H), 3,70-3,80 (m, 2H), 3,81 (s, 3H), 6,75 (ddd, 1H), 6,95-7,02 (m, 2H), 7,20 (d, 1H), 7,72 (dd, 1H), 8,05-8,08 (m, 2H), 8,28 (d, 1H), 8,63-8,69 (m, 1H), 11,12 (s, 1H) 568 [M + 1] + DMSO-d6: 1.35-1.62 (m, 8H), 1.78-1.85 (m, 2H), 2.30-2.40 (m, 1H), 2.41-2.52 (m, 4H), 2.60-2.70 (m, 2H), 2.78 (d, 3H), 3.70-3.80 (m, 2H), 3.81 (s, 3H), 6.75 (ddd, 1H), 6.95-7.02 (m, 2H), 7.20 (d, 1H), 7.72 (dd, 1H), 8.05-8.08 (m, 2H), 8.28 (d, 1H), 8.63-8.69 (m, 1H), 11.12 (s, 1H)

Ejemplo de referencia 16B 10 [0116] Reference Example 16B 10 [0116]

45 CDCl3: 3,01-3,10 (m, 4H), 3,63-3,68 (m, 4H), 3,89 (s, 3H), 6,59 (ddd, 1H), 6,66 (dd, 1H), 7,20-7,26 (m, 1H), 7,36 (s, 1H), 7,57-7,63 (m, 1H), 7,84 (dd, 1H), 8,09-8,14 (m, 1H), 8,14 (s, 1H), 8,53 (d, 1H), 9,30 (s, 1H). 45 CDCl3: 3.01-3.10 (m, 4H), 3.63-3.68 (m, 4H), 3.89 (s, 3H), 6.59 (ddd, 1H), 6.66 (dd, 1H), 7.20-7.26 (m, 1H), 7.36 (s, 1H), 7.57-7.63 (m, 1H), 7.84 (dd, 1H), 8.09-8.14 (m, 1H), 8.14 (s, 1H), 8.53 (d, 1H), 9.30 (s, 1H).

imagen1image 1

5 Ejemplo de referencia 16C 5 Reference example 16C

[0117] [0117]

imagen1image 1

10 CDCl3: 3,56-3,65 (m, 2H), 3,88 (s, 3H), 5,11-5,19 (m, 1H), 6,50-6,56 (m, 1H), 6,61-6,66 (m, 1H), 7,25-7,29 (m, 1H), 7,38 (sa, 1H), 7,58-7,62 (m, 1H), 7,97 (dd, 1H), 8,02-8,10 (m, 1H), 8,15 (s, 1H), 8,41 (dd, 1H), 8,81 (s, 1H). 10 CDCl3: 3.56-3.65 (m, 2H), 3.88 (s, 3H), 5.11-5.19 (m, 1H), 6.50-6.56 (m, 1H) , 6.61-6.66 (m, 1H), 7.25-7.29 (m, 1H), 7.38 (sa, 1H), 7.58-7.62 (m, 1H), 7 , 97 (dd, 1H), 8.02-8.10 (m, 1H), 8.15 (s, 1H), 8.41 (dd, 1H), 8.81 (s, 1H).

[0118] La siguiente 2-(5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino)-5-fluoro-N-metil-benzamida, que es un ejemplo de referencia (marcado mediante un (*)), se prepara a partir de 2-(2,5-dicloro-pirimidin-4-ilamino)-5-fluoro-N[0118] The following 2- (5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino) -5-fluoro-N-methyl-benzamide, which is a reference example (marked by a (*) ), is prepared from 2- (2,5-dichloro-pyrimidin-4-ylamino) -5-fluoro-N

imagen10image10

Ej. nº Ex. Nº

Rx Masa (m/z) RMN (400 MHz) δ (ppm) Rx Mass (m / z) NMR (400 MHz) δ (ppm)

18-1* 18-1 *

595* [M+1]+ DMSO-d6: 2,06 (s, 3H), 2,78 (d, 3H), 3,05-3,18 (m, 8H), 3,53-3,64 (m, 4H), 3,68-3,77 (m, 4H), 3,77 (s, 3H), 6,51 (dd, 1H), 6,69 (d, 1H), 6,88 (da, 1H), 7,20 (d, 1H), 7,43 (d, 1H), 7,99-8,03 (m, 2H), 8,34 (da, 1H), 8,63-8,71 (m, 1H), 11,15 (s, 1H) 595 * [M + 1] + DMSO-d6: 2.06 (s, 3H), 2.78 (d, 3H), 3.05-3.18 (m, 8H), 3.53-3.64 (m, 4H), 3, 68-3.77 (m, 4H), 3.77 (s, 3H), 6.51 (dd, 1H), 6.69 (d, 1H), 6.88 (da, 1H), 7.20 (d, 1H), 7.43 (d, 1H), 7.99-8.03 (m, 2H), 8.34 (da, 1H), 8.63-8.71 (m, 1H), 11.15 (s, 1 H)

[0119] Las siguientes 2-[5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-isopropil-bencenosulfonamidas se preparan a partir de 2-(5-cloro-2-cloro-pirimidin-4-ilamino)-N-isopropil-bencenosulfonamida y la anilina 5 correspondiente según el procedimiento del ejemplo de referencia 7A: [0119] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-isopropyl-benzenesulfonamides are prepared from 2- (5-chloro-2-chloro-pyrimidin- 4-ylamino) -N-isopropyl-benzenesulfonamide and the corresponding aniline 5 according to the procedure of reference example 7A:

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

19-1* 19-1 *

0,39 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,94 (d, 6H), 1,75-1,84 (m, 1H), 2,07-2,16 (m, 1H), 2,33 (s, 3H), 2,98-3,04 (m, 1H), 3,22-3,36 (m, 5H), 3,42-3,47 (m, 1H), 3,74 (s, 3H), 6,05 (dd, 1H), 6,18 (d, 1H), 7,18 (dd, 1H), 7,25 (d, 1H), 7,35-7,45 (m, 1H), 7,77-7,82 (m, 1H), 7,70-8,10 (m, 1H), 8,09-8,17 (m, 2H), 8,45-8,63 (m, 1H), 9,34 (s, 1H) 0.39 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.94 (d, 6H), 1.75-1.84 (m, 1H), 2.07-2.16 (m, 1H), 2.33 (s, 3H), 2, 98-3.04 (m, 1H), 3.22-3.36 (m, 5H), 3.42-3.47 (m, 1H), 3.74 (s, 3H), 6.05 ( dd, 1H), 6.18 (d, 1H), 7.18 (dd, 1H), 7.25 (d, 1H), 7.35-7.45 (m, 1H), 7.77-7 , 82 (m, 1H), 7.70-8.10 (m, 1H), 8.09-8.17 (m, 2H), 8.45-8.63 (m, 1H), 9.34 (s, 1H)

19-2* 19-2 *

0,40 (n-hexano:AcOEt = 1:1) CDCl3: 1,00 (d, 6H), 1,13 (t, 3H), 1,831,92 (m, 1H), 2,23-2,30 (m, 1H), 2,702,78 (m, 2H), 3,08-3,13 (m, 1H), 3,273,54 (m, 5H), 3,85 (s, 3H), 4,33 (d, 1H), 6,05 (d, 1H), 6,13 (s, 1H), 7,13 (sa, 1H), 7,18-7,22 (m, 1H), 7,52-7,56 (m, 1H), 7,83-7,86 (m, 1H), 7,95-7,98 (m, 1H), 8,09 (s, 1H), 8,47-8,49 (m, 1H), 8,89 (s, 1H) 0.40 (n-hexane: AcOEt = 1: 1) CDCl3: 1.00 (d, 6H), 1.13 (t, 3H), 1,831.92 (m, 1H), 2.23-2.30 (m, 1H), 2,702.78 (m, 2H) , 3.08-3.13 (m, 1H), 3,273.54 (m, 5H), 3.85 (s, 3H), 4.33 (d, 1H), 6.05 (d, 1H), 6.13 (s, 1H), 7.13 (sa, 1H), 7.18-7.22 (m, 1H), 7.52-7.56 (m, 1H), 7.83-7, 86 (m, 1H), 7.95-7.98 (m, 1H), 8.09 (s, 1H), 8.47-8.49 (m, 1H), 8.89 (s, 1H)

19-3* 19-3 *

0,30 (n-hexano:AcOEt = 1:1) CDCl3: 0,93 (d, 6H), 1,05-1,09 (m, 1H), 1,48-1,99 (m, 6H), 2,16 (s, 3H), 2,612,67 (m, 1H), 2,80-2,83 (m, 1H), 3,75 (s, 3H), 3,80-3,89 (m, 2H), 6,44-6,47 (m, 1H), 6,62-6,63 (m, 1H), 7,18-7,22 (m, 1H), 7,42-7,46 (m, 1H), 7,80-7,89 (m, 2H), 8,17 (s, 1H), 8,23 (s, 1H), 8,42-8,44 (m, 1H), 8,89 (s, 1H) 0.30 (n-hexane: AcOEt = 1: 1) CDCl3: 0.93 (d, 6H), 1.05-1.09 (m, 1H), 1.48-1.99 (m, 6H), 2.16 (s, 3H), 2,612.67 ( m, 1H), 2.80-2.83 (m, 1H), 3.75 (s, 3H), 3.80-3.89 (m, 2H), 6.44-6.47 (m, 1H), 6.62-6.63 (m, 1H), 7.18-7.22 (m, 1H), 7.42-7.46 (m, 1H), 7.80-7.89 ( m, 2H), 8.17 (s, 1H), 8.23 (s, 1H), 8.42-8.44 (m, 1H), 8.89 (s, 1H)

19-4* 19-4 *

0,69 (MeOH:CH2Cl2 = 1:3) DMSO-d6: 0,94 (d, 6H), 1,45-1,57 (m, 2H), 1,80-1,88 (m, 2H), 2,14 (s, 3H), 2,25-2,35 (m, 4H), 2,45-2,55 (m, 4H), 2,62-2,70 (m, 2H), 3,28-3,37 (m, 1H), 3,68-3,74 (m, 2H), 3,75 (s, 3H), 6,44 (dd, 1H, J=8,82, 2,0 Hz), 6,61 (d, 1H, J=2,0 Hz), 7,21 (dd, 1H), 7,37 (d, 1H), 7,45 (dd, 1H), 7,81 (dd, 1H, J=1,82, 1,52 Hz), 7,84-7,92 (m, 1H), 8,12-8,20 (m, 1H), 8,16 (s, 1H), 8,43-8,51 (m, 1H), 9,31 (s, 1H) 0.69 (MeOH: CH2Cl2 = 1: 3) DMSO-d6: 0.94 (d, 6H), 1.45-1.57 (m, 2H), 1.80-1.88 (m, 2H), 2.14 (s, 3H), 2, 25-2.35 (m, 4H), 2.45-2.55 (m, 4H), 2.62-2.70 (m, 2H), 3.28-3.37 (m, 1H), 3.68-3.74 (m, 2H), 3.75 (s, 3H), 6.44 (dd, 1H, J = 8.82, 2.0 Hz), 6.61 (d, 1H, J = 2.0 Hz), 7.21 (dd, 1H), 7.37 (d, 1H), 7.45 (dd, 1H), 7.81 (dd, 1H, J = 1.82, 1 , 52 Hz), 7.84-7.92 (m, 1H), 8.12-8.20 (m, 1H), 8.16 (s, 1H), 8.43-8.51 (m, 1H), 9.31 (s, 1H)

19-5* 19-5 *

0,35 (n-hexano:AcOEt = 1:1) CDCl3: 0,93 (d, 6H), 2,23 (s, 3H), 2,452,48 (m, 4H), 3,12-3,15 (m, 4H), 3,75 (s, 3H), 6,42-6,45 (m, 1H), 6,63 (s, 1H), 7,19-7,23 (m, 1H), 7,38-7,47 (m, 2H), 7,80-7,89 (m, 2H), 8,16 (s, 1H), 8,468,48 (m, 1H), 9,34 (s, 1H) 0.35 (n-hexane: AcOEt = 1: 1) CDCl3: 0.93 (d, 6H), 2.23 (s, 3H), 2,452.48 (m, 4H), 3.12-3.15 (m, 4H), 3.75 (s, 3H) , 6.42-6.45 (m, 1H), 6.63 (s, 1H), 7.19-7.23 (m, 1H), 7.38-7.47 (m, 2H), 7 , 80-7.89 (m, 2H), 8.16 (s, 1H), 8.468.48 (m, 1H), 9.34 (s, 1H)

19-6 19-6

0,45 (n-hexano:AcOEt = 1:1) CDCl3: 0,99 (d, 6H), 3,40-3,49 (m, 1H), 3,88 (s, 3H), 4,29-4,31 (d, 1H), 6,51-6,56 (m, 1H), 6,62-6,65 (m, 1H), 7,24-7,28 (m, 1H), 7,37 (s, 1H), 7,56-7,60 (m, 1H), 7,98-8,15 (m, 3H), 8,34-8,37 (m, 1H), 8,89 (s, 1H) 0.45 (n-hexane: AcOEt = 1: 1) CDCl3: 0.99 (d, 6H), 3.40-3.49 (m, 1H), 3.88 (s, 3H), 4.29-4.31 (d, 1H), 6.51- 6.56 (m, 1H), 6.62-6.65 (m, 1H), 7.24-7.28 (m, 1H), 7.37 (s, 1H), 7.56-7, 60 (m, 1H), 7.98-8.15 (m, 3H), 8.34-8.37 (m, 1H), 8.89 (s, 1H)

19-7 19-7

0,28 (n-hexano:AcOEt = 1:1) CDCl3: 0,93 (d, 6H), 1,59-1,67 (m, 2H), 1,90-1,93 (m, 2H), 2,10-2,24 (m, 5H), 2,60-2,67 (m, 2H), 3,74 (s, 3H), 4,334,37 (m, 1H), 6,47-6,50 (m, 1H), 6,63 (d, 1H), 7,18-7,22 (m, 1H), 7,41-7,45 (m, 2H), 7,79-7,87 (m, 2H), 8,16 (s, 1H), 8,21 (s, 1H), 8,41-8,43 (m, 1H), 9,29 (s, 1H) 0.28 (n-hexane: AcOEt = 1: 1) CDCl3: 0.93 (d, 6H), 1.59-1.67 (m, 2H), 1.90-1.93 (m, 2H), 2.10-2.24 (m, 5H), 2.60-2.67 (m, 2H), 3.74 (s, 3H), 4,334.37 (m, 1H), 6.47-6.50 (m, 1H), 6.63 (d, 1H), 7.18-7.22 (m, 1H), 7.41-7.45 (m, 2H), 7.79-7.87 (m, 2H), 8.16 (s, 1H) , 8.21 (s, 1H), 8.41-8.43 (m, 1H), 9.29 (s, 1H)

19-8 19-8

0,25 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,93 (d, 6H), 3,09-3,12 (m, 4H), 3,74-3,76 (m, 7H), 6,43-6,46 (m, 1H), 6,64 (s, 1H), 7,19-7,23 (m, 1H), 7,41-7,48 (m, 2H), 7,80 (d, 1H), 7,82 (d, 1H), 8,17 (s, 1H), 8,46-8,48 (m, 1H), 9,31 (s, 1H) 0.25 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.93 (d, 6H), 3.09-3.12 (m, 4H), 3.74-3.76 (m, 7H), 6.43-6.46 (m, 1H ), 6.64 (s, 1H), 7.19-7.23 (m, 1H), 7.41-7.48 (m, 2H), 7.80 (d, 1H), 7.82 ( d, 1H), 8.17 (s, 1H), 8.46-8.48 (m, 1H), 9.31 (s, 1H)

19-9* 19-9 *

0,56 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,93 (d, 6H), 1,89-1,90 (m, 1H), 2,30 (sa, 6H), 3,13-3,50 (m, 6H), 3,74 (s, 3H), 6,10 (d, 1H), 6,22 (s, 1H), 7,16-7,20 (m, 1H), 7,25-7,27 (m, 1H), 7,40 (sa, 1H), 7,79-7,81 (m, 1H), 7,867,88 (m, 1H), 8,12 (s, 1H), 8,15 (s, 1H), 8,51 (s, 1H), 9,34 (s, 1H) 0.56 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.93 (d, 6H), 1.89-1.90 (m, 1H), 2.30 (sa, 6H), 3.13-3.50 (m, 6H), 3, 74 (s, 3H), 6.10 (d, 1H), 6.22 (s, 1H), 7.16-7.20 (m, 1H), 7.25-7.27 (m, 1H) , 7.40 (sa, 1H), 7.79-7.81 (m, 1H), 7.867.88 (m, 1H), 8.12 (s, 1H), 8.15 (s, 1H), 8.51 (s, 1H), 9.34 (s, 1H)

19-10* 19-10 *

0,45 (MeOH:CH2Cl2 = 1:4) CDCl3: 0,99 (d, 12H), 2,27 (s, 2H), 2,31 (s, 6H), 2,96 (s, 2H), 3,39-3,48 (m, 1H), 3,83 (s, 3H), 4,30 (d, 1H), 6,09-6,12 (m, 1H), 6,19 (d, 1H), 7,11 (s, 1H), 7,19-7,23 (m, 1H), 7,51-7,57 (m, 1H), 7,76-7,79 (m, 1H), 7,95 (d, 1H), 8,09 (s, 1H), 8,46-8,49 (m, 1H), 8,88 (s, 1H) 0.45 (MeOH: CH2Cl2 = 1: 4) CDCl3: 0.99 (d, 12H), 2.27 (s, 2H), 2.31 (s, 6H), 2.96 (s, 2H), 3.39-3.48 (m, 1H) , 3.83 (s, 3H), 4.30 (d, 1H), 6.09-6.12 (m, 1H), 6.19 (d, 1H), 7.11 (s, 1H), 7.19-7.23 (m, 1H), 7.51-7.57 (m, 1H), 7.76-7.79 (m, 1H), 7.95 (d, 1H), 8, 09 (s, 1H), 8.46-8.49 (m, 1H), 8.88 (s, 1H)

19-11 19-11

0,30 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,93 (d, 6H), 2,96-2,99 (m, 4H), 3,74-3,76 (m, 7H), 6,67-6,72 (m, 1H), 7,21-7,25 (m, 1H), 7,31-7,34 (m, 1H), 7,44-7,48 (m, 1H), 7,80-7,83 (m, 1H), 7,88 (d, 1H), 8,21 (s, 1H), 8,42 (d, 1H), 8,58 (s, 1H), 9,30 (s, 1H) 0.30 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.93 (d, 6H), 2.96-2.99 (m, 4H), 3.74-3.76 (m, 7H), 6.67-6.72 (m, 1H ), 7.21-7.25 (m, 1H), 7.31-7.34 (m, 1H), 7.44-7.48 (m, 1H), 7.80-7.83 (m , 1H), 7.88 (d, 1H), 8.21 (s, 1H), 8.42 (d, 1H), 8.58 (s, 1H), 9.30 (s, 1H)

19-12* 19-12 *

0,42 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,94 (d, 6H), 1,68-1,76 (m, 1H), 1,99-2,07 (m, 1H), 2,29 (s, 3H), 3,05-3,49 (m, 6H), 3,75 (s, 3H), 6,366,40 (m, 1H), 7,10-7,37 (m, 3H), 7,707,80 (m, 1H), 8,08-8,39 (m, 3H), 9,24 (s, 1H) 0.42 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.94 (d, 6H), 1.68-1.76 (m, 1H), 1.99-2.07 (m, 1H), 2.29 (s, 3H), 3, 05-3.49 (m, 6H), 3.75 (s, 3H), 6.366.40 (m, 1H), 7.10-7.37 (m, 3H), 7.707.80 (m, 1H) , 8.08-8.39 (m, 3H), 9.24 (s, 1H)

19-13* 19-13 *

0,50 (MeOH:CH2Cl2 = 1:4) CDCl3: 1,01 (d, 6H), 1,94-1,96 (m, 1H), 2,01 (s, 3H), 2,29-2,37 (m, 1H), 3,193,58 (m, 5H), 3,86 (s, 3H), 4,42 (d, 1H), 4,59-4,63 (m, 1H), 5,70 (d, 1H), 6,056,08 (m, 1H), 6,15-6,16 (m, 1H), 7,177,24 (m, 2H), 7,53-7,57 (m, 1H), 7,90 (d, 1H), 7,91-7,98 (m, 1H), 8,09 (s, 1H), 8,47 (d, 1H), 8,91 (s, 1H) 0.50 (MeOH: CH2Cl2 = 1: 4) CDCl3: 1.01 (d, 6H), 1.94-1.96 (m, 1H), 2.01 (s, 3H), 2.29-2.37 (m, 1H), 3,193.58 ( m, 5H), 3.86 (s, 3H), 4.42 (d, 1H), 4.59-4.63 (m, 1H), 5.70 (d, 1H), 6.056.08 (m , 1H), 6.15-6.16 (m, 1H), 7.177.24 (m, 2H), 7.53-7.57 (m, 1H), 7.90 (d, 1H), 7, 91-7.98 (m, 1H), 8.09 (s, 1H), 8.47 (d, 1H), 8.91 (s, 1H)

19-14* 19-14 *

0,53 (MeOH:CH2Cl2 = 1:4) CDCl3: 1,00 (d, 6H), 2,04 (s, 3H), 2,052,29 (m, 2H), 2,96 (s, 3H), 3,19-3,54 (m, 5H), 3,86 (s, 3H), 4,57-4,63 (m, 1H), 5,39-5,46 (m, 1H), 6,07-6,09 (m, 1H), 6,16 (d, 1H), 7,18-7,26 (m, 2H), 7,537,57 (m, 1H), 7,89-7,98 (m, 2H), 8,08 (s, 1H), 8,47 (d, 1H), 8,94 (d, 1H) 0.53 (MeOH: CH2Cl2 = 1: 4) CDCl3: 1.00 (d, 6H), 2.04 (s, 3H), 2,052.29 (m, 2H), 2.96 (s, 3H), 3.19-3.54 (m, 5H) , 3.86 (s, 3H), 4.57-4.63 (m, 1H), 5.39-5.46 (m, 1H), 6.07-6.09 (m, 1H), 6 , 16 (d, 1H), 7.18-7.26 (m, 2H), 7.537.57 (m, 1H), 7.89-7.98 (m, 2H), 8.08 (s, 1H ), 8.47 (d, 1H), 8.94 (d, 1H)

19-15* 19-15 *

0,56 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,93 (d, 6H), 1,48-1,56 (m, 2H), 1,65-1,75 (m, 4H), 1,90-1,93 (m, 2H), 2,05-2,15 (m, 1H), 2,45-2,55 (m, 5H), 2,69-2,75 (m, 2H), 3,61 (d, 2H), 3,74 (s, 1H), 6,42-6,51 (m, 1H), 6,61 (d, 1H), 7,18-7,22 (m, 1H), 7,37 (d, 1H), 7,43-7,47 (m, 1H), 7,80 (d, 1H), 7,817,89 (m, 1H), 8,16 (d, 1H), 8,46-8,48 (m, 1H), 9,31 (s, 1H) 0.56 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.93 (d, 6H), 1.48-1.56 (m, 2H), 1.65-1.75 (m, 4H), 1.90-1.93 (m, 2H ), 2.05-2.15 (m, 1H), 2.45-2.55 (m, 5H), 2.69-2.75 (m, 2H), 3.61 (d, 2H), 3.74 (s, 1H), 6.42-6.51 (m, 1H), 6.61 (d, 1H), 7.18-7.22 (m, 1H), 7.37 (d, 1H), 7.43-7.47 (m, 1H), 7.80 (d, 1H), 7,817.89 (m, 1H), 8.16 (d, 1H), 8.46-8.48 (m, 1H), 9.31 (s, 1H)

19-16* 19-16 *

0,56 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,92 (d, 6H), 1,65-1,75 (m, 4H), 1,88-2,00 (m, 4H), 2,39-2,43 (m, 2H), 2,60-2,65 (m, 2H), 3,03-3,07 (m, 1H), 3,03-3,40 (m, 2H), 3,70 (s, 3H), 3,77-3,78 (m, 1H), 6,09 (d, 1H), 6,23 (s, 1H), 7,13-7,17 (m, 1H), 7,23-7,25 (m, 1H), 7,30-7,42 (m, 1H), 7,78 (d, 1H), 7,86 (d, 1H), 8,10 (s, 1H), 8,13 (s, 1H), 8,40-8,50 (m, 1H), 9,31 (s, 1H) 0.56 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.92 (d, 6H), 1.65-1.75 (m, 4H), 1.88-2.00 (m, 4H), 2.39-2.43 (m, 2H ), 2.60-2.65 (m, 2H), 3.03-3.07 (m, 1H), 3.03-3.40 (m, 2H), 3.70 (s, 3H), 3.77-3.78 (m, 1H), 6.09 (d, 1H), 6.23 (s, 1H), 7.13-7.17 (m, 1H), 7.23-7, 25 (m, 1H), 7.30-7.42 (m, 1H), 7.78 (d, 1H), 7.86 (d, 1H), 8.10 (s, 1H), 8.13 (s, 1H), 8.40-8.50 (m, 1H), 9.31 (s, 1H)

19-17* 19-17 *

0,23 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,93 (d, 6H), 1,24-1,57 (m, 4H), 1,69-1,78 (m, 2H), 1,98-2,04 (m, 1H), 2,15-2,33 (m, 5H), 2,70-2,80 (m, 1H), 3,74 (s, 3H), 3,91-3,94 (m, 1H), 4,05-4,09 (m, 1H), 6,46-6,49 (m, 1H), 6,63 (d, 1H), 7,18-7,22 (m, 1H), 7,427,46 (m, 2H), 7,80 (d, 1H), 7,89 (d, 1H), 8,17 (s, 1H), 8,25 (s, 1H), 8,42-8,44 (m, 1H), 9,31 (s, 1H) 0.23 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.93 (d, 6H), 1.24-1.57 (m, 4H), 1.69-1.78 (m, 2H), 1.98-2.04 (m, 1H ), 2.15-2.33 (m, 5H), 2.70-2.80 (m, 1H), 3.74 (s, 3H), 3.91-3.94 (m, 1H), 4.05-4.09 (m, 1H), 6.46-6.49 (m, 1H), 6.63 (d, 1H), 7.18-7.22 (m, 1H), 7.427, 46 (m, 2H), 7.80 (d, 1H), 7.89 (d, 1H), 8.17 (s, 1H), 8.25 (s, 1H), 8.42-8.44 (m, 1H), 9.31 (s, 1H)

19-18* 19-18 *

0,48 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,93 (d, 6H), 1,03 (t, 3H), 1,13 (t, 3H), 1,42-1,81 (m, 4H), 2,57-2,83 (m, 4H), 3,17-3,41 (m, 4H), 3,65-3,75 (m, 1H), 3,80 (s, 3H), 4,21 (sa, 1H), 6,426,47 (m, 2H), 6,51 (d, 1H), 6,63 (d, 1H), 7,18-7,22 (m, 1H), 7,38-7,47 (m, 2H), 7,80-7,82 (m, 1H), 7,89 (d, 1H), 8,16 (s, 1H), 8,47-8,49 (m, 1H), 9,31 (s, 1H) 0.48 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.93 (d, 6H), 1.03 (t, 3H), 1.13 (t, 3H), 1.42-1.81 (m, 4H), 2.57-2, 83 (m, 4H), 3.17-3.41 (m, 4H), 3.65-3.75 (m, 1H), 3.80 (s, 3H), 4.21 (sa, 1H) , 6,426.47 (m, 2H), 6.51 (d, 1H), 6.63 (d, 1H), 7.18-7.22 (m, 1H), 7.38-7.47 (m , 2H), 7.80-7.82 (m, 1H), 7.89 (d, 1H), 8.16 (s, 1H), 8.47-8.49 (m, 1H), 9, 31 (s, 1H)

19-19* 19-19 *

0,44 (CH2Cl2:MeOH = 9:1) CDCl3: 1,45-1,62 (m, 2H), 1,72-1,78 (m, 1H), 1,82-1,90 (m, 1H), 2,40-2,46 (m, 1H), 2,61-2,75 (m, 2H), 3,75-3,70 (m, 2H), 3,76 (s, 3H), 6,45 (dd, 1H), 6,62 (d, 1H), 6,85 (s, 1H), 7,19-7,23 (m, 1H), 7,36-7,48 (m, 3H), 7,80-7,82 (m, 1H), 7,85-7,93 (a, 1H), 8,16 (s, 2H), 8,43-8,52 (m, 1H), 9,31 (s, 1H) 0.44 (CH2Cl2: MeOH = 9: 1) CDCl3: 1.45-1.62 (m, 2H), 1.72-1.78 (m, 1H), 1.82-1.90 (m, 1H), 2.40-2.46 (m , 1H), 2.61-2.75 (m, 2H), 3.75-3.70 (m, 2H), 3.76 (s, 3H), 6.45 (dd, 1H), 6, 62 (d, 1H), 6.85 (s, 1H), 7.19-7.23 (m, 1H), 7.36-7.48 (m, 3H), 7.80-7.82 ( m, 1H), 7.85-7.93 (a, 1H), 8.16 (s, 2H), 8.43-8.52 (m, 1H), 9.31 (s, 1H)

19-20* 19-20 *

EM: 547 DMSO-d6: 0,94 (d, 6H), 1,73-1,82 (m, 1H), 2,23-2,33 (m, 4H), 2,34-2,41 (m, 1H), 2,54-2,62 (m, 1H), 2,62-2,69 (m, 1H), 2,77-2,82 (m, 1H), 3,25-3,35 (m, 1H), 3,74 (s, 3H), 4,85-4,92 (m, 1H), 6,4 (dd, 1H), 6,57 (d, 1H), 7,16-7,24 (m, 1H), 7,38-7,51 (m, 1H), 7,81 (d, 1H), 7,827,94 (m, 1H), 8,16 (s, 1H), 8,22 (sa, 1H), 8,38-8,48 (m, 1H), 9,3 (sa, 1H) MS: 547 DMSO-d6: 0.94 (d, 6H), 1.73-1.82 (m, 1H), 2.23-2.33 (m, 4H), 2.34-2.41 (m, 1H ), 2.54-2.62 (m, 1H), 2.62-2.69 (m, 1H), 2.77-2.82 (m, 1H), 3.25-3.35 (m , 1H), 3.74 (s, 3H), 4.85-4.92 (m, 1H), 6.4 (dd, 1H), 6.57 (d, 1H), 7.16-7, 24 (m, 1H), 7.38-7.51 (m, 1H), 7.81 (d, 1H), 7.827.94 (m, 1H), 8.16 (s, 1H), 8.22 (sa, 1H), 8.38-8.48 (m, 1H), 9.3 (sa, 1H)

19-21 19-21

EM: 579 DMSO-d6: 0,92 (d, 6H), 1,61-1,71 (m, 2H), 1,86-1,96 (m, 2H), 2,12-2,22 (m, 5H), 2,57-2,64 (m, 2H), 3,2-3,4 (m, 1H), 3,77 (s, 3H), 4,27-4,35 (m, 1H), 6,86 (dd, 1H), 7,19-7,27 (m, 1H), 7,39-7,46 (m, 1H), 7,81 (dd, 1H), 7,84-7,92 (m, 1H), 8,21 (s, 1H), 8,36-8,42 (m, 1H), 8,62 (s, 1H), 9,28 (s, 1H) MS: 579 DMSO-d6: 0.92 (d, 6H), 1.61-1.71 (m, 2H), 1.86-1.96 (m, 2H), 2.12-2.22 (m, 5H ), 2.57-2.64 (m, 2H), 3.2-3.4 (m, 1H), 3.77 (s, 3H), 4.27-4.35 (m, 1H), 6.86 (dd, 1H), 7.19-7.27 (m, 1H), 7.39-7.46 (m, 1H), 7.81 (dd, 1H), 7.84-7, 92 (m, 1H), 8.21 (s, 1H), 8.36-8.42 (m, 1H), 8.62 (s, 1H), 9.28 (s, 1H)

19-22* 19-22 *

EM: 549 DMSO-d6: 0,90 (s, 6H), 0,94 (d, 6H), 2,9 (d, 2H), 3,24 (d, 2H), 3,25-3,35 (m, 1H), 3,27-3,36 (m, 1H), 3,68 (s, 3H), 4,58 (t, 1H), 5,3 (t, 1H), 6,16 (dd, 1H), 6,39 (d, 1H), 7,13 (d, 1H), 7,15-7,21 (m, 1H), 7,35-7,45 (m, 1H), 7,8 (dd, 1H), 7,837,92 (m, 1H), 8,09 (s, 1H), 8,11 (s, 1H), 8,45-8,57 (m, 1H), 9,33 (s, 1H) MS: 549 DMSO-d6: 0.90 (s, 6H), 0.94 (d, 6H), 2.9 (d, 2H), 3.24 (d, 2H), 3.25-3.35 (m, 1H), 3.27-3.36 (m, 1H), 3.68 (s, 3H), 4.58 (t, 1H), 5.3 (t, 1H), 6.16 (dd, 1H ), 6.39 (d, 1H), 7.13 (d, 1H), 7.15-7.21 (m, 1H), 7.35-7.45 (m, 1H), 7.8 ( dd, 1H), 7,837.92 (m, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.45-8.57 (m, 1H), 9.33 (s , 1 HOUR)

19-23* 19-23 *

Rf: 0,51 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,94 (d, 6H), 1,22 (s, 6H), 3,25-3,35 (m, 1H), 3,36 (d, 2H), 3,68 (s, 3H), 4,73-4,79 (sa, 1H), 4,81 (t, 1H), 6,29 (dd, 1H), 6,44 (d, 1H), 7,14-7,22 (m, 2H), 7,38-7,46 (m, 1H), 7,8 (dd, 1H), 7,85-7,9 (m, 1H), 8,1 (s, 1H), 8,13 (s, 1H), 8,458,55 (m, 1H), 9,32 (s, 1H) Rf: 0.51 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.94 (d, 6H), 1.22 (s, 6H), 3.25-3.35 (m, 1H), 3.36 (d, 2H), 3.68 (s, 3H), 4.73-4.79 (sa, 1H), 4.81 (t, 1H), 6.29 (dd, 1H), 6.44 (d, 1H), 7.14-7.22 (m, 2H), 7.38-7.46 (m, 1H), 7.8 (dd, 1H), 7.85-7.9 (m, 1H), 8.1 (s, 1H), 8.13 (s, 1H), 8.458.55 (m, 1H), 9.32 (s, 1H)

19-24* 19-24 *

EM: 577 DMSO-d6: 0,93 (d, 6H), 0,96 (s, 6H), 2,22 (s, 6H), 3,25-3,35 (m, 1H), 3,7 (s, 3H), 3,75 (s, 3H), 6,46 (dd, 1H), 6,62 (d, 1H), 7,16-7,23 (m, 1H), 7,38-7,47 (m, 1H), 7,81 (dd, 1H), 7,85-7,9 (m, 1H), 8,17 (s, 1H), 8,23 (s, 1H), 8,38-8,48 (m, 1H), 9,31 (s, 1H) MS: 577 DMSO-d6: 0.93 (d, 6H), 0.96 (s, 6H), 2.22 (s, 6H), 3.25-3.35 (m, 1H), 3.7 (s, 3H), 3.75 (s, 3H), 6.46 (dd, 1H), 6.62 (d, 1H), 7.16-7.23 (m, 1H), 7.38-7.47 (m, 1H), 7.81 (dd, 1H), 7.85-7.9 (m, 1H), 8.17 (s, 1H), 8.23 (s, 1H), 8.38- 8.48 (m, 1H), 9.31 (s, 1H)

19-25 19-25

EM: 521 DMSO-d6: 0,94 (d, 6H), 3,12 (t, 4H), 3,25-3,35 (m, 1H), 3,75 (t, 4H), 6,73 (dd, 1H), 6,85 (dd, 1H), 7,16-7,24 (m, 1H), 7,25-7,32 (m, 1H), 7,38-7,47 (m, 1H), 7,8 (dd, 1H), 7,88 (d, 1H), 8,18 (s, 1H), 8,428,52 (m, 1H), 8,86 (s, 1H), 9,36 (s, 1H) MS: 521 DMSO-d6: 0.94 (d, 6H), 3.12 (t, 4H), 3.25-3.35 (m, 1H), 3.75 (t, 4H), 6.73 (dd, 1H), 6.85 (dd, 1H), 7.16-7.24 (m, 1H), 7.25-7.32 (m, 1H), 7.38-7.47 (m, 1H) , 7.8 (dd, 1H), 7.88 (d, 1H), 8.18 (s, 1H), 8.428.52 (m, 1H), 8.86 (s, 1H), 9.36 ( s, 1H)

19-26 19-26

EM: 565 DMSO-d6: 0,93 (d, 6H), 2,4-2,56 (m, 4H), 2,69 (t, 2H), 3,25-3,38 (m, 1H), 3,59 (t, 4H), 4,11 (t, 1H), 6,75 (dd, 1H), 6,93 (dd, 1H), 7,16-7,23 (m, 1H), 7,3-7,4 (m, 1H), 7,4-7,38 (m, 1H), 7,8 (dd, 1H), 7,88 (d, 1H), 8,19 (s, 1H), 8,36-8,5 (m, 1H), 8,92 (s, 1H), 9,34 (s, 1H) MS: 565 DMSO-d6: 0.93 (d, 6H), 2.4-2.56 (m, 4H), 2.69 (t, 2H), 3.25-3.38 (m, 1H), 3, 59 (t, 4H), 4.11 (t, 1H), 6.75 (dd, 1H), 6.93 (dd, 1H), 7.16-7.23 (m, 1H), 7.3 -7.4 (m, 1H), 7.4-7.38 (m, 1H), 7.8 (dd, 1H), 7.88 (d, 1H), 8.19 (s, 1H), 8.36-8.5 (m, 1H), 8.92 (s, 1H), 9.34 (s, 1H)

19-27* 19-27 *

EM: 614 DMSO-d6: 0,93 (d, 6H), 1,3-1,62 (m, 8H), 1,75-1,85 (m, sH), 2,26-2,4 (m, 1H), 2,42,58 (m, 4H), 3,28-3,38 (m, 1H), 3,683,78 (m, 5H), 6,42 (dd, 1H), 6,64 (d, 1H), 7,18-7,24 (m, 1H), 7,42-7,5 (m, 2H), 7,77 (d, 1H), 7,82 (dd, 1H), 8,13 (s, 1H), 8,17 (s, 1H), 8,4-8,5 (m, 1H), 9,36 (s, 1H) MS: 614 DMSO-d6: 0.93 (d, 6H), 1.3-1.62 (m, 8H), 1.75-1.85 (m, sH), 2.26-2.4 (m, 1H ), 2.42.58 (m, 4H), 3.28-3.38 (m, 1H), 3.683.78 (m, 5H), 6.42 (dd, 1H), 6.64 (d, 1H), 7.18-7.24 (m, 1H), 7.42-7.5 (m, 2H), 7.77 (d, 1H), 7.82 (dd, 1H), 8.13 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.36 (s, 1H)

19-28 19-28

Rf: 0,5 (MeOH:CH2Cl2 = 3:7) DMSO-d6: 0,93 (d, 6H), 1,6-1,7 (m, 2H), 1,88-1,98 (m, 2H), 2,17-2,35 (m, 5H), 2,6-2,73 (m, 2H), 3,25-3,4 (m, 1H), 4,344,44 (m, 1H), 6,75 (dd, 1H), 6,93 (dd, 1H), 7,16-7,23 (m, 1H), 7,29-7,36 (m, 1H), 7,37-7,47 (m, 1H), 7,8 (dd, 1H), 7,89 (d, 1H), 8,19 (s, 1H), 8,36-8,46 (m, 1H), 8,92 (s, 1H), 9,31 (s, 1H) Rf: 0.5 (MeOH: CH2Cl2 = 3: 7) DMSO-d6: 0.93 (d, 6H), 1.6-1.7 (m, 2H), 1.88-1.98 (m, 2H), 2.17-2.35 (m, 5H ), 2.6-2.73 (m, 2H), 3.25-3.4 (m, 1H), 4,344.44 (m, 1H), 6.75 (dd, 1H), 6.93 ( dd, 1H), 7.16-7.23 (m, 1H), 7.29-7.36 (m, 1H), 7.37-7.47 (m, 1H), 7.8 (dd, 1H), 7.89 (d, 1H), 8.19 (s, 1H), 8.36-8.46 (m, 1H), 8.92 (s, 1H), 9.31 (s, 1H )

19-29 19-29

EM: 577 DMSO-d6: 0,93 (d, 6H), 2,45-2,55 (m, 4H), 2,7 (t, 2H), 3,25-3,35 (m, 1H), 3,59 (t, 3H), 3,76 (s, 3H), 4,1 (t, 1H), 6,48 (dd, 1H), 6,65 (d, 1H), 7,18-7,24 (m, 1H), 7,47,5 (m, 2H), 7,82 (dd, 1H), 7,88 (d, 1H), 8,17 (s, 1H), 8,24 (s, 1H), 8,4-8,48 (m, 1H), 9,31 (s, 1H) MS: 577 DMSO-d6: 0.93 (d, 6H), 2.45-2.55 (m, 4H), 2.7 (t, 2H), 3.25-3.35 (m, 1H), 3, 59 (t, 3H), 3.76 (s, 3H), 4.1 (t, 1H), 6.48 (dd, 1H), 6.65 (d, 1H), 7.18-7.24 (m, 1H), 7.47.5 (m, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.4-8.48 (m, 1H), 9.31 (s, 1H)

19-30* 19-30 *

EM: 590 DMSO-d6: 0,93 (d, 6H), 2,15 (s, 3H), 2,22,4 (m, 4H), 2,4-2,6 (m, 4H), 2,69 (t, 2H), 3,25-3,35 (m, 1H), 3,75 (s, 3H), 4,08 (t, 2H), 6,47 (dd, 1H), 6,64 (d, 1H), 7,187,24 (m, 1H), 7,41-7,49 (m, 2H), 7,81 (dd, 1H), 7,86-7,91 (m, 1H), 8,17 (s, 1H), 8,24 (s, 1H), 8,39-8,46 (m, 1H), 9,31 (s, 1H) MS: 590 DMSO-d6: 0.93 (d, 6H), 2.15 (s, 3H), 2.22.4 (m, 4H), 2.4-2.6 (m, 4H), 2.69 ( t, 2H), 3.25-3.35 (m, 1H), 3.75 (s, 3H), 4.08 (t, 2H), 6.47 (dd, 1H), 6.64 (d , 1H), 7,187.24 (m, 1H), 7.41-7.49 (m, 2H), 7.81 (dd, 1H), 7.86-7.91 (m, 1H), 8, 17 (s, 1H), 8.24 (s, 1H), 8.39-8.46 (m, 1H), 9.31 (s, 1H)

19-31* 19-31 *

EM: 588 DMSO-d6: 0,94 (d, 6H), 2,19-2,36 (m, 4H), 2,66-2,85 (m, 3H), 3,15-3,21-(m, 1H), 3,73-3,8 (m, 5H), 6,43 (dd, 1H), 6,63 (d, 1H), 7,18-7,25 (m, 1H), 7,4 (d, 1H), 7,43-7,5 (m, 1H), 7,81 (dd, 1H), 7,89 (d, 1H), 8,16 (s, 1H), 8,17 (s, 1H), 8,42-8,52 (m, 1H), 9,32 (s, 1H) MS: 588 DMSO-d6: 0.94 (d, 6H), 2.19-2.36 (m, 4H), 2.66-2.85 (m, 3H), 3.15-3.21- (m, 1H), 3.73-3.8 (m, 5H), 6.43 (dd, 1H), 6.63 (d, 1H), 7.18-7.25 (m, 1H), 7.4 (d, 1H), 7.43-7.5 (m, 1H), 7.81 (dd, 1H), 7.89 (d, 1H), 8.16 (s, 1H), 8.17 ( s, 1H), 8.42-8.52 (m, 1H), 9.32 (s, 1H)

19-32* 19-32 *

EM: 560 CDCl3: 1,01 (s, 6H), 1,45-1,56 (m, 2H), 2,03-2,11 (m, 2H), 2,11-2,2 (m, 2H), 2,31 (s, 3H), 2,78-2,87 (m, 2H), 3,22-3,31 (m, 1H), 3,39-3,5 (m, 1H), 3,82 (s, 3H), 4,54,6 (m, 1H), 6,13 (dd, 1H), 6,21 (d, 1H), 7,16 (s, 1H), 7,18-7,24 (m, 1H), 7,5-7,57 (m, 1H), 7,82 (d, 1H), 7,97 (dd, 1H), 8,16 (s, 1H), 8,08 (s, 1H), 8,46 (d, 1H), 8,92 (s, 1H) MS: 560 CDCl3: 1.01 (s, 6H), 1.45-1.56 (m, 2H), 2.03-2.11 (m, 2H), 2.11-2.2 (m, 2H), 2.31 (s, 3H), 2.78-2.87 (m, 2H), 3.22-3.31 (m, 1H), 3.39-3.5 (m, 1H), 3, 82 (s, 3H), 4.54.6 (m, 1H), 6.13 (dd, 1H), 6.21 (d, 1H), 7.16 (s, 1H), 7.18-7 , 24 (m, 1H), 7.5-7.57 (m, 1H), 7.82 (d, 1H), 7.97 (dd, 1H), 8.16 (s, 1H), 8, 08 (s, 1H), 8.46 (d, 1H), 8.92 (s, 1H)

[0120] Las siguientes 2-[5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-metil-bencenosulfonamidas, que abarcan ejemplos de la invención y ejemplos de referencia, se preparan a partir de 2-(5-cloro-2-cloro-pirimidin-4ilamino)-N-metil-bencenosulfonamida y la anilina correspondiente según el procedimiento del ejemplo de referencia [0120] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-methyl-benzenesulfonamides, encompassing examples of the invention and reference examples, are prepared from 2 - (5-Chloro-2-chloro-pyrimidin-4-lamino) -N-methyl-benzenesulfonamide and the corresponding aniline according to the procedure of the reference example

5 7A. (Un (*) marca un ejemplo de referencia). 5 7A. (A (*) mark a reference example).

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

20-1 20-1

0,50 (AcOEt) CDCl3: 2,63 (d, 3H), 3,14 (t, 4H), 3,873,90 (m, 7H), 4,64 (m, 1H), 6,45 (dd, 1H), 6,55 (d, 1H), 7,23-7,26 (m, 1H), 7,51-7,55 (m, 1H), 7,91 (d, 1H), 7,95 (dd, 1H), 8,06 (s, 1H), 8,47 (d, 1H), 9,26 (s, 1H) 0.50 (AcOEt) CDCl3: 2.63 (d, 3H), 3.14 (t, 4H), 3.873.90 (m, 7H), 4.64 (m, 1H), 6.45 (dd, 1H), 6.55 (d, 1H), 7.23-7.26 (m, 1H), 7.51-7.55 (m, 1H), 7.91 (d, 1H), 7.95 (dd, 1H), 8.06 (s, 1H), 8.47 (d, 1H), 9.26 (s, 1H)

20-2* 20-2 *

m/z 546, 548 (M+1) DMSO-d6: 2,06 (s, 3H), 2,43 (s, 3H), 3,10 (m, 2H), 3,16 (m, 2H), 3,59-3,62 (m, 4H), 3,77 (s, 3H), 6,49 (dd, 1H), 6,68 (d, 1H), 7,21-7,25 (m, 1H), 7,42 (d, 1H), 7,49 (dd, 1H), 7,75-7,77 (m, 1H), 7,78 (s, 1H), 8,16 (s, 1H), 8,21 (s, 1H), 8,50 (d, 1H), 9,35 (s, 1H) m / z 546, 548 (M + 1) DMSO-d6: 2.06 (s, 3H), 2.43 (s, 3H), 3.10 (m, 2H), 3.16 (m, 2H), 3.59-3.62 (m, 4H), 3.77 (s, 3H), 6.49 (dd, 1H), 6.68 (d, 1H), 7.21-7.25 (m, 1H), 7.42 (d, 1H ), 7.49 (dd, 1H), 7.75-7.77 (m, 1H), 7.78 (s, 1H), 8.16 (s, 1H), 8.21 (s, 1H) , 8.50 (d, 1H), 9.35 (s, 1H)

20-3* 20-3 *

0,27 (n-hexano:AcOEt = 3:1) CDCl3: 2,65 (d, 3H), 4,45-4,49 (m, 1H), 6,99-7,04 (m, 1H), 7,17-7,28 (m, 4H), 7,56-7,60 (m, 1H), 7,96-7,98 (m, 1H), 8,18 (s, 1H), 8,31-8,34 (m, 1H), 8,418,44 (m, 1H), 9,14 (s, 1H) 0.27 (n-hexane: AcOEt = 3: 1) CDCl3: 2.65 (d, 3H), 4.45-4.49 (m, 1H), 6.99-7.04 (m, 1H), 7.17-7.28 (m, 4H), 7.56-7.60 (m, 1H), 7.96-7.98 (m, 1H), 8.18 (s, 1H), 8.31-8.34 (m, 1H), 8.418, 44 (m, 1H), 9.14 (s, 1H)

20-4* 20-4 *

0,27 (n-hexano:AcOEt = 3:1) CDCl3: 2,65 (d, 3H), 4,54-4,58 (m, 1H), 6,53 (dd, 1H), 6,98-7,02 (m, 1H), 7,117,15 (m, 2H), 7,24-7,28 (m, 1H), 7,35 (sa, 1H), 7,57-7,61 (m, 1H), 7,95-7,98 (m, 1H), 8,16 (s, 1H), 8,29-8,32 (m, 1H), 8,42-8,46 (m, 1H), 9,14 (s, 1H) 0.27 (n-hexane: AcOEt = 3: 1) CDCl3: 2.65 (d, 3H), 4.54-4.58 (m, 1H), 6.53 (dd, 1H), 6.98-7.02 (m, 1H), 7.117.15 ( m, 2H), 7.24-7.28 (m, 1H), 7.35 (sa, 1H), 7.57-7.61 (m, 1H), 7.95-7.98 (m, 1H), 8.16 (s, 1H), 8.29-8.32 (m, 1H), 8.42-8.46 (m, 1H), 9.14 (s, 1H)

20-5* 20-5 *

0,46 (MeOH:CH2Cl2 = 1:4) CDCl3: 1,95-2,00 (m, 5H), 2,29-2,37 (m, 1H), 2,62 (d, 3H), 3,20-3,78 (m, 4H), 3,86 (s, 3H), 4,60-4,64 (m, 2H), 5,685,69 (m, 1H), 6,09-6,16 (m, 2H), 7,15 (sa, 1H), 7,19-7,23 (m, 1H), 7,54-7,58 (m, 1H), 7,88-7,95 (m, 2H), 8,06 (s, 1H), 8,55-8,57 (m, 1H), 9,08 (s, 1H) 0.46 (MeOH: CH2Cl2 = 1: 4) CDCl3: 1.95-2.00 (m, 5H), 2.29-2.37 (m, 1H), 2.62 (d, 3H), 3.20-3.78 (m, 4H), 3.86 (s, 3H), 4.60-4.64 (m, 2H), 5,685.69 (m, 1H), 6.09-6.16 (m, 2H), 7.15 (sa, 1H), 7.19-7.23 (m, 1H), 7.54-7.58 (m, 1H), 7.88-7.95 (m, 2H), 8.06 (s, 1H) , 8.55-8.57 (m, 1H), 9.08 (s, 1H)

20-6 20-6

518 [M+1]+ DMSO-d6: 2,23 (s, 3H), 2,43 (s, 3H), 2,45-2,50 (m, 4H), 3,12-3,17 (m, 4H), 3,76 (s, 3H), 6,45 (dd, 1H), 6,63 (d, 1H), 7,22 (dd, 1H), 7,37 (d, 1H), 7,45-7,50 (m, 1H), 7,74-7,78 (m, 1H), 7,76 (d, 1H), 8,15 (s, 1H), 8,19 (s, 1H), 8,468,53 (m, 1H), 9,35 (sa, 1H) 518 [M + 1] + DMSO-d6: 2.23 (s, 3H), 2.43 (s, 3H), 2.45-2.50 (m, 4H), 3.12-3.17 (m, 4H), 3, 76 (s, 3H), 6.45 (dd, 1H), 6.63 (d, 1H), 7.22 (dd, 1H), 7.37 (d, 1H), 7.45-7.50 (m, 1H), 7.74-7.78 (m, 1H), 7.76 (d, 1H), 8.15 (s, 1H), 8.19 (s, 1H), 8.468.53 ( m, 1H), 9.35 (sa, 1H)

20-7 20-7

504 [M+1]+ DMSO-d6: 2,43 (s, 3H), 2,80-2,89 (m, 4H), 2,99-3,07 (m, 4H), 3,76 (s, 3H), 6,44 (dd, 1H), 6,61 (d, 1H), 7,18-7,24 (m, 1H), 7,37 (d, 1H), 7,44-7,50 (m, 1H), 7,76 (dd, 1H), 8,15 (s, 1H), 8,18 (s, 1H), 8,45-8,55 (m, 1H), 9,20-9,45 (m, 1H) 504 [M + 1] + DMSO-d6: 2.43 (s, 3H), 2.80-2.89 (m, 4H), 2.99-3.07 (m, 4H), 3.76 (s, 3H), 6, 44 (dd, 1H), 6.61 (d, 1H), 7.18-7.24 (m, 1H), 7.37 (d, 1H), 7.44-7.50 (m, 1H) , 7.76 (dd, 1H), 8.15 (s, 1H), 8.18 (s, 1H), 8.45-8.55 (m, 1H), 9.20-9.45 (m , 1 HOUR)

20-8* 20-8 *

586 [M+1]+ DMSO-d6: 1,35-1,43 (m, 2H), 1,45-1,61 (m, 6H), 1,75-1,85 (m, 2H), 2,30-2,40 (m, 1H), 2,43 (d, 3H), 2,42-2,55 (m, 4H), 2,60-2,70 (m, 2H), 3,68-3,77 (m, 2H), 3,75 (s, 3H), 6,45 (dd, 1H), 6,62 (d, 1H), 7,21 (dd, 1H), 7,36 (d, 1H), 7,437,51 (m, 1H), 7,73-7,81 (m, 1H), 7,75 (dd, 1H), 8,15 (s, 1H), 8,17 (s, 1H), 8,45-8,52 (m, 1H), 9,34 (sa, 1H) 586 [M + 1] + DMSO-d6: 1.35-1.43 (m, 2H), 1.45-1.61 (m, 6H), 1.75-1.85 (m, 2H), 2.30-2.40 (m, 1H), 2.43 (d, 3H), 2.42-2.55 (m, 4H), 2.60-2.70 (m, 2H), 3.68-3.77 (m , 2H), 3.75 (s, 3H), 6.45 (dd, 1H), 6.62 (d, 1H), 7.21 (dd, 1H), 7.36 (d, 1H), 7.437 , 51 (m, 1H), 7.73-7.81 (m, 1H), 7.75 (dd, 1H), 8.15 (s, 1H), 8.17 (s, 1H), 8, 45-8.52 (m, 1H), 9.34 (sa, 1H)

20-9* 20-9 *

569 [M+1]+ DMSO-d6: 1,85-1,95 (m, 2H), 2,15 (s, 3H), 2,18 (t, 2H), 2,22-2,40 (m, 8H), 2,43 (s, 3H), 4,17 (t, 2H), 6,65 (d, 1H), 7,06 (dd, 1H), 7,20 (d, 1H), 7,22 (ddd, 1H), 7,25 (d, 1H), 7,39-7,47 (m, 2H), 7,72-7,82 (m, 1H), 7,77 (dd, 1H), 8,26 (s, 1H), 8,52 (d, 1H), 9,22 (s, 1H), 9,36 (s, 1H) 569 [M + 1] + DMSO-d6: 1.85-1.95 (m, 2H), 2.15 (s, 3H), 2.18 (t, 2H), 2.22-2.40 (m, 8H), 2, 43 (s, 3H), 4.17 (t, 2H), 6.65 (d, 1H), 7.06 (dd, 1H), 7.20 (d, 1H), 7.22 (ddd, 1H ), 7.25 (d, 1H), 7.39-7.47 (m, 2H), 7.72-7.82 (m, 1H), 7.77 (dd, 1H), 8.26 ( s, 1H), 8.52 (d, 1H), 9.22 (s, 1H), 9.36 (s, 1H)

20-10* 20-10 *

556 [M+1]+ DMSO-d6: 1,85-1,95 (m, 2H), 2,19 (t, 2H), 2,25-2,35 (m, 4H), 2,43 (s, 3H), 3,55-3,60 (m, 4H), 4,19 (t, 2H), 6,66 (d, 1H), 7,06 (dd, 1H), 7,17-7,24 (m, 1H), 7,21 (d, 1H), 7,27 (d, 1H), 7,39-7,45 (m, 1H), 7,44 (d, 1H), 7,70-7,80 (m, 1H), 7,76 (dd, 1H), 8,26 (s, 1H), 8,52 (d, 1H), 9,21 (s, 1H), 9,36 (s, 1H) 556 [M + 1] + DMSO-d6: 1.85-1.95 (m, 2H), 2.19 (t, 2H), 2.25-2.35 (m, 4H), 2.43 (s, 3H), 3, 55-3.60 (m, 4H), 4.19 (t, 2H), 6.66 (d, 1H), 7.06 (dd, 1H), 7.17-7.24 (m, 1H) , 7.21 (d, 1H), 7.27 (d, 1H), 7.39-7.45 (m, 1H), 7.44 (d, 1H), 7.70-7.80 (m , 1H), 7.76 (dd, 1H), 8.26 (s, 1H), 8.52 (d, 1H), 9.21 (s, 1H), 9.36 (s, 1H)

20-11 20-11

Rf (hexano:AcOEt = 1:1) 0,29 DMSO-d6: 2,64 (d, 3H), 2,87-2,96 (m, 4H), 3,65-3,74 (m, 4H), 3,86 (s, 3H), 4,41-4,51 (m, 1H), 6,50 (dd, 1H), 6,81 (d, 1H), 7,55-7,64 (m, 2H), 7,96 (d, 1H), 8,01 (s, 1H), 8,19 (s, 1H), 8,49 (d, 1H), 9,07 (s, 1H) Rf (hexane: AcOEt = 1: 1) 0.29 DMSO-d6: 2.64 (d, 3H), 2.87-2.96 (m, 4H), 3.65-3.74 (m, 4H), 3.86 (s, 3H), 4, 41-4.51 (m, 1H), 6.50 (dd, 1H), 6.81 (d, 1H), 7.55-7.64 (m, 2H), 7.96 (d, 1H) , 8.01 (s, 1H), 8.19 (s, 1H), 8.49 (d, 1H), 9.07 (s, 1H)

20-12 20-12

EM 535 DMSO-d6: 2,64 (d, 3H), 3,05 (sa, 4H), 3,59 (sa, 3H), 3,87 (sa, 3H), 3,89 (sa, 4H), 4,52-4,48 (m, 1H), 6,57 (sa, 1H), 7,25-7,20 (m, 1H), 7,44-7,32 (m, 1H), 7,63-7,52 (m, 1H), 7,94 (sa, 1H), 8,06 (d, 1H), 8,25 (s, 1H), 8,48 (d, 1H), 9,06 (sa, 1H) MS 535 DMSO-d6: 2.64 (d, 3H), 3.05 (sa, 4H), 3.59 (sa, 3H), 3.87 (sa, 3H), 3.89 (sa, 4H), 4 , 52-4.48 (m, 1H), 6.57 (sa, 1H), 7.25-7.20 (m, 1H), 7.44-7.32 (m, 1H), 7.63 -7.52 (m, 1H), 7.94 (sa, 1H), 8.06 (d, 1H), 8.25 (s, 1H), 8.48 (d, 1H), 9.06 ( sa, 1H)

20-13 20-13

EM 548 DMSO-d6: 2,17 (sa, 3H), 2,63 (d, 3H), 2,68 (sa, 4H), 3,10 (sa, 4H), 3,57 (s, 3H), 4,54-4,46 (m, 1H), 6,59 (sa, 1H), 7,27-7,18 (m, 1H), 7,37 (sa, 1H), 7,627,55 (m, 1H), 7,94 (sa, 1H), 7,95 (d, 1H), 8,16 (s, 1H), 8,48 (d, 1H), 9,04 (sa, 1H) MS 548 DMSO-d6: 2.17 (sa, 3H), 2.63 (d, 3H), 2.68 (sa, 4H), 3.10 (sa, 4H), 3.57 (s, 3H), 4 , 54-4.46 (m, 1H), 6.59 (sa, 1H), 7.27-7.18 (m, 1H), 7.37 (sa, 1H), 7.627.55 (m, 1H ), 7.94 (sa, 1H), 7.95 (d, 1H), 8.16 (s, 1H), 8.48 (d, 1H), 9.04 (sa, 1H)

20-14* 20-14 *

EM 546 DMSO-d6: 1,06 (t, 3H), 1,86 (dd, 2H), 2,37 (s, 3H), 2,62-2,59 (m, 4H), 2,64 (d, 3H), 4,00-3,97 (m, 4H), 4,62-4,54 (m, 1H), 6,44 (dd, 1H), 6,54 (d, 1H), 7,277,22 (m, 1H), 7,34 (sa, 1H), 7,58-7,54 (m, 1H), 7,95 (dd, 1H), 8,02 (d, 1H), 8,11 (s, 1H), 8,53 (d, 1H), 9,07 (sa, 1H) MS 546 DMSO-d6: 1.06 (t, 3H), 1.86 (dd, 2H), 2.37 (s, 3H), 2.62-2.59 (m, 4H), 2.64 (d, 3H), 4.00-3.97 (m, 4H), 4.62-4.54 (m, 1H), 6.44 (dd, 1H), 6.54 (d, 1H), 7.277.22 (m, 1H), 7.34 (sa, 1H), 7.58-7.54 (m, 1H), 7.95 (dd, 1H), 8.02 (d, 1H), 8.11 ( s, 1H), 8.53 (d, 1H), 9.07 (sa, 1H)

20-15* 20-15 *

CL-EM 545 DMSO-d6: 1,46-1,62 (m, 2H), 1,72-1,79 (m, 1H), 1,82-1,90 (m, 1H), 2,38-2,46 (m, 1H), 2,43 (s, 3H), 2,62-2,76 (m, 2H), 3,59-3,69 (m, 2H), 3,43 (s, 3H), 6,47 (dd, 1H), 6,63 (d, 1H), 6,82-6,89 (a, 1H), 7,21 (dd, 1H), 7,32-7,41 (m, 2H), 7,44-7,52 (m, 1H), 7,71-7,82 (m, 2H), 8,15 (s, 1H), 8,15-8,20 (a, 1H), 8,44-8,53 (m, 1H), 9,28-9,38 (m, 1H) CL-EM 545 DMSO-d6: 1.46-1.62 (m, 2H), 1.72-1.79 (m, 1H), 1.82-1.90 (m, 1H), 2.38-2.46 (m, 1H), 2.43 (s, 3H), 2.62-2.76 (m, 2H), 3.59-3.69 (m, 2H), 3.43 (s, 3H), 6.47 (dd, 1H), 6.63 (d, 1H), 6.82-6.89 (a, 1H), 7.21 (dd, 1H), 7.32-7.41 (m, 2H), 7.44-7.52 (m, 1H), 7.71-7.82 (m, 2H), 8.15 (s, 1H), 8.15-8.20 (a, 1H) , 8.44-8.53 (m, 1H), 9.28-9.38 (m, 1H)

20-16* 20-16 *

0,24 (CH2Cl2:MeOH = 8:2) DMSO-d6: 1,47-1,55 (m, 2H), 1,80-1,91 (m, 2H), 2,16 (s, 3H), 2,25-2,41 (m, 5H), 2,42-2,48 (m, 3H), 2,61-2,73 (m, 2H), 3,68-3,79 (m, 5H), 6,45 (dd, 1H), 6,62 (d, 1H), 7,21 (dd, 1H), 7,34 (d, 1H), 7,45-7,49 (m, 1H), 7,73-7,80 (m, 2H), 8,15 (s, 1H), 8,20 (s, 1H), 8,458,54 (m, 1H), 9,34 (s, 1H) 0.24 (CH2Cl2: MeOH = 8: 2) DMSO-d6: 1.47-1.55 (m, 2H), 1.80-1.91 (m, 2H), 2.16 (s, 3H), 2.25-2.41 (m, 5H ), 2.42-2.48 (m, 3H), 2.61-2.73 (m, 2H), 3.68-3.79 (m, 5H), 6.45 (dd, 1H), 6.62 (d, 1H), 7.21 (dd, 1H), 7.34 (d, 1H), 7.45-7.49 (m, 1H), 7.73-7.80 (m, 2H), 8.15 (s, 1H), 8.20 (s, 1H), 8.458.54 (m, 1H), 9.34 (s, 1H)

20-17* 20-17 *

CL-EM 518 DMSO-d6: 1,76-1,84 (m, 1H), 2,08-2,16 (m, 1H), 2,33 (s, 3H), 2,42 (s, 3H), 3,003,03 (m, 1H), 3,23-3,27 (m, 3H), 3,423,46 (m, 1H), 3,74 (s, 3H), 6,06 (dd, 1H), 6,18-6,20 (m, 1H), 7,17-7,23 (m, 1H), 7,38-7,48 (a, 1H), 7,72-7,77 (m, 1H), 8,12 (s, 1H), 8,17-8,21 (a, 1H), 8,46-8,58 (a, 1H), 9,30-9,40 (a, 1H) CL-EM 518 DMSO-d6: 1.76-1.84 (m, 1H), 2.08-2.16 (m, 1H), 2.33 (s, 3H), 2.42 (s, 3H), 3.003, 03 (m, 1H), 3.23-3.27 (m, 3H), 3,423.46 (m, 1H), 3.74 (s, 3H), 6.06 (dd, 1H), 6.18 -6.20 (m, 1H), 7.17-7.23 (m, 1H), 7.38-7.48 (a, 1H), 7.72-7.77 (m, 1H), 8 , 12 (s, 1H), 8.17-8.21 (a, 1H), 8.46-8.58 (a, 1H), 9.30-9.40 (a, 1H)

20-18 20-18

CL-EM 601 DMSO-d6: 1,36-1,49 (m, 2H), 1,69-1,76 (m, 2H), 2,13 (s, 3H), 2,15-2,23 (m, 1H), 2,24-2,36 (a, 4H), 2,39-2,48 (m, 5H), 2,43 (s, 3H), 3,27-3,40 (m, 2H), 3,74 (s, 3H), 6,62 (dd, 1H), 6,90 (d, 1H), 7,22-7,26 (m, 1H), 7,41-7,46 (m, 1H), 7,49-7,53 (m, 1H), 7,55-7,86 (a, 1H), 7,77 (dd, 1H), 8,16 (s, 1H), 8,25 (s, 1H), 8,42 (d, 1H), 9,28 (s, 1H) CL-EM 601 DMSO-d6: 1.36-1.49 (m, 2H), 1.69-1.76 (m, 2H), 2.13 (s, 3H), 2.15-2.23 (m, 1H ), 2.24-2.36 (a, 4H), 2.39-2.48 (m, 5H), 2.43 (s, 3H), 3.27-3.40 (m, 2H), 3.74 (s, 3H), 6.62 (dd, 1H), 6.90 (d, 1H), 7.22-7.26 (m, 1H), 7.41-7.46 (m, 1H), 7.49-7.53 (m, 1H), 7.55-7.86 (a, 1H), 7.77 (dd, 1H), 8.16 (s, 1H), 8.25 (s, 1H), 8.42 (d, 1H), 9.28 (s, 1H)

20-19* 20-19 *

CL-EM 519 DMSO-d6: 1,37-1,46 (m, 2H), 1,69-1,75 (m, 2H), 2,43 (s, 3H), 2,53-2,61 (m, 2H), 3,18-3,26 (m, 2H), 3,40-3,74 (m, 2H), 4,62 (d, 1H), 6,62 (dd, 1H), 6,90 (d, 1H), 7,22-7,26 (m, 1H), 7,42-7,46 (a, 1H), 7,48-7,55 (m, 1H), 7,77-7,80 (m, 2H), 8,13-8,18 (a, 1H), 8,25 (s, 1H), 8,40-8,45 (m, 1H), 9,25-9,30 (m, 1H) CL-EM 519 DMSO-d6: 1.37-1.46 (m, 2H), 1.69-1.75 (m, 2H), 2.43 (s, 3H), 2.53-2.61 (m, 2H ), 3.18-3.26 (m, 2H), 3.40-3.74 (m, 2H), 4.62 (d, 1H), 6.62 (dd, 1H), 6.90 ( d, 1H), 7.22-7.26 (m, 1H), 7.42-7.46 (a, 1H), 7.48-7.55 (m, 1H), 7.77-7, 80 (m, 2H), 8.13-8.18 (a, 1H), 8.25 (s, 1H), 8.40-8.45 (m, 1H), 9.25-9.30 ( m, 1H)

20-20* 20-20 *

CL-EM 532 DMSO-d6: 1,66-1,76 (m, 1H), 2,00-2,07 (m, 1H), 2,14 (s, 6H), 2,43 (s, 3H), 2,682,76 (m, 1H), 2,87-2,91 (m, 1H), 2,993,10 (m, 2H), 3,24-3,28 (m, 1H), 3,71 (s, 3H), 6,25 (dd, 1H), 6,90 (d, 1H), 7,00-7,03 (m, 1H), 7,21-7,24 (m, 1H), 7,40-7,45 (m, 1H), 7,78-7,83 (m, 2H), 8,19 (s, 1H), 8,24 (s, 1H), 8,46 (d, 1H), 9,27-9,36 (a, 1H) CL-EM 532 DMSO-d6: 1.66-1.76 (m, 1H), 2.00-2.07 (m, 1H), 2.14 (s, 6H), 2.43 (s, 3H), 2.682, 76 (m, 1H), 2.87-2.91 (m, 1H), 2,993.10 (m, 2H), 3.24-3.28 (m, 1H), 3.71 (s, 3H) , 6.25 (dd, 1H), 6.90 (d, 1H), 7.00-7.03 (m, 1H), 7.21-7.24 (m, 1H), 7.40-7 , 45 (m, 1H), 7.78-7.83 (m, 2H), 8.19 (s, 1H), 8.24 (s, 1H), 8.46 (d, 1H), 9, 27-9.36 (a, 1H)

20-21 20-21

EM: 549 DMSO-d6: 2,37-2,47 (m, 4H), 2,48-2,53 (m, 3H), 2,64 (t, 2H), 3,57 (t, 3H), 3,77 (s, 3H), 3,92 (t, 2H), 6,61 (dd, 1H), 6,93 (d, 1H), 7,28 (dd, 1H), 7,56-7,63 (m, 2H), 7,75-7,85 (m, 2H), 7,74-7,84 (m, 2H), 8,14 (s, 1H), 8,29 (s, 1H), 8,46 (d, 1H), 9,33 (s, 1H) MS: 549 DMSO-d6: 2.37-2.47 (m, 4H), 2.48-2.53 (m, 3H), 2.64 (t, 2H), 3.57 (t, 3H), 3, 77 (s, 3H), 3.92 (t, 2H), 6.61 (dd, 1H), 6.93 (d, 1H), 7.28 (dd, 1H), 7.56-7.63 (m, 2H), 7.75-7.85 (m, 2H), 7.74-7.84 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H), 8.46 (d, 1H), 9.33 (s, 1H)

20-22* 20-22 *

EM: 562 DMSO-d6: 2,20 (s, 3H), 2,3-2,5 (m, 11H), 2,64 (t, 2H), 3,77 (s, 3H), 3,91 (t, 2H), 6,61 (dd, 1H), 6,94 (d, 1H), 7,257,31 (m, 1H), 7,57 (d, 1H), 7,58-7,64 (m, 1H), 7,74-7,84 (m, 2H), 8,12 (sa, 1H), 8,28 (s, 1H), 8,46 (d, 1H), 9,33 (sa, 1H) MS: 562 DMSO-d6: 2.20 (s, 3H), 2.3-2.5 (m, 11H), 2.64 (t, 2H), 3.77 (s, 3H), 3.91 (t, 2H), 6.61 (dd, 1H), 6.94 (d, 1H), 7.257.31 (m, 1H), 7.57 (d, 1H), 7.58-7.64 (m, 1H ), 7.74-7.84 (m, 2H), 8.12 (sa, 1H), 8.28 (s, 1H), 8.46 (d, 1H), 9.33 (sa, 1H)

20-23 20-23

EM: 438 DMSO-d6: 2,42-2,45 (m, 3H), 3,83 (s, 2H), 6,83 (ddd, 1H), 7,02 (dd, 1H), 7,37,36 (m, 1H), 7,58-7,64 (m, 1H), 7,747,8 (m, 1H), 7,82 (dd, 1H), 7,85 (dd, 1H), 8,18 (sa, 1H), 8,31 (s, 1H), 8,41 (d, 1H), 9,3 (sa, 1H) MS: 438 DMSO-d6: 2.42-2.45 (m, 3H), 3.83 (s, 2H), 6.83 (ddd, 1H), 7.02 (dd, 1H), 7.37.36 ( m, 1H), 7.58-7.64 (m, 1H), 7.747.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1H), 8.18 (sa , 1H), 8.31 (s, 1H), 8.41 (d, 1H), 9.3 (sa, 1H)

20-24 20-24

EM: 438 DMSO-d6: 2,41-2,45 (m, 3H), 3,79 (s, 2H), 6,74 (ddd, 1H), 7,0 (dd, 1H), 7,227,28 (m, 1H), 7,49-7,55 (m, 1H), 7,6 (dd, 1H), 7,75-7,8 (m, 2H), 8,21 (s, 1H), 8,37 (sa, 1H), 8,39-8,45 (m, 1H), 9,34 (sa, 1H) MS: 438 DMSO-d6: 2.41-2.45 (m, 3H), 3.79 (s, 2H), 6.74 (ddd, 1H), 7.0 (dd, 1H), 7.227.28 (m, 1H), 7.49-7.55 (m, 1H), 7.6 (dd, 1H), 7.75-7.8 (m, 2H), 8.21 (s, 1H), 8.37 (sa, 1H), 8.39-8.45 (m, 1H), 9.34 (sa, 1H)

20-25* 20-25 *

EM: 547 DMSO-d6: 1,24-1,38 (m, 2H), 1,64-1,8 (m, 3H), 1,83-1,92 (m, 2H), 2,16 (s, 3H), 2,41-2,45 (m, 3H), 2,76-2,83 (m, 2H), 3,75 (s, 3H), 3,84 (d, 2H), 6,48 (dd, 1H), 6,64 (d, 1H), 7,2-7,25 (m, 1H), 7,41 (d, 1H), 7,43-7,5 (m, 1H), 7,74-7,8 (m, 2H), 8,16 (s, 1H), 8,26 (sa, 1H), 8,44-8,5 (m, 1H), 9,34 (sa, 1H) MS: 547 DMSO-d6: 1.24-1.38 (m, 2H), 1.64-1.8 (m, 3H), 1.83-1.92 (m, 2H), 2.16 (s, 3H ), 2.41-2.45 (m, 3H), 2.76-2.83 (m, 2H), 3.75 (s, 3H), 3.84 (d, 2H), 6.48 ( dd, 1H), 6.64 (d, 1H), 7.2-7.25 (m, 1H), 7.41 (d, 1H), 7.43-7.5 (m, 1H), 7 , 74-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (sa, 1H), 8.44-8.5 (m, 1H), 9.34 (sa, 1H )

20-26* 20-26 *

EM: 547 DMSO-d6: 1,18-1,3 (m, 2H), 1,56-1,7 (m, 3H), 1,8-1,88 (m, 2H), 2,15 (s, 3H), 2,41-2,45 (m, 3H), 2,73-2,8 (m, 2H), 3,75 (s, 3H), 3,65 (d, 2H), 3,77 (s, 3H), 6,57 (dd, 1H), 6,93 (d, 1H), 7,25 (dd, 1H), 7,51-7,6 (m, 2H), 7,7-7,9 (m, 2H), 8,09 (sa, 1H), 8,28 (s, 1H), 8,45 (d, 1H), 9,31 (sa, 1H) MS: 547 DMSO-d6: 1.18-1.3 (m, 2H), 1.56-1.7 (m, 3H), 1.8-1.88 (m, 2H), 2.15 (s, 3H ), 2.41-2.45 (m, 3H), 2.73-2.8 (m, 2H), 3.75 (s, 3H), 3.65 (d, 2H), 3.77 ( s, 3H), 6.57 (dd, 1H), 6.93 (d, 1H), 7.25 (dd, 1H), 7.51-7.6 (m, 2H), 7.7-7 , 9 (m, 2H), 8.09 (sa, 1H), 8.28 (s, 1H), 8.45 (d, 1H), 9.31 (sa, 1H)

20-27 20-27

EM: 533 DMSO-d6: 1,62-1,72 (m, 2H), 1,9-1,99 (m, 2H), 2,3-2,35 (m, 5H), 2,41-2,45 (m, 3H), 2,64-2,74 (m, 2H), 3,75 (s, 3H), 4,35-4,43 (m, 1H), 6,52 (dd, 1H), 6,65 (d, 1H), 7,19-7,25 (m, 1H), 7,41 (d, 1H), 7,43-7,49 (m, 1H), 7,74-7,8 (m, 2H), 8,16 (s, 1H), 8,27 (sa, 1H), 8,42-8,5 (m, 1H), 9,34 (sa, 1H) MS: 533 DMSO-d6: 1.62-1.72 (m, 2H), 1.9-1.99 (m, 2H), 2.3-2.35 (m, 5H), 2.41-2.45 (m, 3H), 2.64-2.74 (m, 2H), 3.75 (s, 3H), 4.35-4.43 (m, 1H), 6.52 (dd, 1H), 6.65 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.43-7.49 (m, 1H), 7.74-7, 8 (m, 2H), 8.16 (s, 1H), 8.27 (sa, 1H), 8.42-8.5 (m, 1H), 9.34 (sa, 1H)

20-28* 20-28 *

EM: 547 DMSO-d6: 0,96-1,2 (m, 2H), 1,75-1,9 (m, 9H), 2,2-2,3 (m, 1H), 2,35-2,45 (m, 1H), 2,41-2,45 (m, 2H), 2,43 (d, 3H), 2,6-3,0 (m, 3H), 3,76 (s, 3H), 4,85-5,0 (m, 1H), 6,43-6,49 (m, 1H), 6,57-6,64 (m, 1H), 7,18-7,25 (m, 1H), 7,39-7,52 (m, 2H), 7,73-7,83 (m, 2H), 8,17 (s, 1H), 8,27 (sa, 1H), 8,44-8,51 (m, 1H), 9,35 (sa, 1H) MS: 547 DMSO-d6: 0.96-1.2 (m, 2H), 1.75-1.9 (m, 9H), 2.2-2.3 (m, 1H), 2.35-2.45 (m, 1H), 2.41-2.45 (m, 2H), 2.43 (d, 3H), 2.6-3.0 (m, 3H), 3.76 (s, 3H), 4.85-5.0 (m, 1H), 6.43-6.49 (m, 1H), 6.57-6.64 (m, 1H), 7.18-7.25 (m, 1H ), 7.39-7.52 (m, 2H), 7.73-7.83 (m, 2H), 8.17 (s, 1H), 8.27 (sa, 1H), 8.44- 8.51 (m, 1H), 9.35 (sa, 1H)

20-29* 20-29 *

EM: 519 DMSO-d6: 1,74-1,83 (m, 1H), 2,23-2,31 (m, 1H), 2,28 (s, 3H), 2,35-2,4 (m, 1H), 2,41-2,45 (m, 3H), 2,58-2,63 (m, 1H), 2,63-2,7 (m, 1H), 2,78-2,83 (m, 1H), 3,75 (s, 3H), 4,86-4,92 (m, 1H), 6,43 (dd, 1H), 6,58 (d, 1H), 7,19-7,25 (m, 1H), 7,41 (d, 1H), 7,44-7,51 (m, 1H), 7,73-7,83 (m, 2H), 8,16 (s, 1H), 8,26 (sa, 1H), 8,43-8,52 (m, 1H), 9,34 (sa, 1H) MS: 519 DMSO-d6: 1.74-1.83 (m, 1H), 2.23-2.31 (m, 1H), 2.28 (s, 3H), 2.35-2.4 (m, 1H ), 2.41-2.45 (m, 3H), 2.58-2.63 (m, 1H), 2.63-2.7 (m, 1H), 2.78-2.83 (m , 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.43 (dd, 1H), 6.58 (d, 1H), 7.19-7, 25 (m, 1H), 7.41 (d, 1H), 7.44-7.51 (m, 1H), 7.73-7.83 (m, 2H), 8.16 (s, 1H) , 8.26 (sa, 1H), 8.43-8.52 (m, 1H), 9.34 (sa, 1H)

20-30* 20-30 *

EM: 533 DMSO-d6: 1,04 (t, 3H), 1,74-1,82 (m, 1H), 2,23-2,33 (m, 1H), 2,47-2,5 (m, 6H), 2,62-2,72 (m, 2H), 2,8-2,87 (m, 1H), 3,75 (s, 3H), 4,86-4,92 (m, 1H), 6,44 (dd, 1H), 6,59 (d, 1H), 7,19-7,25 (m, 1H), 7,41 (d, 1H), 7,44-7,51 (m, 1H), 7,73-7,8 (m, 2H), 8,16 (s, 1H), 8,26 (sa, 1H), 8,44-8,51 (m, 1H), 9,34 (sa, 1H) MS: 533 DMSO-d6: 1.04 (t, 3H), 1.74-1.82 (m, 1H), 2.23-2.33 (m, 1H), 2.47-2.5 (m, 6H ), 2.62-2.72 (m, 2H), 2.8-2.87 (m, 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.44 (dd, 1H), 6.59 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.44-7.51 (m, 1H), 7.73-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (sa, 1H), 8.44-8.51 (m, 1H), 9.34 (sa, 1H)

20-31 20-31

EM: 518 DMSO-d6: 2,23 (s, 3H), 2,38-2,47 (m, 7H), 2,87-2,93 (m, 4H), 3,75 (s, 3H), 6,63 (dd, 1H), 6,93 (d, 1H), 7,22-7,28 (m, 1H), 7,42 (d, 1H), 7,48-7,54 (m, 1H), 7,76-7,84 (m, 1H), 8,2 (s, 1H), 8,25 (s, 1H), 8,43 (dd, 1H), 9,29 (s, 1H) MS: 518 DMSO-d6: 2.23 (s, 3H), 2.38-2.47 (m, 7H), 2.87-2.93 (m, 4H), 3.75 (s, 3H), 6, 63 (dd, 1H), 6.93 (d, 1H), 7.22-7.28 (m, 1H), 7.42 (d, 1H), 7.48-7.54 (m, 1H) , 7.76-7.84 (m, 1H), 8.2 (s, 1H), 8.25 (s, 1H), 8.43 (dd, 1H), 9.29 (s, 1H)

20-32* 20-32 *

EM: 586 DMSO-d6: 1,35-1,55 (m, 8H), 1,66-1,75 (m, 2H), 2,23 (s, 3H), 2,41-2,45 (m, 3H), 3,74 (s, 3H), 6,63 (dd, 1H), 6,91 (d, 1H), 7,21-7,28 (m, 1H), 7,44 (d, 1H), 7,48-7,54 (m, 1H), 7,76-7,87 (m, 1H), 8,16 (s, 1H), 8,25 (s, 1H), 8,43 (dd, 1H), 9,29 (s, 1H) MS: 586 DMSO-d6: 1.35-1.55 (m, 8H), 1.66-1.75 (m, 2H), 2.23 (s, 3H), 2.41-2.45 (m, 3H ), 3.74 (s, 3H), 6.63 (dd, 1H), 6.91 (d, 1H), 7.21-7.28 (m, 1H), 7.44 (d, 1H) , 7.48-7.54 (m, 1H), 7.76-7.87 (m, 1H), 8.16 (s, 1H), 8.25 (s, 1H), 8.43 (dd , 1H), 9.29 (s, 1H)

20-33* 20-33 *

EM: 518 DMSO-d6: 1,62-1,71 (m, 1H), 1,95-2,04 (m, 1H), 2,23-2,27 (m, 3H), 2,39-2,43 (m, 3H), 2,93-3,1 (m, 2H), 3,13-3,26 (m, 2H), 3,71 (s, 3H), 6,19 (dd, 1H), 6,88 (d, 1H), 7,07-7,13 (m, 1H), 7,13-7,2 (m, 1H), 7,4-7,48 (m, 1H), 7,75 (dd, 1H), 8,06 (sa, 1H), 8,18 (s, 1H), 8,4 (d, 1H) MS: 518 DMSO-d6: 1.62-1.71 (m, 1H), 1.95-2.04 (m, 1H), 2.23-2.27 (m, 3H), 2.39-2.43 (m, 3H), 2.93-3.1 (m, 2H), 3.13-3.26 (m, 2H), 3.71 (s, 3H), 6.19 (dd, 1H), 6.88 (d, 1H), 7.07-7.13 (m, 1H), 7.13-7.2 (m, 1H), 7.4-7.48 (m, 1H), 7, 75 (dd, 1H), 8.06 (sa, 1H), 8.18 (s, 1H), 8.4 (d, 1H)

20-34* 20-34 *

EM: 546 DMSO-d6: 2,02 (m, 1H), 2,42-2,46 (m, 3H), 2,71-2,91 (m, 4H), 3,44-3,51 (m, 4H), 3,76 (s, 3H), 6,66 (dd, 1H), 6,94 (d, 1H), 7,21-7,27 (m, 1H), 7,75-7,85 (m, 2H), 8,19 (s, 1H), 8,26 (s, 1H), 8,41 (d, 1H), 9,28 (sa, 1H) MS: 546 DMSO-d6: 2.02 (m, 1H), 2.42-2.46 (m, 3H), 2.71-2.91 (m, 4H), 3.44-3.51 (m, 4H ), 3.76 (s, 3H), 6.66 (dd, 1H), 6.94 (d, 1H), 7.21-7.27 (m, 1H), 7.75-7.85 ( m, 2H), 8.19 (s, 1H), 8.26 (s, 1H), 8.41 (d, 1H), 9.28 (sa, 1H)

20-35 20-35

EM (ESI) 464 (M+H) Tiempo de retención HPLC (min) 2,68 MS (ESI) 464 (M + H) HPLC retention time (min) 2.68

[0121] Las siguientes 2-[5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-sec.-butil-bencenosulfonamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(5-cloro-2-cloro-pirimidin-4ilamino)-N-sec.-butil-bencenosulfonamida y la anilina correspondiente según el procedimiento del ejemplo de [0121] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-sec.-butyl-benzenesulfonamides, which are all reference examples (marked with a (*)) , are prepared from 2- (5-chloro-2-chloro-pyrimidin-4-ylamino) -N-sec.-butyl-benzenesulfonamide and the corresponding aniline according to the procedure of the example of

5 referencia 7A: [0122] Las siguientes 2-[5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-isobutil-bencenosulfonamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(5-cloro-2-cloro-pirimidin-4ilamino)-N-sec.-butil-bencenosulfonamida y la anilina correspondiente según el procedimiento del ejemplo de 5 reference 7A: [0122] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-isobutyl-benzenesulfonamides, which are all reference examples (marked with a (*) ), are prepared from 2- (5-chloro-2-chloro-pyrimidin-4 -lamino) -N-sec.-butyl-benzenesulfonamide and the corresponding aniline according to the procedure of the example of

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

21-1* 21-1 *

0,35 (n-hexano:AcOEt = 1:1) CDCl3: 0,62, (t, 3H), 0,88 (d, 3H), 1,221,29 (m, 2H), 2,23 (s, 3H), 2,45-2,47 (m, 4H), 3,05-3,14 (m, 5H), 3,75 (s, 3H), 6,406,43 (m, 1H), 6,62 (s, 1H), 7,18-7,22 (m, 1H), 7,39-7,47 (m, 2H), 7,80-7,82 (m, 1H), 8,15-8,16 (m, 2H), 8,44-8,46 (m, 1H), 9,32 (s, 1H) 0.35 (n-hexane: AcOEt = 1: 1) CDCl3: 0.62, (t, 3H), 0.88 (d, 3H), 1,221.29 (m, 2H), 2.23 (s, 3H), 2.45-2.47 (m, 4H ), 3.05-3.14 (m, 5H), 3.75 (s, 3H), 6.406.43 (m, 1H), 6.62 (s, 1H), 7.18-7.22 ( m, 1H), 7.39-7.47 (m, 2H), 7.80-7.82 (m, 1H), 8.15-8.16 (m, 2H), 8.44-8, 46 (m, 1H), 9.32 (s, 1H)

21-2* 21-2 *

0,30 (n-hexano:AcOEt = 3:1) DMSO-d6: 0,62 (t, 3H), 0,87 (d, 3H), 1,171,26 (m, 2H), 3,03-3,10 (m, 1H), 3,79 (s, 3H), 6,66-6,71 (m, 1H), 6,96-7,00 (m, 1H), 7,21-7,25 (m, 1H), 7,47-7,51 (m, 1H), 7,60-7,64 (m, 1H), 7,79-7,83 (m, 2H), 8,21 (s, 1H), 8,31 (s, 1H), 8,35-8,37 (m, 1H), 9,29 (s, 1H) 0.30 (n-hexane: AcOEt = 3: 1) DMSO-d6: 0.62 (t, 3H), 0.87 (d, 3H), 1,171.26 (m, 2H), 3.03-3.10 (m, 1H), 3.79 (s, 3H), 6.66-6.71 (m, 1H), 6.96-7.00 (m, 1H), 7.21-7.25 (m, 1H), 7.47-7.51 ( m, 1H), 7.60-7.64 (m, 1H), 7.79-7.83 (m, 2H), 8.21 (s, 1H), 8.31 (s, 1H), 8 , 35-8.37 (m, 1H), 9.29 (s, 1H)

21-3* 21-3 *

0,30 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,61 (t, 3H), 0,87 (d, 3H), 1,211,29 (m, 2H), 1,58-1,67 (m, 2H), 1,86-1,93 (m, 2H), 2,14-2,20 (m, 5H), 2,59-2,67 (m, 2H), 3,06-3,08 (m, 1H), 3,74 (s, 3H), 4,324,36 (m, 1H), 6,46-6,48 (m, 1H), 6,63 (d, 1H), 7,17-7,21 (m, 1H), 7,40-7,50 (m, 2H), 7,79-7,81 (m, 2H), 8,16 (s, 1H), 8,21 (sa, 1H), 8,35-8,42 (m, 1H), 9,29 (s, 1H) 0.30 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.61 (t, 3H), 0.87 (d, 3H), 1,211.29 (m, 2H), 1.58-1.67 (m, 2H), 1.86-1, 93 (m, 2H), 2.14-2.20 (m, 5H), 2.59-2.67 (m, 2H), 3.06-3.08 (m, 1H), 3.74 ( s, 3H), 4,324.36 (m, 1H), 6.46-6.48 (m, 1H), 6.63 (d, 1H), 7.17-7.21 (m, 1H), 7 , 40-7.50 (m, 2H), 7.79-7.81 (m, 2H), 8.16 (s, 1H), 8.21 (sa, 1H), 8.35-8.42 (m, 1H), 9.29 (s, 1H)

21-4* 21-4 *

0,30 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,61 (t, 3H), 0,87 (d, 3H), 1,221,29 (m, 2H), 2,43-2,47 (m, 2H), 2,61-2,63 (m, 1H), 2,68-2,70 (m, 2H), 3,04-3,11 (m, 1H), 3,56-3,60 (m, 5H), 3,75 (s, 3H), 3,933,96 (m, 1H), 4,08-4,11 (m, 2H), 6,45-6,47 (m, 1H), 6,64 (d, 1H), 7,18-7,22 (m, 1H), 7,43-7,46 (m, 2H), 7,80-7,82 (m, 2H), 8,17 (s, 1H), 8,21 (s, 1H), 8,42-8,44 (m, 1H), 9,31 (s, 1H) 0.30 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.61 (t, 3H), 0.87 (d, 3H), 1,221.29 (m, 2H), 2.43-2.47 (m, 2H), 2.61-2, 63 (m, 1H), 2.68-2.70 (m, 2H), 3.04-3.11 (m, 1H), 3.56-3.60 (m, 5H), 3.75 ( s, 3H), 3,933.96 (m, 1H), 4.08-4.11 (m, 2H), 6.45-6.47 (m, 1H), 6.64 (d, 1H), 7 , 18-7.22 (m, 1H), 7.43-7.46 (m, 2H), 7.80-7.82 (m, 2H), 8.17 (s, 1H), 8.21 (s, 1H), 8.42-8.44 (m, 1H), 9.31 (s, 1H)

5 referencia 7A: 5 reference 7A:

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

22-1* 22-1 *

0,30 (n-hexano:AcOEt = 3:1) DMSO-d6: 0,69 (d, 6H), 1,52-1,59 (m, 1H), 2,57-2,58 (m, 2H), 3,82 (s, 3H), 6,75-6,80 (m, 1H), 6,99-7,02 (m, 1H), 7,29-7,33 (m, 1H), 7,56-7,60 (m, 1H), 7,82-7,93 (m, 3H), 8,14 (sa, 1H), 8,31 (s, 1H), 8,33 (s, 1H), 9,23 (s, 1H) 0.30 (n-hexane: AcOEt = 3: 1) DMSO-d6: 0.69 (d, 6H), 1.52-1.59 (m, 1H), 2.57-2.58 (m, 2H), 3.82 (s, 3H), 6, 75-6.80 (m, 1H), 6.99-7.02 (m, 1H), 7.29-7.33 (m, 1H), 7.56-7.60 (m, 1H), 7.82-7.93 (m, 3H), 8.14 (sa, 1H), 8.31 (s, 1H), 8.33 (s, 1H), 9.23 (s, 1H)

22-2* 22-2 *

0,30 (n-hexano:AcOEt = 3:1) CDCl3: 0,74 (d, 6H), 1,57-1,64 (m, 1H), 2,72-2,76 (m, 2H), 3,88 (s, 3H), 4,55-4,56 (m, 1H), 6,52-6,57 (m, 1H), 6,62-6,65 (m, 1H), 7,24-7,28 (m, 2H), 7,36 (sa, 1H), 7,56-7,60 (m, 1H), 7,95-8,08 (m, 1H), 8,10-8,14 (m, 2H), 8,36-8,39 (m, 1H), 8,98 (sa, 1H) 0.30 (n-hexane: AcOEt = 3: 1) CDCl3: 0.74 (d, 6H), 1.57-1.64 (m, 1H), 2.72-2.76 (m, 2H), 3.88 (s, 3H), 4.55- 4.56 (m, 1H), 6.52-6.57 (m, 1H), 6.62-6.65 (m, 1H), 7.24-7.28 (m, 2H), 7, 36 (sa, 1H), 7.56-7.60 (m, 1H), 7.95-8.08 (m, 1H), 8.10-8.14 (m, 2H), 8.36- 8.39 (m, 1H), 8.98 (sa, 1H)

22-3* 22-3 *

0,54 (AcOEt) DMSO-d6: 0,73 (d, 6H), 1,55-1,62 (m, 1H), 2,56-2,59 (m, 2H), 3,10-3,12 (m, 4H), 3,74-3,76 (m, 7H), 6,43-6,46 (m, 1H), 6,65 (d, 1H), 7,20-7,24 (m, 1H), 7,40-7,48 (m, 2H), 7,76-7,78 (m, 1H), 7,90-7,95 (m, 1H), 8,16 (s, 1H), 8,17(s, 1H), 8,43-8,45 (m, 1H), 9,32 (s, 1H) 0.54 (AcOEt) DMSO-d6: 0.73 (d, 6H), 1.55-1.62 (m, 1H), 2.56-2.59 (m, 2H), 3.10-3.12 (m, 4H ), 3.74-3.76 (m, 7H), 6.43-6.46 (m, 1H), 6.65 (d, 1H), 7.20-7.24 (m, 1H), 7.40-7.48 (m, 2H), 7.76-7.78 (m, 1H), 7.90-7.95 (m, 1H), 8.16 (s, 1H), 8, 17 (s, 1H), 8.43-8.45 (m, 1H), 9.32 (s, 1H)

[0123] Las siguientes 2-[5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-(1-etilpropil)-bencenosulfonamidas, [0123] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N- (1-ethylpropyl) -benzenesulfonamides,

10 que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(5-cloro-2-cloro-pirimidin-4ilamino)-N-(1-etilpropil)-bencenosulfonamida y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A: 10 which are all reference examples (marked with a (*)), are prepared from 2- (5-chloro-2-chloro-pyrimidin-4 -lamino) -N- (1-ethylpropyl) -benzenesulfonamide and the corresponding aniline according to the procedure of reference example 7A:

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm)

23-1* 23-1 *

0,46 (MeOH:CH2Cl2 = 3:7) DMSO-d6: 0,58 (t, 6H), 1,14-1,34 (m, 4H), 1,58-1,68 (m, 2H), 1,87-1,96 (m, 2H), 2,12-2,22 (m, 2H), 2,18 (s, 3H), 2,57-2,65 (m, 2H), 2,86-2,96 (m, 1H), 3,75 (s, 3H), 4,30-4,39 (m, 1H), 6,46 (dd, 1H), 6,63 (d, 1H), 7,19 (dd, 1H), 7,39-7,48 (m, 2H), 7,75-7,84 (m, 2H), 8,18 (s, 1H), 8,20 (s, 1H), 8,39 (m, 1H), 9,33 (sa, 1H) 0.46 (MeOH: CH2Cl2 = 3: 7) DMSO-d6: 0.58 (t, 6H), 1.14-1.34 (m, 4H), 1.58-1.68 (m, 2H), 1.87-1.96 (m, 2H ), 2.12-2.22 (m, 2H), 2.18 (s, 3H), 2.57-2.65 (m, 2H), 2.86-2.96 (m, 1H), 3.75 (s, 3H), 4.30-4.39 (m, 1H), 6.46 (dd, 1H), 6.63 (d, 1H), 7.19 (dd, 1H), 7 , 39-7.48 (m, 2H), 7.75-7.84 (m, 2H), 8.18 (s, 1H), 8.20 (s, 1H), 8.39 (m, 1H ), 9.33 (sa, 1H)

23-2* 23-2 *

0,35 (n-hexano:AcOEt = 1:1) CDCl3: 0,59 (t, 6H), 1,14-1,34 (m, 4H), 2,23 (s, 3H), 2,45-2,47 (m, 4H), 2,90-2,95 (m, 1H), 3,11-3,14 (m, 4H), 3,76 (s, 3H), 6,39-6,42 (m, 1H), 6,62 (s, 1H), 7,18-7,22 (m, 1H), 7,41-7,46 (m, 2H), 7,76-7,82 (m, 2H), 8,12 (s, 1H), 8,16 (s, 1H), 8,43-8,44 (m, 1H), 9,35 (s, 1H) 0.35 (n-hexane: AcOEt = 1: 1) CDCl3: 0.59 (t, 6H), 1.14-1.34 (m, 4H), 2.23 (s, 3H), 2.45-2.47 (m, 4H), 2.90- 2.95 (m, 1H), 3.11-3.14 (m, 4H), 3.76 (s, 3H), 6.39-6.42 (m, 1H), 6.62 (s, 1H), 7.18-7.22 (m, 1H), 7.41-7.46 (m, 2H), 7.76-7.82 (m, 2H), 8.12 (s, 1H) , 8.16 (s, 1H), 8.43-8.44 (m, 1H), 9.35 (s, 1H)

23-3* 23-3 *

0,41 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,59 (t, 6H), 1,16-1,35 (m, 4H), 1,75-1,89 (m, 1H), 2,08-2,15 (m, 1H), 2,32 (s, 3H), 2,90-3,02 (m, 2H), 3,21-3,45 (m, 4H), 3,73 (s, 3H), 6,02 (dd, 1H), 6,18 (d, 1H), 7,16 (dd, 1H), 7,27 (d, 1H), 7,357,45 (m, 1H), 7,77-7,82 (m, 2H), 8,10 (s, 1H), 8,12 (s, 1H), 8,45-8,55 (m, 1H), 9,38 (s, 1H) 0.41 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.59 (t, 6H), 1.16-1.35 (m, 4H), 1.75-1.89 (m, 1H), 2.08-2.15 (m, 1H ), 2.32 (s, 3H), 2.90-3.02 (m, 2H), 3.21-3.45 (m, 4H), 3.73 (s, 3H), 6.02 ( dd, 1H), 6.18 (d, 1H), 7.16 (dd, 1H), 7.27 (d, 1H), 7.357.45 (m, 1H), 7.77-7.82 (m , 2H), 8.10 (s, 1H), 8.12 (s, 1H), 8.45-8.55 (m, 1H), 9.38 (s, 1H)

23-4* 23-4 *

0,41 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 0,60 (t, 6H), 1,04 (t, 3H), 1,171,35 (m, 4H), 1,76-1,83 (m, 1H), 2,102,15 (m, 1H), 2,56-2,64 (m, 2H), 2,913,01 (m, 2H), 3,21-3,47 (m, 4H), 3,74 (s, 3H), 6,02 (dd, 1H), 6,18 (d, 1H), 7,147,17 (m, 1H), 7,28 (d, 1H), 7,35-7,45 (m, 1H), 7,77-7,82 (m, 2H), 8,11 (s, 1H), 8,12 (s, 1H), 8,45-8,55 (m, 1H), 9,38 (s, 1H) 0.41 (MeOH: CH2Cl2 = 1: 4) DMSO-d6: 0.60 (t, 6H), 1.04 (t, 3H), 1,171.35 (m, 4H), 1.76-1.83 (m, 1H), 2,102.15 (m, 1H), 2.56-2.64 (m, 2H), 2.913.01 (m, 2H), 3.21-3.47 (m, 4H), 3.74 (s, 3H), 6.02 (dd, 1H), 6.18 (d, 1H), 7.147.17 (m, 1H), 7.28 (d, 1H), 7.35-7.45 (m, 1H), 7.77- 7.82 (m, 2H), 8.11 (s, 1H), 8.12 (s, 1H), 8.45-8.55 (m, 1H), 9.38 (s, 1H)

23-5* 23-5 *

0,25 (n-hexano:AcOEt = 1:1) DMSO-d6: 0,58 (t, 6H), 1,06-2,16 (m, 1H), 2,16 (s, 3H), 2,62-2,67 (m, 1H), 2,81-2,94 (m, 2H), 3,75 (s, 3H), 3,80-3,89 (m, 2H), 6,41-6,44 (m, 1H), 6,62 (d, 1H), 7,17-7,21 (m, 1H), 7,42-7,47 (m, 2H), 7,77-7,82 (m, 2H), 8,18 (s, 1H), 8,19 (s, 1H), 8,35-8,42 (m, 1H), 9,35 (s, 1H) 0.25 (n-hexane: AcOEt = 1: 1) DMSO-d6: 0.58 (t, 6H), 1.06-2.16 (m, 1H), 2.16 (s, 3H), 2.62-2.67 (m, 1H), 2, 81-2.94 (m, 2H), 3.75 (s, 3H), 3.80-3.89 (m, 2H), 6.41-6.44 (m, 1H), 6.62 ( d, 1H), 7.17-7.21 (m, 1H), 7.42-7.47 (m, 2H), 7.77-7.82 (m, 2H), 8.18 (s, 1H), 8.19 (s, 1H), 8.35-8.42 (m, 1H), 9.35 (s, 1H)

23-6* 23-6 *

EM: 561 DMSO-d6: 0,59 (t, 6H), 1,14-1,38 (m, 4H), 2,87-2,98 (m, 1H), 3,1 (t, 4H), 3,72-3,79 (m, 7H), 6,42 (dd, 1H), 6,64 (d, 1H), 7,187,24 (m, 1H), 7,42-7,5 (m, 2H), 7,77 (d, 1H), 7,81 (dd, 1H), 8,13 (s, 1H), 8,17 (s, 1H), 8,4-8,5 (m, 1H), 9,36 (s, 1H) MS: 561 DMSO-d6: 0.59 (t, 6H), 1.14-1.38 (m, 4H), 2.87-2.98 (m, 1H), 3.1 (t, 4H), 3, 72-3.79 (m, 7H), 6.42 (dd, 1H), 6.64 (d, 1H), 7,187.24 (m, 1H), 7.42-7.5 (m, 2H) , 7.77 (d, 1H), 7.81 (dd, 1H), 8.13 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.36 (s, 1 H)

23-7* 23-7 *

EM: 575 DMSO-d6: 0,58 (t, 6H), 1,13-1,37 (m, 4H), 1,72-1,82 (m, 1H), 2,21-2,31 (m, 4H), 2,32-2,4 (m, 1H), 2,54-2,61 (m, 1H), 2,622,68 (m, 1H), 2,75-2,82 (m, 1H), 2,872,97 (m, 1H), 3,75 (s, 3H), 4,84-4,91 (m, 1H), 6,37 (dd, 1H), 6,56 (d, 1H), 7,147,24 (m, 1H), 7,38-7,52 (m, 2H), 7,727,86 (m, 1H), 8,12-8,25 (m, 2H), 8,348,45 (m, 1H), 9,33 (sa, 1H) MS: 575 DMSO-d6: 0.58 (t, 6H), 1.13-1.37 (m, 4H), 1.72-1.82 (m, 1H), 2.21-2.31 (m, 4H ), 2.32-2.4 (m, 1H), 2.54-2.61 (m, 1H), 2,622.68 (m, 1H), 2.75-2.82 (m, 1H), 2,872.97 (m, 1H), 3.75 (s, 3H), 4.84-4.91 (m, 1H), 6.37 (dd, 1H), 6.56 (d, 1H), 7.147 , 24 (m, 1H), 7.38-7.52 (m, 2H), 7,727.86 (m, 1H), 8.12-8.25 (m, 2H), 8,348.45 (m, 1H ), 9.33 (sa, 1H)

23-8* 23-8 *

EM: 605 DMSO-d6: 0,58 (t, 6H), 1,14-1,36 (m, 4H), 2,43-2,53 (m, 4H), 2,69 (t, 2H), 2,89-2,95 (m, 1H), 3,59 (t, 4H), 3,76 (s, 3H), 4,09 (t, 1H), 6,45 (dd, 1H), 6,64 (d, 1H), 7,177,23 (m, 1H), 7,41-7,52 (m, 2H), 7,78 (d, 1H), 7,81 (dd, 1H), 8,18 (s, 1H), 8,19 (s, 1H), 8,36-8,46 (m, 1H), 9,35 (s, 1H) MS: 605 DMSO-d6: 0.58 (t, 6H), 1.14-1.36 (m, 4H), 2.43-2.53 (m, 4H), 2.69 (t, 2H), 2, 89-2.95 (m, 1H), 3.59 (t, 4H), 3.76 (s, 3H), 4.09 (t, 1H), 6.45 (dd, 1H), 6.64 (d, 1H), 7,177.23 (m, 1H), 7.41-7.52 (m, 2H), 7.78 (d, 1H), 7.81 (dd, 1H), 8.18 ( s, 1H), 8.19 (s, 1H), 8.36-8.46 (m, 1H), 9.35 (s, 1H)

23-9* 23-9 *

EM: 618 DMSO-d6: 0,58 (t, 6H), 1,14-1,37 (m, 4H), 2,15 (s, 1H), 2,25-2,4 (m, 4H), 2,45-2,55 (m, 4H), 2,68 (t, 2H), 2,88-2,97 (m, 1H), 3,76 (s, 3H), 4,07 (t, 1H), 6,44 (dd, 1H), 6,64 (d, 1H), 7,15-7,23 (m, 1H), 7,41-7,51 (m, 2H), 7,7-7,84 (m, 2H), 8,12-8,22 (m, 1H), 8,34-8,44 (m, 1H), 9,34 (s, 1H) MS: 618 DMSO-d6: 0.58 (t, 6H), 1.14-1.37 (m, 4H), 2.15 (s, 1H), 2.25-2.4 (m, 4H), 2, 45-2.55 (m, 4H), 2.68 (t, 2H), 2.88-2.97 (m, 1H), 3.76 (s, 3H), 4.07 (t, 1H) , 6.44 (dd, 1H), 6.64 (d, 1H), 7.15-7.23 (m, 1H), 7.41-7.51 (m, 2H), 7.7-7 , 84 (m, 2H), 8.12-8.22 (m, 1H), 8.34-8.44 (m, 1H), 9.34 (s, 1H)

[0124] Las siguientes 2-[5-cloro-2-(fenilamino sust.)-pirimidin-4-ilamino]-N-isobutil-bencenosulfonamidas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de 2-(5-cloro-2-cloro-pirimidin-4ilamino)-N-ciclobutil-bencenosulfonamida y la anilina correspondiente según el procedimiento del ejemplo de [0124] The following 2- [5-chloro-2- (substituted phenylamino) -pyrimidin-4-ylamino] -N-isobutyl-benzenesulfonamides, which are all reference examples (marked with a (*)), are prepared from 2- (5-Chloro-2-chloro-pyrimidin-4-ylamino) -N-cyclobutyl-benzenesulfonamide and the corresponding aniline according to the procedure of the example of

5 referencia 7A: 5 reference 7A:

imagen11image11

Ej. nº Ex. Nº

Rx EM RMN (400 MHz), δ (ppm) Rx EM NMR (400 MHz), δ (ppm)

25-1* 25-1 *

EM: 559 DMSO-d6: 1,2-1,38 (m, 4H), 1,4-1,65 (m, 4H), 3,11 (t, 4H), 3,42-3,5 (m, 1H), 3,7-3,8 (m, 7H), 6,44 (dd, 1H), 6,64 (d, 1H), 7,18-7,26 (m, 1H), 7,38-7,5 (m, 2H), 7,81 (d, 1H), 7,88-7,96 (m, 1H), 8,16 (s, 1H), 8,17 (s, 1H), 8,4-8,5 (m, 1H), 9,34 (s, 1H) MS: 559 DMSO-d6: 1.2-1.38 (m, 4H), 1.4-1.65 (m, 4H), 3.11 (t, 4H), 3.42-3.5 (m, 1H ), 3.7-3.8 (m, 7H), 6.44 (dd, 1H), 6.64 (d, 1H), 7.18-7.26 (m, 1H), 7.38- 7.5 (m, 2H), 7.81 (d, 1H), 7.88-7.96 (m, 1H), 8.16 (s, 1H), 8.17 (s, 1H), 8 , 4-8.5 (m, 1H), 9.34 (s, 1H)

25-2* 25-2 *

EM: 587 DMSO-d6: 1,2-1,38 (m, 4H), 1,42-1,6 (m, 6H), 1,88-1,98 (m, 2H), 2,1-2,25 (m, 5H), 2,55-2,65 (m, 2H), 3,4-3,5 (m, 1H), 3,74 (s, 3H), 4,3-4,4 (m, 1H), 6,48 (dd, 1H), 6,63 (d, 1H), 7,18-7,24 (m, 1H), 7,38-7,47 (m, 1H), 7,77-7,82 (m, 1H), 7,88-7,96 (m, 1H), 8,17 (s, 1H), 8,22 (s, 1H), 8,36-8,46 (m, 1H), 9,31 (s, 1H) MS: 587 DMSO-d6: 1.2-1.38 (m, 4H), 1.42-1.6 (m, 6H), 1.88-1.98 (m, 2H), 2.1-2.25 (m, 5H), 2.55-2.65 (m, 2H), 3.4-3.5 (m, 1H), 3.74 (s, 3H), 4.3-4.4 (m , 1H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.18-7.24 (m, 1H), 7.38-7.47 (m, 1H), 7, 77-7.82 (m, 1H), 7.88-7.96 (m, 1H), 8.17 (s, 1H), 8.22 (s, 1H), 8.36-8.46 ( m, 1H), 9.31 (s, 1H)

[0125] Las siguientes 5-cloro-N2-(fenil sust.)-N4-[2-(propano-1-sulfonil)-fenil]-pirimidin-2,4-diaminas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de (2,5-dicloro-pirimidin-4-il)-[2-(propano-1sulfonil)-fenil]-amina y la anilina correspondiente según el procedimiento del ejemplo de referencia 7A: imagen1 [0125] The following 5-chloro-N2- (phenyl substitu) - N4- [2- (propane-1-sulfonyl) -phenyl] -pyrimidin-2,4-diamines, which are all reference examples (labeled with a (*)), are prepared from (2,5-dichloro-pyrimidin-4-yl) - [2- (propane-1sulfonyl) -phenyl] -amine and the corresponding aniline according to the procedure of reference example 7A : image 1

Ej. nº Ex. Nº

Rx Rf (disolvente), EM o p.f. RMN (400 MHz), δ (ppm) Rx Rf (solvent), MS or m.p. NMR (400 MHz), δ (ppm)

26-1* 26-1 *

0,58 (AcOEt) CDCl3: 0,97 (t, 3H), 1,72-1,82 (m, 2H), 3,08-3,14 (m, 6H), 3,87-3,89 (m, 7H), 6,46 (dd, 1H), 6,53 (d, 1H), 7,24-7,28 (m, 1H), 7,30 (s, 1H), 7,60-7,64 (m, 1H), 7,94 (dd, 1H), 8,05 (d, 1H), 8,15 (s, 1H), 8,59 (d, 1H), 9,40 (s, 1H) 0.58 (AcOEt) CDCl3: 0.97 (t, 3H), 1.72-1.82 (m, 2H), 3.08-3.14 (m, 6H), 3.87-3.89 (m, 7H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.24-7.28 (m, 1H), 7.30 (s, 1H), 7.60-7.64 (m, 1H), 7.94 (dd, 1H), 8.05 (d, 1H), 8.15 (s, 1H), 8.59 (d, 1H), 9.40 (s, 1H)

26-2* 26-2 *

0,57 (MeOH:AcOEt = 1:4) CDCl3: 0,98 (t, 3H), 1,85-1,68 (m, 2H), 2,15 (s, 3H), 3,16-3,07 (m, 6H), 3,67-3,62 (m, 2H), 3,81-3,78 (m, 2H), 3,89 (s, 3H), 6,47 (d, 1H), 6,55 (d, 1H), 7,36-7,33 (m, 1H), 7,62 (dd, 1H), 7,95 (dd, 1H), 8,08 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) 0.57 (MeOH: AcOEt = 1: 4) CDCl3: 0.98 (t, 3H), 1.85-1.68 (m, 2H), 2.15 (s, 3H), 3.16-3.07 (m, 6H), 3.67- 3.62 (m, 2H), 3.81-3.78 (m, 2H), 3.89 (s, 3H), 6.47 (d, 1H), 6.55 (d, 1H), 7 , 36-7.33 (m, 1H), 7.62 (dd, 1H), 7.95 (dd, 1H), 8.08 (d, 1H), 8.15 (s, 1H), 8, 58 (d, 1H), 9.41 (s, 1H)

26-3* 26-3 *

0,13 (MeOH:AcOEt = 1:4) CDCl3: 0,97 (t, 3H), 1,43-1,52 (m, 2H), 1,52-1,67 (m, 4H), 1,69-1,72 (m, 4H), 1,90-1,98 (m, 2H), 2,34-2,46 (m, 1H), 2,51-2,59 (m, 4H), 2,64-2,74 (m, 2H), 3,11 (dd, 2H), 3,64-3,73 (m, 2H), 3,87 (s, 3H), 6,47 (dd, 1H), 6,56 (d, 1H), 7,247,33 (m, 1H), 7,62 (dd, 1H), 7,94 (dd, 1H), 8,00 (d, 1H), 8,14 (s, 1H), 8,59 (d, 1H), 9,39 (sa, 1H) 0.13 (MeOH: AcOEt = 1: 4) CDCl3: 0.97 (t, 3H), 1.43-1.52 (m, 2H), 1.52-1.67 (m, 4H), 1.69-1.72 (m, 4H), 1.90-1.98 (m, 2H), 2.34-2.46 (m, 1H), 2.51-2.59 (m, 4H), 2.64-2.74 (m, 2H ), 3.11 (dd, 2H), 3.64-3.73 (m, 2H), 3.87 (s, 3H), 6.47 (dd, 1H), 6.56 (d, 1H) , 7,247.33 (m, 1H), 7.62 (dd, 1H), 7.94 (dd, 1H), 8.00 (d, 1H), 8.14 (s, 1H), 8.59 ( d, 1H), 9.39 (sa, 1H)

26-4* 26-4 *

0,22 (AcOEt) CDCl3: 0,97 (t, 3H), 1,45 (d, 1H), 1,681,82 (m, 4H), 2,0-2,1 (m, 2H), 2,91 (ddd, 2H), 3,10 (ddd, 2H), 3,46-3,51 (m, 2H), 3,84-3,92 (m, 1H), 3,88 (s, 1H), 6,48 (dd, 1H), 6,57 (d, 1H), 7,23-7,32 (m, 1H), 7,62 (dd, 1H), 7,94 (dd, 1H), 8,02 (dd, 1H), 8,14 (s, 1H), 8,59 (d, 1H), 9,39 (sa, 1H) 0.22 (AcOEt) CDCl3: 0.97 (t, 3H), 1.45 (d, 1H), 1,681.82 (m, 4H), 2.0-2.1 (m, 2H), 2.91 (ddd, 2H) , 3.10 (ddd, 2H), 3.46-3.51 (m, 2H), 3.84-3.92 (m, 1H), 3.88 (s, 1H), 6.48 (dd , 1H), 6.57 (d, 1H), 7.23-7.32 (m, 1H), 7.62 (dd, 1H), 7.94 (dd, 1H), 8.02 (dd, 1H), 8.14 (s, 1H), 8.59 (d, 1H), 9.39 (sa, 1H)

26-5* 26-5 *

0,1 (AcOEt) CDCl3: 0,97 (t, 3H), 1,71-1,82 (m, 2H), 1,86-1,98 (m, 2H), 2,01-2,08 (m, 2H), 2,25-2,37 (m, 1H), 2,75 (ddd, 2H), 3,10 (ddd, 2H), 3,63-3,66 (m, 2H), 3,88 (s, 3H), 5,25-5,40 (m, 1H), 5,40-5,58 (m, 1H), 6,48 (dd, 1H), 6,57 (d, 1H), 7,227,34 (m, 1H), 7,62 (ddd, 1H), 7,93 (d, 1H), 7,94 (dd, 1H), 8,02 (d, 1H), 8,14 (s, 1H), 8,59 (d, 1H), 9,40 (m, 1H) 0.1 (AcOEt) CDCl3: 0.97 (t, 3H), 1.71-1.82 (m, 2H), 1.86-1.98 (m, 2H), 2.01-2.08 (m, 2H), 2.25-2.37 (m, 1H), 2.75 (ddd, 2H), 3.10 (ddd, 2H), 3.63-3.66 (m, 2H), 3.88 (s, 3H), 5.25-5.40 (m, 1H), 5.40-5.58 (m, 1H), 6.48 (dd, 1H), 6.57 (d, 1H), 7.227.34 (m, 1H), 7.62 (ddd, 1H), 7.93 (d, 1H), 7.94 (dd, 1H), 8.02 (d, 1H), 8.14 (s, 1H) , 8.59 (d, 1H), 9.40 (m, 1H)

26-6* 26-6 *

EM 587 CDCl3: 0,97 (t, 3H), 1,77 (ddd, 2H), 2,001,85 (m, 4H), 2,27-2,18 (m, 1H), 2,72 (ddd, 2H), 3,12-3,08 (m, 2H), 3,69-3,61 (m, 2H), 3,58-3,46 (m, 1H), 3,64 (t, 2H), 3,80 (t, 2H), 3,88 (s, 3H), 5,56-5,46 (m, 1H), 6,47 (dd, 1H), 6,55 (d, 1H), 7,327,23 (m, 1H), 7,30 (sa, 1H), 7,64-7,60 (m, 1H), 7,94 (dd, 1H), 8,02 (d, 1H), 8,14 (s, 1H), 8,59 (d, 1H), 9,40 (s, 1H) MS 587 CDCl3: 0.97 (t, 3H), 1.77 (ddd, 2H), 2.001.85 (m, 4H), 2.27-2.18 (m, 1H), 2.72 (ddd, 2H) , 3.12-3.08 (m, 2H), 3.69-3.61 (m, 2H), 3.58-3.46 (m, 1H), 3.64 (t, 2H), 3 , 80 (t, 2H), 3.88 (s, 3H), 5.56-5.46 (m, 1H), 6.47 (dd, 1H), 6.55 (d, 1H), 7.327, 23 (m, 1H), 7.30 (sa, 1H), 7.64-7.60 (m, 1H), 7.94 (dd, 1H), 8.02 (d, 1H), 8.14 (s, 1H), 8.59 (d, 1H), 9.40 (s, 1H)

26-7* 26-7 *

EM 587 CDCl3: 0,98 (t, 3H), 1,46 (sa, 6H), 1,821,73 (m, 2H), 2,17 (s, 3H), 3,58-3,46 (m, 1H), 2,95-2,84 (m, 2H), 3,12-3,08 (m, 2H), 3,90 (s, 3H), 6,48 (dd, 1H), 6,52 (d, 1H), 7,30-7,22 (m, 1H), 7,31 (sa, 1H), 7,66-7,60 (m, 1H), 7,95 (dd, 1H), 8,06 (d, 1H), 8,15 (s, 1H), 8,59 (d, 1H), 9,43 (s, 1H) MS 587 CDCl3: 0.98 (t, 3H), 1.46 (sa, 6H), 1,821.73 (m, 2H), 2.17 (s, 3H), 3.58-3.46 (m, 1H) , 2.95-2.84 (m, 2H), 3.12-3.08 (m, 2H), 3.90 (s, 3H), 6.48 (dd, 1H), 6.52 (d , 1H), 7.30-7.22 (m, 1H), 7.31 (sa, 1H), 7.66-7.60 (m, 1H), 7.95 (dd, 1H), 8, 06 (d, 1H), 8.15 (s, 1H), 8.59 (d, 1H), 9.43 (s, 1H)

26-8* 26-8 *

EM 573 CDCl3: 0,97 (t, 3H), 1,19 (t, 3H), 1,77 (ddd, 2H), 2,41 (m, 2H), 3,18-3,09 (m, 6H), 3,68-3,64 (m, 2H), 3,85-3,78 (m, 2H), 3,89 (s, 3H), 6,47 (dd, 1H), 6,55 (d, 1H), 7,29-7,25 (m, 1H), 7,34 (sa, 1H), 7,64-7,60 (m, 1H), 7,95 (dd, 1H), 8,07 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) MS 573 CDCl3: 0.97 (t, 3H), 1.19 (t, 3H), 1.77 (ddd, 2H), 2.41 (m, 2H), 3.18-3.09 (m, 6H) , 3.68-3.64 (m, 2H), 3.85-3.78 (m, 2H), 3.89 (s, 3H), 6.47 (dd, 1H), 6.55 (d , 1H), 7.29-7.25 (m, 1H), 7.34 (sa, 1H), 7.64-7.60 (m, 1H), 7.95 (dd, 1H), 8, 07 (d, 1H), 8.15 (s, 1H), 8.58 (d, 1H), 9.41 (s, 1H)

26-9* 26-9 *

EM 587 CDCl3: 0,97 (t, 3H), 1,17 (d, 3H), 1,76 (ddd, 2H), 2,88-2,81 (m, 2H), 3,18-3,05 (m, 6H), 3,74-3,67 (m, 2H), 3,86-3,78 (m, 2H), 3,89 (s, 3H), 6,47 (dd, 1H), 6,55 (d, 1H), 7,29-7,20 (m, 1H), 7,34 (sa, 1H), 7,64-7,60 (m, 1H), 7,95 (dd, 1H), 8,07 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) MS 587 CDCl3: 0.97 (t, 3H), 1.17 (d, 3H), 1.76 (ddd, 2H), 2.88-2.81 (m, 2H), 3.18-3.05 ( m, 6H), 3.74-3.67 (m, 2H), 3.86-3.78 (m, 2H), 3.89 (s, 3H), 6.47 (dd, 1H), 6 , 55 (d, 1H), 7.29-7.20 (m, 1H), 7.34 (sa, 1H), 7.64-7.60 (m, 1H), 7.95 (dd, 1H ), 8.07 (d, 1H), 8.15 (s, 1H), 8.58 (d, 1H), 9.41 (s, 1H)

26-10* 26-10 *

EM 517 CDCl3: 0,97 (t, 3H), 1,76 (ddd, 2H), 2,86 (d, 3H), 3,14-3,08 (m, 2H), 3,13 (t, 4H), 3,55 (t, 4H), 3,89 (s, 3H), 4,48-4,39 (m, 1H), 6,46 (dd, 1H), 6,55 (d, 1H), 7,297,21 (m, 1H), 7,34 (sa, 1H), 7,64-7,60 (m, 1H), 7,95 (dd, 1H), 8,06 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) EM 517 CDCl3: 0.97 (t, 3H), 1.76 (ddd, 2H), 2.86 (d, 3H), 3.14-3.08 (m, 2H), 3.13 (t, 4H) , 3.55 (t, 4H), 3.89 (s, 3H), 4.48-4.39 (m, 1H), 6.46 (dd, 1H), 6.55 (d, 1H), 7.297.21 (m, 1H), 7.34 (sa, 1H), 7.64-7.60 (m, 1H), 7.95 (dd, 1H), 8.06 (d, 1H), 8 , 15 (s, 1H), 8.58 (d, 1H), 9.41 (s, 1H)

26-11* 26-11 *

EM 587 CDCl3: 0,98 (t, 3H), 1,51 (s, 6H), 1,821,72 (m, 1H), 2,13 (s, 3H), 3,12-3,08 (m, 2H), 3,26 (s, 2H), 3,44 (t, 2H), 3,74 (t, 2H), 3,88 (s, 3H), 5,56-5,46 (m, 1H), 6,45 (dd, 1H), 6,51 (d, 1H), 7,00 (sa, 1H), 7,62-7,58 (m, 1H), 7,64-7,60 (m, 1H), 7,93 (d, 1H), 7,96 (dd, 1H), 8,13 (s, 1H), 8,62 (d, 1H), 9,42 (s, 1H) MS 587 CDCl3: 0.98 (t, 3H), 1.51 (s, 6H), 1,821.72 (m, 1H), 2.13 (s, 3H), 3.12-3.08 (m, 2H) , 3.26 (s, 2H), 3.44 (t, 2H), 3.74 (t, 2H), 3.88 (s, 3H), 5.56-5.46 (m, 1H), 6.45 (dd, 1H), 6.51 (d, 1H), 7.00 (sa, 1H), 7.62-7.58 (m, 1H), 7.64-7.60 (m, 1H), 7.93 (d, 1H), 7.96 (dd, 1H), 8.13 (s, 1H), 8.62 (d, 1H), 9.42 (s, 1H)

26-12* 26-12 *

EM 559 CDCl3: 0,98 (t, 3H), 1,81-1,71 (m, 3H), 1,95-1,84 (m, 3H), 2,68-2,63 (m, 1H), 3,12-3,08 (m, 4H), 3,28 (d, 2H), 3,89 (s, 3H), 5,45-5,38 (m, 1H), 6,53 (dd, 1H), 6,59 (d, 1H), 6,71-6,62 (m, 1H), 7,28-7,21 (m, 1H), 7,35 (sa, 1H), 7,65-7,61 (m, 1H), 7,95 (dd, 1H), 8,08 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) MS 559 CDCl3: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63 (m, 1H), 3.12-3.08 (m, 4H), 3.28 (d, 2H), 3.89 (s, 3H), 5.45-5.38 (m, 1H), 6.53 (dd, 1H), 6.59 (d, 1H), 6.71-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.35 (sa, 1H), 7.65 -7.61 (m, 1H), 7.95 (dd, 1H), 8.08 (d, 1H), 8.15 (s, 1H), 8.58 (d, 1H), 9.41 ( s, 1H)

26-13* 26-13 *

EM 559 CDCl3: 0,98 (t, 3H), 1,81-1,71 (m, 3H), 1,95-1,84 (m, 3H), 2,68-2,63 (m, 1H), 3,12-3,08 (m, 4H), 3,28 (d, 2H), 3,89 (s, 3H), 5,45-5,38 (m, 1H), 6,53 (dd, 1H), 6,59 (d, 1H), 6,71-6,62 (m, 1H), 7,28-7,21 (m, 1H), 7,35 (sa, 1H), 7,65-7,61 (m, 1H), 7,95 (dd, 1H), 8,08 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) MS 559 CDCl3: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63 (m, 1H), 3.12-3.08 (m, 4H), 3.28 (d, 2H), 3.89 (s, 3H), 5.45-5.38 (m, 1H), 6.53 (dd, 1H), 6.59 (d, 1H), 6.71-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.35 (sa, 1H), 7.65 -7.61 (m, 1H), 7.95 (dd, 1H), 8.08 (d, 1H), 8.15 (s, 1H), 8.58 (d, 1H), 9.41 ( s, 1H)

26-14* 26-14 *

EM 559 CDCl3: 0,98 (t, 3H), 1,85-1,74 (m, 3H), 2,00-1,86 (m, 3H), 2,70-2,51 (m, 1H), 3,13-3,08 (m, 4H), 3,29-3,27 (m, 2H), 3,89 (s, 3H), 5,46-5,37 (m, 1H), 6,53 (dd, 1H), 6,59 (d, 1H), 6,69-6,56 (m, 1H), 7,29-7,19 (m, 1H), 7,34 (sa, 1H), 7,657,61 (m, 1H), 7,95 (dd, 1H), 8,08 (d, 1H), 8,15 (s, 1H), 8,58 (d, 1H), 9,41 (s, 1H) MS 559 CDCl3: 0.98 (t, 3H), 1.85-1.74 (m, 3H), 2.00-1.86 (m, 3H), 2.70-2.51 (m, 1H), 3.13-3.08 (m, 4H), 3.29-3.27 (m, 2H), 3.89 (s, 3H), 5.46-5.37 (m, 1H), 6, 53 (dd, 1H), 6.59 (d, 1H), 6.69-6.56 (m, 1H), 7.29-7.19 (m, 1H), 7.34 (sa, 1H) , 7,657.61 (m, 1H), 7.95 (dd, 1H), 8.08 (d, 1H), 8.15 (s, 1H), 8.58 (d, 1H), 9.41 ( s, 1H)

26-15* 26-15 *

EM 559 CDCl3: 0,99 (t, 3H), 1,79-1,72 (m, 2H), 2,92 (t, 2H), 2,98 (t, 2H), 3,16-3,12 (m, 2H), 3,53 (t, 2H), 3,67 (t, 2H), 3,87 (s, 3H), 6,54 (dd, 1H), 6,82 (d, 1H), 7,297,19 (m, 1H), 7,56 (sa, 1H), 7,67-7,62 (m, 1H), 7,96 (dd, 1H), 8,07 (d, 1H), 8,21 (s, 1H), 8,59 (dd, 1H), 9,46 (s, 1H) MS 559 CDCl3: 0.99 (t, 3H), 1.79-1.72 (m, 2H), 2.92 (t, 2H), 2.98 (t, 2H), 3.16-3.12 ( m, 2H), 3.53 (t, 2H), 3.67 (t, 2H), 3.87 (s, 3H), 6.54 (dd, 1H), 6.82 (d, 1H), 7.297.19 (m, 1H), 7.56 (sa, 1H), 7.67-7.62 (m, 1H), 7.96 (dd, 1H), 8.07 (d, 1H), 8 , 21 (s, 1H), 8.59 (dd, 1H), 9.46 (s, 1H)

26-16* 26-16 *

EM 561 CDCl3: 0,98 (t, 3H), 1,81-1,72 (m, 2H), 2,49 (t, 4H), 2,66 (t, 2H), 3,12-3,08 (m, 2H), 3,18 (t, 2H), 3,74 (t, 4H), 3,86 (s, 3H), 6,53 (dd, 1H), 6,20 (dd, 1H), 6,26 (d, 1H), 7,13 (sa, 1H), 7,25-7,21 (m, 1H), 7,62-7,57 (m, 1H), 7,87 (dd, 1H), 7,93 (dd, 1H), 8,12 (s, 1H), 8,62 (d, 1H), 9,40 (s, 1H) MS 561 CDCl3: 0.98 (t, 3H), 1.81-1.72 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 3.12-3.08 ( m, 2H), 3.18 (t, 2H), 3.74 (t, 4H), 3.86 (s, 3H), 6.53 (dd, 1H), 6.20 (dd, 1H), 6.26 (d, 1H), 7.13 (sa, 1H), 7.25-7.21 (m, 1H), 7.62-7.57 (m, 1H), 7.87 (dd, 1H), 7.93 (dd, 1H), 8.12 (s, 1H), 8.62 (d, 1H), 9.40 (s, 1H)

26-17* 26-17 *

EM 518 CDCl3: 0,98 (t, 3H), 1,78-1,73 (m, 2H), 2,49 (t, 4H), 2,66 (t, 2H), 2,94-2,92 (m, 4H), 3,15-3,11 (m, 2H), 3,76-3,73 (m, 4H), 3,88 (s, 3H), 6,52 (dd, 1H), 6,82 (d, 1H), 7,28-7,24 (m, 1H), 7,57 (sa, 1H), 7,25-7,21 (m, 1H), 7,68-7,63 (m, 1H), 7,95 (dd, 1H), 8,02 (d, 1H), 8,20 (s, 1H), 8,56 (d, 1H), 9,41 (s, 1H) EM 518 CDCl3: 0.98 (t, 3H), 1.78-1.73 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 2.94-2.92 ( m, 4H), 3.15-3.11 (m, 2H), 3.76-3.73 (m, 4H), 3.88 (s, 3H), 6.52 (dd, 1H), 6 , 82 (d, 1H), 7.28-7.24 (m, 1H), 7.57 (sa, 1H), 7.25-7.21 (m, 1H), 7.68-7.63 (m, 1H), 7.95 (dd, 1H), 8.02 (d, 1H), 8.20 (s, 1H), 8.56 (d, 1H), 9.41 (s, 1H)

26-18* 26-18 *

EM 559 CDCl3: 0,97 (t, 3H), 1,81-1,72 (m, 2H), 2,08-2,00 (m, 2H), 2,49 (t, 4H), 2,66 (t, 2H), 2,40 (t, 2H), 3,59 (t, 2H), 3,69 (t, 2H), 3,87 (s, 3H), 6,41 (dd, 1H), 6,51 (d, 1H), 7,29-7,25 (m, 2H), 7,65-7,60 (m, 1H), 7,95 (dd, 1H), 8,05 (d, 1H), 8,15 (s, 1H), 8,56 (d, 1H), 9,41 (s, 1H) MS 559 CDCl3: 0.97 (t, 3H), 1.81-1.72 (m, 2H), 2.08-2.00 (m, 2H), 2.49 (t, 4H), 2.66 ( t, 2H), 2.40 (t, 2H), 3.59 (t, 2H), 3.69 (t, 2H), 3.87 (s, 3H), 6.41 (dd, 1H), 6.51 (d, 1H), 7.29-7.25 (m, 2H), 7.65-7.60 (m, 1H), 7.95 (dd, 1H), 8.05 (d, 1H), 8.15 (s, 1H), 8.56 (d, 1H), 9.41 (s, 1H)

26-19* 26-19 *

EM 587 CDCl3: 0,98 (t, 3H), 1,82-1,73 (m, 2H), 2,14 (s, 3H), 3,12-3,08 (m, 2H), 3,55-3,45 (m, 2H), 3,66-3,56 (m, 4H), 3,79-3,68 (m, 2H), 3,95 (s, 3H), 6,95 (dd, 1H), 7,03 (d, 1H), 7,32-7,28 (m, 1H), 7,69-7,64 (m, 1H), 7,71 (s, 1H), 7,97 (dd, 1H), 8,22 (s, 1H), 8,39 (d, 1H), 8,52 (d, 1H), 9,46 (s, 1H) MS 587 CDCl3: 0.98 (t, 3H), 1.82-1.73 (m, 2H), 2.14 (s, 3H), 3.12-3.08 (m, 2H), 3.55- 3.45 (m, 2H), 3.66-3.56 (m, 4H), 3.79-3.68 (m, 2H), 3.95 (s, 3H), 6.95 (dd, 1H), 7.03 (d, 1H), 7.32-7.28 (m, 1H), 7.69-7.64 (m, 1H), 7.71 (s, 1H), 7.97 (dd, 1H), 8.22 (s, 1H), 8.39 (d, 1H), 8.52 (d, 1H), 9.46 (s, 1H)

26-20* 26-20 *

EM 546 CDCl3: 0,97 (t, 3H), 1,82-1,73 (m, 2H), 3,12-3,08 (m, 2H), 3,80-3,58 (m, 8H), 3,94 (s, 3H), 6,94 (dd, 1H), 7,02 (d, 1H), 7,32-7,28 (m, 1H), 7,69-7,64 (m, 1H), 7,32-7,28 (m, 1H), 7,97 (dd, 1H), 8,21 (s, 1H), 8,34 (d, 1H), 8,52 (d, 1H), 9,45 (s, 1H) MS 546 CDCl3: 0.97 (t, 3H), 1.82-1.73 (m, 2H), 3.12-3.08 (m, 2H), 3.80-3.58 (m, 8H), 3.94 (s, 3H), 6.94 (dd, 1H), 7.02 (d, 1H), 7.32-7.28 (m, 1H), 7.69-7.64 (m, 1H), 7.32-7.28 (m, 1H), 7.97 (dd, 1H), 8.21 (s, 1H), 8.34 (d, 1H), 8.52 (d, 1H ), 9.45 (s, 1 H)

26-21* 26-21 *

EM 615 CDCl3: 0,97 (t, 3H), 1,82-1,72 (m, 2H), 2,71 (t, 3H), 3,05 (s, 2H), 3,10 (m, 2H), 3,18 (t, 4H), 3,88 (s, 3H), 4,17-4,08 (m, 1H), 6,47 (dd, 1H), 6,54 (d, 1H), 6,996,89 (m, 1H), 7,28-7,24 (m, 1H), 7,31 (sa, 1H), 7,65-7,60 (m, 1H), 7,32-7,28 (m, 1H), 7,95 (dd, 1H), 8,05 (d, 1H), 8,15 (s, 1H), 8,59 (d, 1H), 9,41 (s, 1H) MS 615 CDCl3: 0.97 (t, 3H), 1.82-1.72 (m, 2H), 2.71 (t, 3H), 3.05 (s, 2H), 3.10 (m, 2H) , 3.18 (t, 4H), 3.88 (s, 3H), 4.17-4.08 (m, 1H), 6.47 (dd, 1H), 6.54 (d, 1H), 6,996.89 (m, 1H), 7.28-7.24 (m, 1H), 7.31 (sa, 1H), 7.65-7.60 (m, 1H), 7.32-7, 28 (m, 1H), 7.95 (dd, 1H), 8.05 (d, 1H), 8.15 (s, 1H), 8.59 (d, 1H), 9.41 (s, 1H )

26-22* 26-22 *

EM 530 CDCl3: 0,98 (t, 3H), 1,80-1,74 (m, 2H), 3,12-3,08 (m, 2H), 3,45-3,42 (m, 2H), 3,55-5,53 (m, 2H), 3,87 (s, 2H), 3,89 (s, 3H), 5,98-5,89 (m, 1H), 6,44 (dd, 1H), 6,50 (d, 1H), 7,35-7,19 (m, 2H), 7,62-7,58 (m, 1H), 7,95 (dd, 1H), 8,09 (d, 1H), 8,15 (s, 1H), 8,57 (d, 1H), 9,43 (s, 1H) EM 530 CDCl3: 0.98 (t, 3H), 1.80-1.74 (m, 2H), 3.12-3.08 (m, 2H), 3.45-3.42 (m, 2H), 3.55-5.53 (m, 2H), 3.87 (s, 2H), 3.89 (s, 3H), 5.98-5.89 (m, 1H), 6.44 (dd, 1H), 6.50 (d, 1H), 7.35-7.19 (m, 2H), 7.62-7.58 (m, 1H), 7.95 (dd, 1H), 8.09 (d, 1H), 8.15 (s, 1H), 8.57 (d, 1H), 9.43 (s, 1H)

26-23* 26-23 *

EM 558 CDCl3: 0,97 (t, 3H), 1,10 (s, 3H), 1,12 (s, 3H), 1,80-1,74 (m, 2H), 2,80-2,63 (m, 5H), 3,12-3,08 (m, 2H), 3,19-3,17 (m, 4H), 3,87 (s, 3H), 6,48 (dd, 1H), 6,56 (d, 1H), 7,30-7,23 (m, 2H), 7,62-7,58 (m, 1H), 7,94 (dd, 1H), 8,00 (d, 1H), 8,14 (s, 1H), 8,59 (d, 1H), 9,40 (s, 1H) MS 558 CDCl3: 0.97 (t, 3H), 1.10 (s, 3H), 1.12 (s, 3H), 1.80-1.74 (m, 2H), 2.80-2.63 ( m, 5H), 3.12-3.08 (m, 2H), 3.19-3.17 (m, 4H), 3.87 (s, 3H), 6.48 (dd, 1H), 6 , 56 (d, 1H), 7.30-7.23 (m, 2H), 7.62-7.58 (m, 1H), 7.94 (dd, 1H), 8.00 (d, 1H ), 8.14 (s, 1H), 8.59 (d, 1H), 9.40 (s, 1H)

26-24* 26-24 *

EM 544 CDCl3: 0,98 (t, 3H), 1,81-1,72 (m, 2H), 2,03-1,91 (m, 1H), 2,28-2,19 (m, 1H), 2,33 (s, 6H), 2,92-2,84 (m, 1H), 3,12-3,08 (m, 2H), 3,17 (t, 1H), 3,35 (ddd, 1H), 3,51-3,42 (m, 2H), 3,87 (s, 3H), 6,11 (dd, 1H), 6,14 (d, 1H), 7,09 (s, 1H), 7,26-7,20 (m, 1H), 7,60-7,56 (m, 1H), 7,85 (d, 1H), 7,92 (dd, 1H), 8,11 (s, 1H), 8,38 (d, 1H), 9,41 (s, 1H) MS 544 CDCl3: 0.98 (t, 3H), 1.81-1.72 (m, 2H), 2.03-1.91 (m, 1H), 2.28-2.19 (m, 1H), 2.33 (s, 6H), 2.92-2.84 (m, 1H), 3.12-3.08 (m, 2H), 3.17 (t, 1H), 3.35 (ddd, 1H), 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.11 (dd, 1H), 6.14 (d, 1H), 7.09 (s, 1H ), 7.26-7.20 (m, 1H), 7.60-7.56 (m, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 8.11 ( s, 1H), 8.38 (d, 1H), 9.41 (s, 1H)

26-25* 26-25 *

EM 530 CDCl3: 0,98 (t, 3H), 1,82-1,71 (m, 2H), 1,96-1,86 (m, 1H), 2,33-2,20 (m, 1H), 2,51 (s, 1H), 3,17-3,08 (m, 3H), 3,35-3,30 (m, 1H), 3,54-3,30 (m, 3H), 3,87 (s, 3H), 6,12 (dd, 1H), 6,16 (d, 1H), 7,09 (s, 1H), 7,32-7,21 (m, 1H), 7,58 (dd, 1H), 7,85 (d, 1H), 7,92 (dd, 1H), 8,11 (s, 1H), 8,64 (d, 1H), 9,40 (s, 1H) EM 530 CDCl3: 0.98 (t, 3H), 1.82-1.71 (m, 2H), 1.96-1.86 (m, 1H), 2.33-2.20 (m, 1H), 2.51 (s, 1H), 3.17-3.08 (m, 3H), 3.35-3.30 (m, 1H), 3.54-3.30 (m, 3H), 3, 87 (s, 3H), 6.12 (dd, 1H), 6.16 (d, 1H), 7.09 (s, 1H), 7.32-7.21 (m, 1H), 7.58 (dd, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 8.11 (s, 1H), 8.64 (d, 1H), 9.40 (s, 1H)

26-26* 26-26 *

EM 546 CDCl3: 0,98 (t, 3H), 1,83-1,71 (m, 2H), 1,98-1,81 (m, 2H), 2,16-2,02 (m, 2H), 2,53-2,28 (m, 5H), 2,87-2,72 (m, 2H), 3,12-3,08 (m, 2H), 3,88 (s, 3H), 4,32 (sa, 3H), 6,44 (dd, 1H), 6,53 (d, 1H), 7,327,25 (m, 2H), 7,63-7,59 (m, 2H), 7,94 (dd, 1H), 8,04 (d, 1H), 8,15 (s, 1H), 8,57 (d, 1H), 9,42 (s, 1H) MS 546 CDCl3: 0.98 (t, 3H), 1.83-1.71 (m, 2H), 1.98-1.81 (m, 2H), 2.16-2.02 (m, 2H), 2.53-2.28 (m, 5H), 2.87-2.72 (m, 2H), 3.12-3.08 (m, 2H), 3.88 (s, 3H), 4, 32 (sa, 3H), 6.44 (dd, 1H), 6.53 (d, 1H), 7.327.25 (m, 2H), 7.63-7.59 (m, 2H), 7.94 (dd, 1H), 8.04 (d, 1H), 8.15 (s, 1H), 8.57 (d, 1H), 9.42 (s, 1H)

26-27* 26-27 *

EM 545 CDCl3: 0,97 (t, 3H), 1,38-1,30 (m, 1H), 1,49-1,40 (m, 2H), 1,70-1,62 (m, 1H), 1,83-1,72 (m, 2H), 1,89 (d, 2H), 2,74-2,10 (m, 2H), 3,12-3,08 (m, 2H), 3,57 (d, 2H), 3,63 (d, 2H), 3,90 (s, 3H), 6,50 (d, 1H), 6,58 (s, 1H), 7,34-7,24 (m, 2H), 7,64-7,60 (m, 1H), 7,94 (dd, 1H), 8,02 (d, 1H), 8,14 (s, 1H), 8,60 (dd, 1H), 9,40 (s, 1H) MS 545 CDCl3: 0.97 (t, 3H), 1.38-1.30 (m, 1H), 1.49-1.40 (m, 2H), 1.70-1.62 (m, 1H), 1.83-1.72 (m, 2H), 1.89 (d, 2H), 2.74-2.10 (m, 2H), 3.12-3.08 (m, 2H), 3, 57 (d, 2H), 3.63 (d, 2H), 3.90 (s, 3H), 6.50 (d, 1H), 6.58 (s, 1H), 7.34-7.24 (m, 2H), 7.64-7.60 (m, 1H), 7.94 (dd, 1H), 8.02 (d, 1H), 8.14 (s, 1H), 8.60 ( dd, 1H), 9.40 (s, 1H)

26-28* 26-28 *

EM 517 CDCl3: 0,97 (t, 3H), 1,88-1,65 (m, 3H), 2,05-1,97 (m, 2H), 2,21-2,08 (m, 1H), 2,67-2,55 (m, 4H), 2,78-2,71 (m, 2H), 3,12-3,08 (m, 2H), 3,61 (d, 2H), 3,87 (s, 3H), 6,47 (dd, 1H), 6,56 (d, 1H), 7,287,23 (m, 2H), 7,64-7,60 (m, 1H), 7,94 (dd, 1H), 7,99 (d, 1H), 8,13 (s, 1H), 8,60 (dd, 1H), 9,39 (s, 1H) EM 517 CDCl3: 0.97 (t, 3H), 1.88-1.65 (m, 3H), 2.05-1.97 (m, 2H), 2.21-2.08 (m, 1H), 2.67-2.55 (m, 4H), 2.78-2.71 (m, 2H), 3.12-3.08 (m, 2H), 3.61 (d, 2H), 3, 87 (s, 3H), 6.47 (dd, 1H), 6.56 (d, 1H), 7.287.23 (m, 2H), 7.64-7.60 (m, 1H), 7.94 (dd, 1H), 7.99 (d, 1H), 8.13 (s, 1H), 8.60 (dd, 1H), 9.39 (s, 1H)

26-29* 26-29 *

EM 585 CDCl3: 0,97 (t, 3H), 1,89-1,65 (m, 8H), 2,03 (d, 2H), 2,20-2,10 (m, 1H), 2,68-2,58 (m, 4H), 2,78-2,72 (m, 2H), 3,12-3,08 (m, 2H), 3,61 (d, 2H), 3,87 (s, 3H), 6,47 (dd, 1H), 6,56 (d, 1H), 7,30-7,23 (m, 2H), 7,64-7,60 (m, 1H), 7,94 (dd, 1H), 7,99 (dd, 1H), 8,13 (s, 1H), 8,60 (dd, 1H), 9,39 (s, 1H) MS 585 CDCl3: 0.97 (t, 3H), 1.89-1.65 (m, 8H), 2.03 (d, 2H), 2.20-2.10 (m, 1H), 2.68- 2.58 (m, 4H), 2.78-2.72 (m, 2H), 3.12-3.08 (m, 2H), 3.61 (d, 2H), 3.87 (s, 3H), 6.47 (dd, 1H), 6.56 (d, 1H), 7.30-7.23 (m, 2H), 7.64-7.60 (m, 1H), 7.94 (dd, 1H), 7.99 (dd, 1H), 8.13 (s, 1H), 8.60 (dd, 1H), 9.39 (s, 1H)

26-30* 26-30 *

EM 0,97 (t, 3H), 1,71-1,82 (m, 2H), 3,06-3,14 EM 0.97 (t, 3H), 1.71-1.82 (m, 2H), 3.06-3.14

451, 453 451, 453

(m, 2H), 3,89 (s, 1H), 6,60 (ddd, 1H), 6,66 (m, 2H), 3.89 (s, 1H), 6.60 (ddd, 1H), 6.66

(dd, 1H), 7,25-7,30 (m, 1H), 7,35 (sa, (dd, 1H), 7.25-7.30 (m, 1H), 7.35 (sa,

1H), 7,63 (dd, 1H), 7,95 (dd, 1H), 8,091H), 7.63 (dd, 1H), 7.95 (dd, 1H), 8.09

8,18 (m, 1H), 8,17 (s, 1H), 8,52 (dd, 1H), 8.18 (m, 1H), 8.17 (s, 1H), 8.52 (dd, 1H),

9,42 (s, 1H) 9.42 (s, 1 H)

26-31* 26-31 *

EM 0,98 (t, 3H), 1,71-1,83 (m, 2H), 2,18 (s, EM 0.98 (t, 3H), 1.71-1.83 (m, 2H), 2.18 (s,

647, 649 647, 649

3H), 2,47-2,64 (m, 4H), 2,72-2,84 (m, 3H), 2.47-2.64 (m, 4H), 2.72-2.84 (m,

2H), 3,08-3,15 (m, 2H), 3,42-3,54 (m, 2H), 3.08-3.15 (m, 2H), 3.42-3.54 (m,

2H), 3,58-3,69 (m, 2H), 3,84 (s, 3H), 2H), 3.58-3.69 (m, 2H), 3.84 (s, 3H),

3,94-4,03 (m, 2H), 6,45-6,51 (m, 1H), 3.94-4.03 (m, 2H), 6.45-6.51 (m, 1H),

6,78 (d, 1H), 7,22-7,27 (m, 1H), 7,60 (s, 6.78 (d, 1H), 7.22-7.27 (m, 1H), 7.60 (s,

1H), 7,67-7,74 (m, 1H), 7,93-7,97 (m, 1H), 7.67-7.74 (m, 1H), 7.93-7.97 (m,

1H), 7,73 (d, 1H), 8,02 (s, 1H), 8,54 (d, 1H), 7.73 (d, 1H), 8.02 (s, 1H), 8.54 (d,

1H), 9,33 (s, 1H) 1H), 9.33 (s, 1H)

26-32* 26-32 *

p.f. 400 MHz, CDCl3, δ (ppm): 0,98 (t, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 0.98 (t, 3H),

139,4 139.4

1,55-1,90 (m, 6H), 2,38 (s, 3H), 2,45-2,80 1.55-1.90 (m, 6H), 2.38 (s, 3H), 2.45-2.80

(m, 6H), 3,13 (m, 2H), 3,47 (m, 2H), 3,84 (m, 6H), 3.13 (m, 2H), 3.47 (m, 2H), 3.84

(s, 3H), 6,54 (dd, 1H), 6,79 (d, 1H), 7,23 (s, 3H), 6.54 (dd, 1H), 6.79 (d, 1H), 7.23

(dd, 1H), 7,51 (s, 1H), 7,64 (dd, 1H), 7,92 (dd, 1H), 7.51 (s, 1H), 7.64 (dd, 1H), 7.92

(d, 1H), 8,00 (s, 1H), 8,19 (s, 1H), 8,57 (d, (d, 1H), 8.00 (s, 1H), 8.19 (s, 1H), 8.57 (d,

1H), 9,41 (s, 1H) 1H), 9.41 (s, 1H)

26-33* 26-33 *

p.f. 400 MHz, CDCl3, δ (ppm): 0,98 (t, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 0.98 (t, 3H),

163,4 163.4

1,50-1,90 (m, 6H), 2,24 (sa, 1H), 2,45 1.50-1.90 (m, 6H), 2.24 (sa, 1H), 2.45

2,65 (m, 6H), 3,12 (m, 2H), 3,45 (m, 2H), 2.65 (m, 6H), 3.12 (m, 2H), 3.45 (m, 2H),

3,77 (m, 4H), 3,85 (s, 3H), 6,55 (dd, 1H), 3.77 (m, 4H), 3.85 (s, 3H), 6.55 (dd, 1H),

6,79 (d, 1H), 7,24 (dd, 1H), 7,52 (s, 1H), 6.79 (d, 1H), 7.24 (dd, 1H), 7.52 (s, 1H),

7,64 (dd, 1H), 7,93 (d, 1H), 8,01 (s, 1H), 7.64 (dd, 1H), 7.93 (d, 1H), 8.01 (s, 1H),

8,20 (s, 1H), 9,42 (s, 1H) 8.20 (s, 1H), 9.42 (s, 1H)

26-34* 26-34 *

p.f. 400 MHz, CDCl3, δ (ppm): 1,00 (s, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 1.00 (s, 3H),

232,9 232.9

1,78 (m, 2H), 2,83 (s, 3H), 3,03 (m, 2H), 1.78 (m, 2H), 2.83 (s, 3H), 3.03 (m, 2H),

3,12 (m, 2H), 3,38-3,60 (m, 8H), 3,88 (s, 3.12 (m, 2H), 3.38-3.60 (m, 8H), 3.88 (s,

3H), 6,56 (m, 1H), 6,82 (d, 1H), 7,29 (m, 3H), 6.56 (m, 1H), 6.82 (d, 1H), 7.29 (m,

1H), 7,60 (s, 1H), 7,64 (m, 1H), 7,95 (d, 1H), 7.60 (s, 1H), 7.64 (m, 1H), 7.95 (d,

1H), 8,12 (s, 1H), 8,20 (s, 1H), 8,59 (d, 1H), 8.12 (s, 1H), 8.20 (s, 1H), 8.59 (d,

1H), 9,50 (s, 1H) 1H), 9.50 (s, 1H)

26-35* 26-35 *

p.f. 400 MHz, CDCl3, δ (ppm): 0,99 (t, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 0.99 (t, 3H),

197,3 197.3

1,43 (m, 1H), 1,63 (m, 2H), 1,77 (m, 2H), 1.43 (m, 1H), 1.63 (m, 2H), 1.77 (m, 2H),

1,90 (m, 2H), 2,70 (m, 2H), 3,13 (m, 2H), 1.90 (m, 2H), 2.70 (m, 2H), 3.13 (m, 2H),

3,28 (m, 2H), 3,75 (s, 1H), 3,84 (s, 3H), 3.28 (m, 2H), 3.75 (s, 1H), 3.84 (s, 3H),

6,55 (m, 1H), 6,80 (d, 1H), 7,24 (m, 1H), 6.55 (m, 1H), 6.80 (d, 1H), 7.24 (m, 1H),

7,53 (s, 1H), 7,64 (s, 1H), 7,93 (d, 1H), 7.53 (s, 1H), 7.64 (s, 1H), 7.93 (d, 1H),

8,02 (s, 1H), 8,20 (s, 1H), 8,58 (d, 1H), 8.02 (s, 1H), 8.20 (s, 1H), 8.58 (d, 1H),

9,41 (s, 1H) 9.41 (s, 1 H)

26-36* 26-36 *

p.f. 400 MHz, CDCl3, δ (ppm): 1,008 (t, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 1.008 (t, 3H),

147,6 147.6

1,78 (m, 2H), 3,12 (m, 2H), 3,56 (m, 1H), 1.78 (m, 2H), 3.12 (m, 2H), 3.56 (m, 1H),

3,87 (s, 3H), 6,53 (dd, 1H), 6,80 (d, 1H), 3.87 (s, 3H), 6.53 (dd, 1H), 6.80 (d, 1H),

7,30 (dd, 1H), 7,52 (s, 1H), 7,64 (m, 1H), 7.30 (dd, 1H), 7.52 (s, 1H), 7.64 (m, 1H),

7,95 (dd, 1H), 8,08 (s, 1H), 8,20 (s, 1H), 7.95 (dd, 1H), 8.08 (s, 1H), 8.20 (s, 1H),

8,60 (d, 1H), 9,48 (s, 1H) 8.60 (d, 1H), 9.48 (s, 1H)

26-37* 26-37 *

p.f. 500 MHz, CDCl3, δ (ppm): 0,96 (t, 3H), m.p. 500 MHz, CDCl3, δ (ppm): 0.96 (t, 3H),

143,2 143.2

1,70 (m, 2H), 3,12 (m, 1H), 2,39 (m, 1H), 1.70 (m, 2H), 3.12 (m, 1H), 2.39 (m, 1H),

2,75 (s, 3H), 3,02 (m, 1H), 3,22 (m, 2H), 2.75 (s, 3H), 3.02 (m, 1H), 3.22 (m, 2H),

3,43 (d, 2H), 3,82 (s, 3H), 3,86 (m, 1H), 3.43 (d, 2H), 3.82 (s, 3H), 3.86 (m, 1H),

6,40 (dd, 1H), 6,94 (d, 1H), 7,34 (ddd, 6.40 (dd, 1H), 6.94 (d, 1H), 7.34 (ddd,

1H), 7,47 (s, 1H), 7,63 (ddd, 1H), 7,93 1H), 7.47 (s, 1H), 7.63 (ddd, 1H), 7.93

(dd, 1H), 8,18 (s, 1H), 8,51 (d, 1H) (dd, 1H), 8.18 (s, 1H), 8.51 (d, 1H)

26-38* 26-38 *

p.f. 400 MHz, CDCl3, δ (ppm): 1,00 (t, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 1.00 (t, 3H),

133,5 133.5

1,70-1,95 (m, 6H), 2,63 (s, 1H), 2,92 (s, 1.70-1.95 (m, 6H), 2.63 (s, 1H), 2.92 (s,

1H), 3,00-3,25 (m, 5H), 3,89 (s, 3H), 5,42 1H), 3.00-3.25 (m, 5H), 3.89 (s, 3H), 5.42

(s, 1H), 6,70 (s, 1H), 6,83 (m, 2H), 7,25 (s, 1H), 6.70 (s, 1H), 6.83 (m, 2H), 7.25

(m, 1H), 7,55 (s, 1H), 7,63 (m, 1H), 8,95 (m, 1H), 7.55 (s, 1H), 7.63 (m, 1H), 8.95

(m, 1H), 8,15 (s, 1H), 8,23 (s, 1H), 8,54 (m, 1H), 8.15 (s, 1H), 8.23 (s, 1H), 8.54

(d, 1H), 9,45 (s, 1H) (d, 1H), 9.45 (s, 1H)

26-39* 26-39 *

p.f. 400 MHz, CDCl3, δ (ppm): 0,99 (t, 3H), m.p. 400 MHz, CDCl3, δ (ppm): 0.99 (t, 3H),

188,8 188.8

1,70-1,90 (m, 3H), 2,08 (m, 1H), 2,28 (s, 1.70-1.90 (m, 3H), 2.08 (m, 1H), 2.28 (s,

6H), 2,83 (s, 1H), 3,00-3,23 (m, 4H), 3,37 6H), 2.83 (s, 1H), 3.00-3.23 (m, 4H), 3.37

(m, 1H), 3,83 (s, 3H), 6,19 (dd, 1H), 6,83 (m, 1H), 3.83 (s, 3H), 6.19 (dd, 1H), 6.83

(d, 1H), 7,23 (dd, 1H), 7,50 (s, 1H), 7,59 (d, 1H), 7.23 (dd, 1H), 7.50 (s, 1H), 7.59

(m, 2H), 7,93 (d, 1H), 8,19 (s, 1H), 8,60 (m, 2H), 7.93 (d, 1H), 8.19 (s, 1H), 8.60

(d, 1H), 9,42 (s, 1H) (d, 1H), 9.42 (s, 1H)

[0126] Las siguientes 5-cloro-N2-(fenil sust.)-N4-[2-etanosulfonil-fenil]-pirimidin-2,4-diaminas, que son todas ejemplos de referencia (marcados con un (*)), se preparan a partir de (2,5-dicloro-pirimidin-4-il)-[2-etanosulfonil-fenil]amina y la anilina correspondiente según el procedimiento del ejemplo 7A: [0126] The following 5-chloro-N2- (phenyl substitu) - N4- [2-ethanesulfonyl-phenyl] -pyrimidin-2,4-diamines, which are all reference examples (marked with a (*)), are prepared from (2,5-dichloro-pyrimidin-4-yl) - [2-ethanesulfonyl-phenyl] amine and the corresponding aniline according to the procedure of Example 7A:

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) o tiempo de retención en min (HPLC) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm) or retention time in min (HPLC)

27-1* 27-1 *

0,53 (AcOEt) CDCl3: 1,28 (t, 3H), 3,12-3,19 (m, 6H), 3,87-3,89 (m, 7H), 6,45 (dd, 1H), 6,53 (d, 1H), 7,24-7,28 (m, 1H), 7,31 (s, 1H), 7,60-7,64 (m, 1H), 7,95 (dd, 1H), 8,04 (d, 1H), 8,14 (s, 1H), 8,58 (d, 1H), 9,39 (s, 1H) 0.53 (AcOEt) CDCl3: 1.28 (t, 3H), 3.12-3.19 (m, 6H), 3.87-3.89 (m, 7H), 6.45 (dd, 1H), 6.53 ( d, 1H), 7.24-7.28 (m, 1H), 7.31 (s, 1H), 7.60-7.64 (m, 1H), 7.95 (dd, 1H), 8 , 04 (d, 1H), 8.14 (s, 1H), 8.58 (d, 1H), 9.39 (s, 1H)

27-2* 27-2 *

585 (M+H) 2,38 585 (M + H) 2.38

23-3* 23-3 *

486 (M+H) 3,07 486 (M + H) 3.07

27-4* 27-4 *

587 (M+H) 2,29 587 (M + H) 2.29

27-5* 27-5 *

545 (M+H) 2,59 545 (M + H) 2.59

27-6* 27-6 *

545 (M+H) 2,45 545 (M + H) 2.45

27-7* 27-7 *

531 (M+H) 2,25 531 (M + H) 2.25

27-8* 27-8 *

545 (M+H) 2,45 545 (M + H) 2.45

27-9* 27-9 *

600 (M+H) 2,17 600 (M + H) 2.17

Condiciones de HPLC Columna: YMC CombiScreen ODS-A (5 μm, 12 nm), 50 x 4,6 mm D.I. Caudal: 2,0 ml/min Eluyente: A) TFA/agua (0,1/100), B) TFA/acetonitrilo (0,1/100) Gradiente: 5-100% B (0-5 min) Detección: UV a 215 nm HPLC Conditions Column: YMC CombiScreen ODS-A (5 μm, 12 nm), 50 x 4.6 mm D.I. Flow rate: 2.0 ml / min Eluent: A) TFA / water (0.1 / 100), B) TFA / acetonitrile (0.1 / 100) Gradient: 5-100% B (0-5 min) Detection: UV at 215 nm

todas ejemplos de referencia (marcados con un (*)), se preparan a partir de (2,5-dicloro-pirimidin-4-il)-[2-(propano-2sulfonil)-fenil]-amina y la anilina correspondiente según el procedimiento del ejemplo 7A: all reference examples (marked with a (*)), are prepared from (2,5-dichloro-pyrimidin-4-yl) - [2- (propane-2-sulfonyl) -phenyl] -amine and the corresponding aniline according to the procedure of example 7A:

imagen1image 1

Ej. nº Ex. Nº

Rx Rf (disolvente) o EM RMN (400 MHz), δ (ppm) o tiempo de retención en min (HPLC) Rx Rf (solvent) or MS NMR (400 MHz), δ (ppm) or retention time in min (HPLC)

28-1* 28-1 *

0,2 (AcOEt) CDCl3: 1,31 (d, 6H), 1,85-1,73 (m, 1H), 1,86-1,98 (m, 3H), 2,62-2,70 (m, 1H), 3,113,13 (m, 2H), 3,21-8,28 (m, 1H), 3,28 (m, 2H), 3,88 (s, 3H), 5,41 (sa, 1H), 6,53 (d, 1H), 6,59 (d, 1H), 6,64 (sa, 1H), 7,28-7,34 (m, 1H), 7,34 (s, 1H), 7,60-7,67 (m, 1H), 7,91 (dd, 1H), 8,08 (d, 1H), 8,13 (s, 1H), 8,60 (d, 1H), 9,55 (s, 1H) 0.2 (AcOEt) CDCl3: 1.31 (d, 6H), 1.85-1.73 (m, 1H), 1.86-1.98 (m, 3H), 2.62-2.70 (m, 1H), 3,113.13 (m, 2H), 3.21-8.28 (m, 1H), 3.28 (m, 2H), 3.88 (s, 3H), 5.41 (sa, 1H), 6 , 53 (d, 1H), 6.59 (d, 1H), 6.64 (sa, 1H), 7.28-7.34 (m, 1H), 7.34 (s, 1H), 7, 60-7.67 (m, 1H), 7.91 (dd, 1H), 8.08 (d, 1H), 8.13 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)

28-2* 28-2 *

EM m/z 561, 563 (M+1) CDCl3: 1,31 (d, 6H), 2,64 (t, 2H), 2,68-2,77 (m, 4H), 3,19 (t, 4H), 3,17-3,28 (m, 1H), 3,68 (t, 2H), 3,88 (s, 3H), 6,48 (dd, 1H), 6,55 (d, 1H), 7,23-7,32 (m, 1H), 7,62 (ddd, 1H), 7,91 (dd, 1H), 8,04 (dd, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,54 (sa, 1H) MS m / z 561, 563 (M + 1) CDCl3: 1.31 (d, 6H), 2.64 (t, 2H), 2.68-2.77 (m, 4H), 3.19 (t, 4H), 3.17-3.28 ( m, 1H), 3.68 (t, 2H), 3.88 (s, 3H), 6.48 (dd, 1H), 6.55 (d, 1H), 7.23-7.32 (m , 1H), 7.62 (ddd, 1H), 7.91 (dd, 1H), 8.04 (dd, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9 , 54 (sa, 1H)

28-3* 28-3 *

0,55 (AcOEt) CDCl3: 1,31 (d, 6H), 3,12-3,14 (m, 4H), 3,21-3,27 (m, 1H), 3,87-3,89 (m, 7H), 6,46 (dd, 1H), 6,53 (d, 1H), 7,23-7,27 (m, 1H), 7,30 (s, 1H), 7,59-7,64 (m, 1H), 7,91 (dd, 1H), 8,05 (d, 1H), 8,14 (s, 1H), 8,60 (d, 1H), 9,55 (s, 1H) 0.55 (AcOEt) CDCl3: 1.31 (d, 6H), 3.12-3.14 (m, 4H), 3.21-3.27 (m, 1H), 3.87-3.89 (m, 7H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.23-7.27 (m, 1H), 7.30 (s, 1H), 7.59-7.64 (m, 1H), 7.91 (dd, 1H), 8.05 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)

28-4* 28-4 *

0,37 (AcOEt) CDCl3: 1,32 (d, 6H), 3,21-3,27 (m, 1H), 4,00 (s, 1H), 7,11 (dd, 1H), 7,26-7,27 (m, 1H), 7,29-7,33 (m, 1H), 7,64 (s, 1H), 7,667,71 (m, 1H), 7,95 (dd, 1H), 8,10 (s, 1H), 8,21 (s, 1H), 8,46 (d, 1H), 8,50 (s, 1H), 8,54 (d, 1H), 9,59 (s, 1H) 0.37 (AcOEt) CDCl3: 1.32 (d, 6H), 3.21-3.27 (m, 1H), 4.00 (s, 1H), 7.11 (dd, 1H), 7.26-7.27 ( m, 1H), 7.29-7.33 (m, 1H), 7.64 (s, 1H), 7.667.71 (m, 1H), 7.95 (dd, 1H), 8.10 (s , 1H), 8.21 (s, 1H), 8.46 (d, 1H), 8.50 (s, 1H), 8.54 (d, 1H), 9.59 (s, 1H)

28-5* 28-5 *

0,03 (AcOEt) CDCl3: 1,31 (d, 6H), 1,67-1,77 (m, 2H), 1,95-2,05 (m, 2H), 2,39-2,48 (m, 1H), 2,482,61 (m, 2H), 2,63-2,78 (m, 8H), 3,24 (sept, 1H), 3,71-3,63 (m, 2H), 3,87 (s, 3H), 6,47 (dd, 1H), 6,55 (d, 1H), 7,21-7,28 (m, 1H), 7,61 (ddd, 1H), 7,91 (dd, 1H), 8,00 (dd, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,53 (sa, 1H) 0.03 (AcOEt) CDCl3: 1.31 (d, 6H), 1.67-1.77 (m, 2H), 1.95-2.05 (m, 2H), 2.39-2.48 (m, 1H), 2,482.61 (m, 2H), 2.63-2.78 (m, 8H), 3.24 (sept, 1H), 3.71-3.63 (m, 2H), 3.87 (s, 3H), 6.47 (dd, 1H), 6.55 (d, 1H), 7.21-7.28 (m, 1H), 7.61 (ddd, 1H), 7.91 (dd, 1H ), 8.00 (dd, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.53 (sa, 1H)

28-6* 28-6 *

502 (M+H) 2,84 502 (M + H) 2.84

28-7* 28-7 *

478 (M+H) 4,53 478 (M + H) 4.53

28-8* 28-8 *

EM 599 CDCl3: 1,31 (d, 6H), 1,51-1,42 (m, 2H), 1,67-1,53 (m, 4H), 1,81-1,68 (m, 2H), 1,961,89 (m, 2H), 2,47-2,36 (m, 1H), 2,57-2,54 (m, 4H), 2,69 (dd, 2H), 3,24 (sept, 1H), 3,67 (d, 1H), 3,87 (s, 1H), 6,48 (dd, 1H), 6,56 (d, 1H), 7,31-7,21 (m, 1H), 7,63-7,59 (m, 1H), 8,00 (d, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,55 (s, 1H) MS 599 CDCl3: 1.31 (d, 6H), 1.51-1.42 (m, 2H), 1.67-1.53 (m, 4H), 1.81-1.68 (m, 2H), 1,961.89 (m, 2H), 2.47-2.36 (m, 1H), 2.57-2.54 (m, 4H), 2.69 (dd, 2H), 3.24 (sept, 1H), 3.67 (d, 1H), 3.87 (s, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.31-7.21 (m, 1H ), 7.63-7.59 (m, 1H), 8.00 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)

28-9* 28-9 *

EM 585 CDCl3: 1,26 (t, 3H), 1,31 (d, 6H), 1,74-1,68 (m, 2H), 1,85-1,76 (m, 4H), 2,08-1,98 (m, 2H), 2,19-2,10 (m, 2H), 2,67-2,58 (m, 4H), 2,79-2,72 (m, 2H), 3,24 (sept, 1H), 3,61 (d, 2H), 3,87 (s, 3H), 6,48 (dd, 1H), 6,56 (d, 1H), 7,29-7,22 (m, 1H), 7,62 (dd, 1H), 7,90 (dd, 1H), 7,99 (d, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,53 (s, 1H) MS 585 CDCl3: 1.26 (t, 3H), 1.31 (d, 6H), 1.74-1.68 (m, 2H), 1.85-1.76 (m, 4H), 2.08- 1.98 (m, 2H), 2.19-2.10 (m, 2H), 2.67-2.58 (m, 4H), 2.79-2.72 (m, 2H), 3, 24 (sept, 1H), 3.61 (d, 2H), 3.87 (s, 3H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.29-7.22 (m, 1H), 7.62 (dd, 1H), 7.90 (dd, 1H), 7.99 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H) , 9.53 (s, 1 H)

28-10* 28-10 *

EM 559 CDCl3: 1,31 (d, 6H), 1,59-1,37 (m, 2H), 1,81-1,69 (m, 1H), 1,87 (d, 2H), 2,73-2,67 (m, 2H), 3,28-3,21 (m, 1H), 3,37 (s, 3H), 3,61 (d, 1H), 3,87 (s, 3H), 6,49 (dd, 1H), 6,57 (s, 1H), 7,31-7,21 (m, 1H), 7,64-7,60 (m, 1H), 7,91 (dd, 1H), 8,00 (d, 1H), 8,60 (d, 1H), 9,53 (s, 1H) MS 559 CDCl3: 1.31 (d, 6H), 1.59-1.37 (m, 2H), 1.81-1.69 (m, 1H), 1.87 (d, 2H), 2.73- 2.67 (m, 2H), 3.28-3.21 (m, 1H), 3.37 (s, 3H), 3.61 (d, 1H), 3.87 (s, 3H), 6 , 49 (dd, 1H), 6.57 (s, 1H), 7.31-7.21 (m, 1H), 7.64-7.60 (m, 1H), 7.91 (dd, 1H ), 8.00 (d, 1H), 8.60 (d, 1H), 9.53 (s, 1H)

28-11* 28-11 *

EM 558 CDCl3: 1,31 (d, 6H), 2,15 (s, 3H), 3,12 (ddd, 4H), 3,24 (sept, 1H), 3,64 (t, 2H), 3,80 (t, 2H), 3,89 (s, 3H), 6,47 (dd, 1H), 6,55 (d, 1H), 7,29-7,24 (m, 1H), 7,33 (sa, 1H), 7,62 (m, 1H), 7,92 (dd, 1H), 8,08 (d, 1H), 8,14 (s, 1H), 8,60 (d, 1H), 9,55 (s, 1H) MS 558 CDCl3: 1.31 (d, 6H), 2.15 (s, 3H), 3.12 (ddd, 4H), 3.24 (sept, 1H), 3.64 (t, 2H), 3.80 (t, 2H), 3.89 (s, 3H), 6.47 (dd, 1H), 6.55 (d, 1H), 7.29-7.24 (m, 1H), 7.33 ( sa, 1H), 7.62 (m, 1H), 7.92 (dd, 1H), 8.08 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1 H)

28-12* 28-12 *

EM 544 CDCl3: 1,16 (t, 3H), 1,31 (d, 6H), 2,56-2,44 (a, 2H), 2,71-2,60 (m, 4H), 3,28-3,17 (m, 5H), 3,88 (s, 3H), 6,48 (dd, 1H), 6,58 (d, 1H), 7,30-7,22 (m, 1H), 7,63-7,58 (m, 1H), 7,90 (dd, 1H), 8,01 (d, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,54 (s, 1H) MS 544 CDCl3: 1.16 (t, 3H), 1.31 (d, 6H), 2.56-2.44 (a, 2H), 2.71-2.60 (m, 4H), 3.28- 3.17 (m, 5H), 3.88 (s, 3H), 6.48 (dd, 1H), 6.58 (d, 1H), 7.30-7.22 (m, 1H), 7 , 63-7.58 (m, 1H), 7.90 (dd, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9, 54 (s, 1H)

28-13* 28-13 *

EM 601 CDCl3: 1,31 (d, 6H, J=6,55), 1,75-1,63 (m, 2H), 2,00-1,91 (m, 2H), 2,37-2,27 (m, 1H), 2,60 (t, 4H, J=4,79), 2,74-2,59 (m, 2H), 3,24 (sept, 1H), 3,66 (d, 2H, J=12,1), 3,75 (t, 4H, J=4,53), 3,88 (s, 3H), 6,48 (dd, 1H, J=2,52, 8,56), 6,56 (d, 1H, J=2,52), 7,337,22 (m, 1H), 7,64-7,59 (m, 1H), 7,91 (dd, 1H, J=8,05, 1,51), 8,01 (d, 1H, J=8,56), 8,12 (s, 1H), 8,61 (d, 1H, J=7,55), 9,54 (s, 1H) MS 601 CDCl3: 1.31 (d, 6H, J = 6.55), 1.75-1.63 (m, 2H), 2.00-1.91 (m, 2H), 2.37-2.27 (m, 1H), 2.60 (t, 4H, J = 4.79), 2.74-2.59 (m, 2H), 3.24 (sept, 1H), 3.66 (d, 2H , J = 12.1), 3.75 (t, 4H, J = 4.53), 3.88 (s, 3H), 6.48 (dd, 1H, J = 2.52, 8.56) , 6.56 (d, 1H, J = 2.52), 7.337.22 (m, 1H), 7.64-7.59 (m, 1H), 7.91 (dd, 1H, J = 8, 05, 1.51), 8.01 (d, 1H, J = 8.56), 8.12 (s, 1H), 8.61 (d, 1H, J = 7.55), 9.54 ( s, 1H)

28-14* 28-14 *

EM 559 CDCl3: 1,11 (d, 6H, J=6,55), 1,31 (d, 6H, J=7,05), 2,82-2,68 (m, 5H), 3,20-3,17 (m, 4H), 3,28-3,17 (m, 1H), 3,87 (s, 3H), 6,48 (dd, 1H, J=2,52, 8,56), 6,56 (d, 1H, J=2,52), 7,33-7,24 (m, 1H), 7,62-7,58 (m, 1H), 7,90 (dd, 1H, J=), 8,01 (d, 1H, J=8,56), 8,12 (s, 1H), 8,60 (d, 1H, J=8,56), 9,54 (s, 1H) MS 559 CDCl3: 1.11 (d, 6H, J = 6.55), 1.31 (d, 6H, J = 7.05), 2.82-2.68 (m, 5H), 3.20-3 , 17 (m, 4H), 3.28-3.17 (m, 1H), 3.87 (s, 3H), 6.48 (dd, 1H, J = 2.52, 8.56), 6 , 56 (d, 1H, J = 2.52), 7.33-7.24 (m, 1H), 7.62-7.58 (m, 1H), 7.90 (dd, 1H, J = ), 8.01 (d, 1H, J = 8.56), 8.12 (s, 1H), 8.60 (d, 1H, J = 8.56), 9.54 (s, 1H)

28-15* 28-15 *

EM 559 CDCl3: 1,31 (d, 6H, J=7,05), 1,97-1,85 (m, 2H), 2,17-1,98 (m, 2H), 2,35-2,25 (m, 1H), 2,75 (m, 2H), 3,24 (sept, 1H), 3,65 (d, 2H), 3,88 (s, 3H), 5,30 (sa, 1H), 5,48 (sa, 1H), 6,48 (dd, 1H, J=2,51, 8,56), 6,56 (d, 1H, J=2,52), 7,33-7,21 (m, 1H), 7,62 (m, 1H), 7,91 (dd, 1H, J=1,51, 8,06), 8,03 (dd, 1H, J=3,02, 8,56), 8,13 (s, 1H), 8,60 (d, 1H, J=8,57), 9,54 (s, 1H) MS 559 CDCl3: 1.31 (d, 6H, J = 7.05), 1.97-1.85 (m, 2H), 2.17-1.98 (m, 2H), 2.35-2.25 (m, 1H), 2.75 (m, 2H), 3.24 (sept, 1H), 3.65 (d, 2H), 3.88 (s, 3H), 5.30 (sa, 1H) , 5.48 (sa, 1H), 6.48 (dd, 1H, J = 2.51, 8.56), 6.56 (d, 1H, J = 2.52), 7.33-7, 21 (m, 1H), 7.62 (m, 1H), 7.91 (dd, 1H, J = 1.51, 8.06), 8.03 (dd, 1H, J = 3.02, 8 , 56), 8.13 (s, 1H), 8.60 (d, 1H, J = 8.57), 9.54 (s, 1H)

28-16* 28-16 *

EM 532 CDCl3: 1,31 (d, 6H, J=7,06), 1,46-1,43 (m, 1H), 1,79-1,68 (m, 2H), 2,08-1,99 (m, 2H), 2,99-2,88 (m, 2H), 3,24 (sept, 1H), 3,513,45 (m, 2H), 3,91-3,80 (m, 1H), 3,88 (s, 3H), 6,49 (dd, 1H, J=2,52, 8,56), 6,57 (d, 1H), J=2,52), 7,34-7,23 (m, 1H), 7,64-7,60 (m, 1H), 7,91 (dd, 1H, J=1,51, 8,06), 8,02 (dd, 1H, J=3,02, 9,06), 8,13 (s, 1H), 8,60 (d, 1H, J=8,06), 9,53 (s, 1H) EM 532 CDCl3: 1.31 (d, 6H, J = 7.06), 1.46-1.43 (m, 1H), 1.79-1.68 (m, 2H), 2.08-1.99 (m, 2H), 2.99-2.88 (m, 2H), 3.24 (sept, 1H), 3,513.45 (m, 2H), 3.91-3.80 (m, 1H), 3.88 (s, 3H), 6.49 (dd, 1H, J = 2.52, 8.56), 6.57 (d, 1H), J = 2.52), 7.34-7, 23 (m, 1H), 7.64-7.60 (m, 1H), 7.91 (dd, 1H, J = 1.51, 8.06), 8.02 (dd, 1H, J = 3 , 02, 9.06), 8.13 (s, 1H), 8.60 (d, 1H, J = 8.06), 9.53 (s, 1H)

28-17* 28-17 *

EM 532 CDCl3: 1,31 (d, 6H, J=6,96), 2,18-2,12 (m, 2H), 3,24 (sept, 1H), 3,37-3,32 (m, 2H), 3,39 (s, 3H), 3,43 (d, 1H, J=8,56), 3,51 (dd, 1H, J=5,04, 10,6), 3,87 (s, 3H), 4,17-4,09 (m, 1H), 6,13 (dd, 1H, J=2,51, 8,56), 6,16 (d, 1H, J=2,52), 7,09 (sa, 1H), 7,31-7,21 (m, 1H), 7,60-7,56 (m, 1H), 7,85 (d, 1H, J=8,56), 7,89 (dd, 1H, J=1,51, 8,06), 8,10 (s, 1H), 8,65 (d, 1H, J=9,06), 9,54 (s, 1H) EM 532 CDCl3: 1.31 (d, 6H, J = 6.96), 2.18-2.12 (m, 2H), 3.24 (sept, 1H), 3.37-3.32 (m, 2H ), 3.39 (s, 3H), 3.43 (d, 1H, J = 8.56), 3.51 (dd, 1H, J = 5.04, 10.6), 3.87 (s , 3H), 4.17-4.09 (m, 1H), 6.13 (dd, 1H, J = 2.51, 8.56), 6.16 (d, 1H, J = 2.52) , 7.09 (sa, 1H), 7.31-7.21 (m, 1H), 7.60-7.56 (m, 1H), 7.85 (d, 1H, J = 8.56) , 7.89 (dd, 1H, J = 1.51, 8.06), 8.10 (s, 1H), 8.65 (d, 1H, J = 9.06), 9.54 (s, 1 HOUR)

28-18* 28-18 *

EM 546 CDCl3: 1,31 (d, 6H, J=7,05), 1,82-1,70 (m, 2H), 2,08-1,99 (m, 2H), 2,96-2,87 (m, 2H), 3,24 (sept, 1H), 3,41-3,33 (m, 1H), 3,40 (s, 3H), 3,51-3,42 (m, 2H), 3,87 (s, 3H), 6,49 (dd, 1H, J=2,52, 9,07), 6,57 (d, 1H, J=2,52), 7,32-7,22 (m, 1H), 7,64-7,60 (m, 1H), 7,91 (dd, 1H), 8,00 (dd, 1H, J=3,02, 9,06), 8,12 (s, 1H), 8,60 (d, 1H, J=8,56), 9,53 (s, 1H) MS 546 CDCl3: 1.31 (d, 6H, J = 7.05), 1.82-1.70 (m, 2H), 2.08-1.99 (m, 2H), 2.96-2.87 (m, 2H), 3.24 (sept, 1H), 3.41-3.33 (m, 1H), 3.40 (s, 3H), 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.49 (dd, 1H, J = 2.52, 9.07), 6.57 (d, 1H, J = 2.52), 7.32-7.22 (m, 1H), 7.64-7.60 (m, 1H), 7.91 (dd, 1H), 8.00 (dd, 1H, J = 3.02, 9.06), 8.12 (s, 1H), 8.60 (d, 1H, J = 8.56), 9.53 (s, 1H)

28-19* 28-19 *

0,33 (AcOEt) CDCl3: 1,31 (d, 6H, J=7,05), 1,82-1,70 (m, 2H), 2,08-1,99 (m, 2H), 2,96-2,87 (m, 2H), 3,24 (sept, 1H), 3,41-3,33 (m, 1H), 3,40 (s, 3H), 3,51-3,42 (m, 2H), 3,87 (s, 3H), 6,49 (dd, 1H, J=2,52, 9,07), 6,57 (d, 1H, J=2,52), 7,32-7,22 (m, 1H), 7,62 (m, 1H), 7,91 (dd, 1H), 8,00 (dd, 1H, J=3,02, 9,06), 8,12 (s, 1H), 8,60 (d, 1H, J=8,56), 9,53 (s, 1H) 0.33 (AcOEt) CDCl3: 1.31 (d, 6H, J = 7.05), 1.82-1.70 (m, 2H), 2.08-1.99 (m, 2H), 2.96-2.87 (m, 2H), 3.24 (sept, 1H), 3.41-3.33 (m, 1H), 3.40 (s, 3H), 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.49 (dd, 1H, J = 2.52, 9.07), 6.57 (d, 1H, J = 2.52), 7.32-7.22 (m, 1H), 7.62 (m, 1H), 7.91 (dd, 1H), 8.00 (dd, 1H, J = 3.02, 9.06), 8.12 (s, 1H ), 8.60 (d, 1H, J = 8.56), 9.53 (s, 1H)

28-20* 28-20 *

EM 544 CDCl3: 1,31 (d, 6H), 1,66-1,53 (m, 2H), 2,10-2,01 (m, 2H), 2,51 (s, 3H), 2,70-2,13 (m, 1H), 2,83-2,74 (m, 2H), 3,24 (sept, 1H), 3,63-3,55 (m, 2H), 3,87 (s, 3H), 4,34-4,25 (m, 1H), 6,48 (dd, 1H), 6,56 (d, 1H), 7,347,24 (m, 1H), 7,64-7,60 (m, 1H), 7,90 (dd, 1H), 8,00 (d, 1H), 8,12 (s, 1H), 8,60 (dd, 1H), 9,53 (s, 1H) MS 544 CDCl3: 1.31 (d, 6H), 1.66-1.53 (m, 2H), 2.10-2.01 (m, 2H), 2.51 (s, 3H), 2.70- 2.13 (m, 1H), 2.83-2.74 (m, 2H), 3.24 (sept, 1H), 3.63-3.55 (m, 2H), 3.87 (s, 3H), 4.34-4.25 (m, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.347.24 (m, 1H), 7.64-7.60 (m, 1H), 7.90 (dd, 1H), 8.00 (d, 1H), 8.12 (s, 1H), 8.60 (dd, 1H), 9.53 (s, 1H)

28-21* 28-21 *

EM 531 CDCl3: 1,30 (s, 3H), 1,32 (s, 3H), 2,33-2,22 (m, 1H), 2,54 (s, 3H), 3,37-3,20 (m, 3H), 3,57-3,44 (m, 3H), 3,86 (s, 3H), 6,12 (dd, 1H), 6,16 (d, 1H), 7,14-7,08 (m, 1H), 7,307,20 (m, 1H), 7,65-7,58 (m, 1H), 7,93-7,87 (m, 1H), 8,10 (s, 1H), 8,64 (d, 1H), 9,54 (s, 1H) MS 531 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 2.33-2.22 (m, 1H), 2.54 (s, 3H), 3.37-3.20 ( m, 3H), 3.57-3.44 (m, 3H), 3.86 (s, 3H), 6.12 (dd, 1H), 6.16 (d, 1H), 7.14-7 , 08 (m, 1H), 7.307.20 (m, 1H), 7.65-7.58 (m, 1H), 7.93-7.87 (m, 1H), 8.10 (s, 1H ), 8.64 (d, 1H), 9.54 (s, 1H)

28-22* 28-22 *

EM 545 CDCl3: 1,30 (s, 3H), 1,32 (s, 3H), 2,03-1,89 (m, 1H), 2,30-2,18 (m, 1H), 2,34 (s, 6H), 2,96-2,83 (m, 1H), 3,29-3,16 (m, 2H), 3,403,34 (m, 1H), 3,53-3,43 (m, 2H), 3,87 (s, 3H), 6,11 (dd, 1H), 6,13 (dd, 1H), 7,08 (sa, 1H), 7,31-7,21 (m, 1H), 7,60-7,56 (m, 1H), 7,85 (d, 1H), 7,89 (dd, 1H), 8,10 (s, 1H), 8,66 (d, 1H), 9,54 (s, 1H) MS 545 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 2.03-1.89 (m, 1H), 2.30-2.18 (m, 1H), 2.34 ( s, 6H), 2.96-2.83 (m, 1H), 3.29-3.16 (m, 2H), 3.403.34 (m, 1H), 3.53-3.43 (m, 2H), 3.87 (s, 3H), 6.11 (dd, 1H), 6.13 (dd, 1H), 7.08 (sa, 1H), 7.31-7.21 (m, 1H ), 7.60-7.56 (m, 1H), 7.85 (d, 1H), 7.89 (dd, 1H), 8.10 (s, 1H), 8.66 (d, 1H) , 9.54 (s, 1 H)

28-23* 28-23 *

EM 545 CDCl3: 1,31 (s, 3H), 1,32 (s, 3H), 3,05 (s, 3H), 3,24 (sept, 1H), 3,50-3,43 (m, 4H), 3,85 (s, 2H), 3,89 (s, 3H), 6,11 (dd, 1H), 6,43 (dd, 1H), 6,50 (d, 1H), 7,31-7,28 (m, 1H), 7,64-7,60 (m, 1H), 7,92 (dd, 1H), 8,09 (d, 1H), 8,13 (s, 1H), 8,58 (d, 1H), 9,55 (s, 1H) MS 545 CDCl3: 1.31 (s, 3H), 1.32 (s, 3H), 3.05 (s, 3H), 3.24 (sept, 1H), 3.50-3.43 (m, 4H) , 3.85 (s, 2H), 3.89 (s, 3H), 6.11 (dd, 1H), 6.43 (dd, 1H), 6.50 (d, 1H), 7.31- 7.28 (m, 1H), 7.64-7.60 (m, 1H), 7.92 (dd, 1H), 8.09 (d, 1H), 8.13 (s, 1H), 8 , 58 (d, 1H), 9.55 (s, 1H)

28-24* 28-24 *

0,05 (AcOEt/MeOH = 4/1) CDCl3: 1,30 (s, 3H), 1,32 (s, 3H), 1,92-1,83 (m, 1H), 2,17-1,95 (m, 1H), 2,43-2,27 (m, 2H), 2,79-2,71 (m, 4H), 3,15-2,97 (m, 4H), 3,23-3,16 (m, 4H), 3,24 (sept, 1H), 3,87 (s, 3H), 6,11 (dd, 1H), 6,47 (dd, 1H), 6,55 (d, 1H), 7,33-7,23 (m, 1H), 7,63-7,59 (m, 1H), 7,95 (dd, 1H), 8,01 (dd, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,54 (s, 1H) 0.05 (AcOEt / MeOH = 4/1) CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.92-1.83 (m, 1H), 2.17-1.95 (m, 1H), 2.43- 2.27 (m, 2H), 2.79-2.71 (m, 4H), 3.15-2.97 (m, 4H), 3.23-3.16 (m, 4H), 3, 24 (sept, 1H), 3.87 (s, 3H), 6.11 (dd, 1H), 6.47 (dd, 1H), 6.55 (d, 1H), 7.33-7.23 (m, 1H), 7.63-7.59 (m, 1H), 7.95 (dd, 1H), 8.01 (dd, 1H), 8.12 (s, 1H), 8.60 ( d, 1H), 9.54 (s, 1H)

28-25* 28-25 *

EM 600 CDCl3: 1,30 (s, 3H), 1,32 (s, 3H), 1,80-1,70 (m, 2H), 2,01-1,93 (m, 2H), 2,49-2,28 (m, 12H), 2,76-2,62 (m, 4H), 3,04-2,96 (m, 4H), 3,16-3,05 (m, 2H), 3,24 (sept, 1H), 3,723,63 (m, 2H), 3,87 (s, 3H), 6,48 (dd, 1H), 6,55 (d, 1H), 7,31-7,23 (m, 1H), 7,66-7,589 (m, 1H), 7,91 (dd, 1H), 8,01 (d, 1H), 8,12 (s, 1H), 8,60 (d, 1H), 9,53 (s, 1H) EM 600 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.80-1.70 (m, 2H), 2.01-1.93 (m, 2H), 2.49- 2.28 (m, 12H), 2.76-2.62 (m, 4H), 3.04-2.96 (m, 4H), 3.16-3.05 (m, 2H), 3, 24 (sept, 1H), 3,723.63 (m, 2H), 3.87 (s, 3H), 6.48 (dd, 1H), 6.55 (d, 1H), 7.31-7.23 (m, 1H), 7.66-7.589 (m, 1H), 7.91 (dd, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.53 (s, 1H)

28-26* 28-26 *

EM 573 CDCl3: 1,30 (s, 3H), 1,32 (s, 3H), 2,59-2,43 (m, 4H), 2,78-2,73 (m, 1H), 3,00-2,86 (m, 2H), 3,38-3,20 (m, 3H), 3,54-2,45 (m, 1H), 3,73 (dd, 1H), 3,84-3,77 (m, 1H), 3,94-3,87 (m, 1H), 3,88 (s, 3H), 6,46 (dd, 1H), 6,53 (d, 1H), 7,32-7,23 (m, 1H), 7,31 (sa, 1H), 7,63-7,52 (m, 1H), 7,91 (dd, 1H), 8,04 (d, 1H), 8,13 (s, 1H), 8,60 (d, 1H), 9,54 (s, 1H) MS 573 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 2.59-2.43 (m, 4H), 2.78-2.73 (m, 1H), 3.00- 2.86 (m, 2H), 3.38-3.20 (m, 3H), 3.54-2.45 (m, 1H), 3.73 (dd, 1H), 3.84-3, 77 (m, 1H), 3.94-3.87 (m, 1H), 3.88 (s, 3H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.32 -7.23 (m, 1H), 7.31 (sa, 1H), 7.63-7.52 (m, 1H), 7.91 (dd, 1H), 8.04 (d, 1H), 8.13 (s, 1H), 8.60 (d, 1H), 9.54 (s, 1H)

28-27* 28-27 *

EM 559 CDCl3: 1,30 (s, 3H), 1,32 (s, 3H), 1,82-1,73 (m, 1H), 1,97-1,84 (m, 3H), 2,73-2,51 (m, 1H), 3,12 (t, 2H), 3,31-3,20 (m, 3H), 3,90 (s, 3H), 5,46-5,37 (m, 1H), 6,53 (dd, 1H), 6,59 (d, 1H), 6,68-6,62 (m, 1H), 7,28-7,21 (m, 1H), 7,33 (sa, 1H), 7,65-7,61 (m, 1H), 7,92 (dd, 1H), 8,08 (d, 1H), 8,14 (s, 1H), 8,60 (d, 1H), 9,55 (s, 1H) MS 559 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.82-1.73 (m, 1H), 1.97-1.84 (m, 3H), 2.73- 2.51 (m, 1H), 3.12 (t, 2H), 3.31-3.20 (m, 3H), 3.90 (s, 3H), 5.46-5.37 (m, 1H), 6.53 (dd, 1H), 6.59 (d, 1H), 6.68-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.33 (sa, 1H), 7.65-7.61 (m, 1H), 7.92 (dd, 1H), 8.08 (d, 1H), 8.14 (s, 1H), 8.60 ( d, 1H), 9.55 (s, 1H)

imagen12image12

Ej. nº Ex. Nº

Rx Tiempo de retención HPLC (min) Masa (ESI) m/z Rx HPLC retention time (min) Mass (ESI) m / z

29-1* 29-1 *

3,30 546 (M+H) 3.30 546 (M + H)

imagen13image13

Ej. nº Ex. Nº

Rx Tiempo de retención HPLC (min) Masa (ESI) m/z Rx HPLC retention time (min) Mass (ESI) m / z

30-1* 30-1 *

2,82 516 (M+H) 2.82 516 (M + H)

30-2* 30-2 *

2,65 557 (M+H) 2.65 557 (M + H)

30-3* 30-3 *

2,50 557 (M+H) 2.50 557 (M + H)

30-4* 30-4 *

3,10 498 (M+H) 3.10 498 (M + H)

30-5* 30-5 *

2,30 543 (M+H) 2.30 543 (M + H)

30-6* 30-6 *

2,52 557 (M+H) 2.52 557 (M + H)

30-7* 30-7 *

2,23 612 (M+H) 2.23 612 (M + H)

imagen14image14

Ej. nº Ex. Nº

Rx EM RMN (400 MHz) en CDCl3, δ (ppm) Rx EM NMR (400 MHz) in CDCl3, δ (ppm)

32-1* 32-1 *

585,3 1,03 (s, 3H), 1,04 (s, 3H), 2,15 (s, 3H), 2,32 (sept, 1H), 3,00 (d, 2H), 3,10 (t, 2H), 3,13 (t, 2H), 3,64 (t, 2H), 3,79 (t, 2H), 3,89 (s, 3H), 6,45 (dd, 1H), 6,55 (d, 1H), 7,34-7,26 (m, 1H), 7,52 (sa, 1H), 7,64-7,60 (m, 1H), 7,97 (dd, 1H), 8,07 (d, 1H), 8,15 (s, 1H), 8,54 (d, 1H), 9,32 (s, 1H) 585.3 1.03 (s, 3H), 1.04 (s, 3H), 2.15 (s, 3H), 2.32 (sept, 1H), 3.00 (d, 2H), 3.10 (t , 2H), 3.13 (t, 2H), 3.64 (t, 2H), 3.79 (t, 2H), 3.89 (s, 3H), 6.45 (dd, 1H), 6 , 55 (d, 1H), 7.34-7.26 (m, 1H), 7.52 (sa, 1H), 7.64-7.60 (m, 1H), 7.97 (dd, 1H ), 8.07 (d, 1H), 8.15 (s, 1H), 8.54 (d, 1H), 9.32 (s, 1H)

imagen15image15

Ej. nº Ex. Nº

Rx Tiempo de retención HPLC (min) Masa (ESI) m/z Rx HPLC retention time (min) Mass (ESI) m / z

34-1* 34-1 *

3,15 532 (M+H) 3.15 532 (M + H)

34-2* 34-2 *

3,34 558 (M+H) 3.34 558 (M + H)

34-3* 34-3 *

3,35 546 (M+H) 3.35 546 (M + H)

34-4* 34-4 *

3,32 546 (M+H) 3.32 546 (M + H)

34-5* 34-5 *

3,09 566 (M+H) 3.09 566 (M + H)

34-7* 34-7 *

EM 435, 436 1,05 (t, 3H), 1,69-1,78 (m, 2H), 2,862,95 (m, 1H), 3,16-3,25 (m, 1H), 6,576,68 (m, 2H), 7,17 (dd, 1H), 7,35-7,39 (m, 1H), 7,50 (dd, 1H), 8,13 (s, 1H), 8,16-8,21 (m, 1H), 8,48 (d, 1H), 10,14 (s, 1H) MS 435, 436 1.05 (t, 3H), 1.69-1.78 (m, 2H), 2,862.95 (m, 1H), 3.16-3.25 (m, 1H), 6,576.68 (m, 2H), 7.17 (dd, 1H), 7.35-7.39 (m, 1H), 7.50 (dd, 1H), 8.13 (s, 1H), 8.16-8.21 (m, 1H), 8.48 (d, 1H), 10.14 (s, 1H)

34-8* 34-8 *

EM 549, 551 0,94 (t, 3H), 1,69-1,80 (m, 2H), 2,38 (s, 3H), 2,55-2,64 (m, 4H), 3,02-3,08 (m, 2H), 3,22-3,29 (m, 4H), 3,88 (s, 3H), 6,55 (ddd, 1H), 6,60-6,66 (m, 1H), 7,13-7,18 (m, 1H), 7,34 (sa, 1H), 7,44 (d, 1H), 8,10 (s, 1H), 8,10-8,23 (m, 2H), 8,88 (s, 1H) MS 549, 551 0.94 (t, 3H), 1.69-1.80 (m, 2H), 2.38 (s, 3H), 2.55-2.64 (m, 4H), 3.02-3, 08 (m, 2H), 3.22-3.29 (m, 4H), 3.88 (s, 3H), 6.55 (ddd, 1H), 6.60-6.66 (m, 1H) , 7.13-7.18 (m, 1H), 7.34 (sa, 1H), 7.44 (d, 1H), 8.10 (s, 1H), 8.10-8.23 (m , 2H), 8.88 (s, 1H)

imagen1image 1

35-1* 35-1 *

567 [M+1]+ DMSO-d6: 2,24 (s, 3H), 2,45-2,50 (m, 4H), 2,78 (d, 3H), 3,10-3,17 (m, 8H), 3,74-3,97 (m, 7H), 6,49 (dd, 1H), 6,66 (d, 1H), 6,85-6,89 (m, 1H), 7,18 (d, 1H), 7,40 (d, 1H), 7,98-8,02 (m, 2H), 8,29 (da, 1H), 8,60-8,66 (m, 1H), 11,17 (s, 1H) 567 [M + 1] + DMSO-d6: 2.24 (s, 3H), 2.45-2.50 (m, 4H), 2.78 (d, 3H), 3.10-3.17 (m, 8H), 3, 74-3.97 (m, 7H), 6.49 (dd, 1H), 6.66 (d, 1H), 6.85-6.89 (m, 1H), 7.18 (d, 1H) , 7.40 (d, 1H), 7.98-8.02 (m, 2H), 8.29 (da, 1H), 8.60-8.66 (m, 1H), 11.17 (s , 1 HOUR)

35-2* 35-2 *

505 [M+1]+ DMSO-d6: 2,24 (s, 3H), 2,46-2,50 (m, 4H), 2,79 (d, 3H), 3,13-3,17 (m, 4H), 3,78 (s, 3H), 6,69 (d, 1H), 6,87 (dd, 1H), 7,07-7,17 (m, 2H), 7,19-7,23 (m, 2H), 7,54 (d, 1H), 8,13 (s, 1H), 8,45 (s, 1H), 8,65-8,75 (m, 1H), 9,04 (s, 1H), 11,19 (s, 1H) 505 [M + 1] + DMSO-d6: 2.24 (s, 3H), 2.46-2.50 (m, 4H), 2.79 (d, 3H), 3.13-3.17 (m, 4H), 3, 78 (s, 3H), 6.69 (d, 1H), 6.87 (dd, 1H), 7.07-7.17 (m, 2H), 7.19-7.23 (m, 2H) , 7.54 (d, 1H), 8.13 (s, 1H), 8.45 (s, 1H), 8.65-8.75 (m, 1H), 9.04 (s, 1H), 11.19 (s, 1 H)

Ejemplo 36 (productos intermedios para L-anilinas)
Example 36 (intermediate products for L-anilines)

5 5

36-1 Preparación de 2-amino-N-metil-benzamida 36-1 Preparation of 2-amino-N-methyl-benzamide

imagen16image16

10 [0129] A una suspensión de 16,3 g (100 mmoles) de anhídrido isatónico en 100 ml de H2O se añaden en porciones a temperatura ambiente 100 ml de una disolución de metilamina 2N en tetrahidrofurano (200 mmoles). La mezcla de reacción se agita durante 1 hora y después se extrae con AcOEt. La fase orgánica se lava con H2O y salmuera, se seca mediante Na2SO4 y se concentra a presión reducida para dar 13,79 g del producto deseado, 2[0129] To a suspension of 16.3 g (100 mmol) of isatonic anhydride in 100 ml of H2O 100 ml of a 2N methylamine solution in tetrahydrofuran (200 mmol) is added portionwise at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic phase is washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give 13.79 g of the desired product, 2

15 amino-N-metil-benzamida (92 mmoles, 92%), en forma de un sólido incoloro. RMN (400 MHz, CDCl3, δ): 2,97 (d, 3H, J = 4,52 Hz), 5,49 (sa, 1H), 6,07 (sa, 1H), 6,64 (ddd, 1H, J = 8,04, 7,56, 1,0 Hz), 6,68 (dd, 1H, J = 8,32, 1,0 Hz), 7,20 (ddd, 1H, J = 8,32, 7,56, 1,52 Hz), 7,29 (dd, 1H, J = 8,04, 1,52 Hz). Amino-N-methyl-benzamide (92 mmol, 92%), in the form of a colorless solid. NMR (400 MHz, CDCl3, δ): 2.97 (d, 3H, J = 4.52 Hz), 5.49 (sa, 1H), 6.07 (sa, 1H), 6.64 (ddd, 1H, J = 8.04, 7.56, 1.0 Hz), 6.68 (dd, 1H, J = 8.32, 1.0 Hz), 7.20 (ddd, 1H, J = 8, 32, 7.56, 1.52 Hz), 7.29 (dd, 1H, J = 8.04, 1.52 Hz).

36-2 20 2-(2,5-Dicloro-pirimidin-4-ilamino)-N-metil-benzamida 36-2 20 2- (2,5-Dichloro-pyrimidin-4-ylamino) -N-methyl-benzamide

[0130] [0130]

imagen1image 1

[0131] A una disolución de 15,0 g (99,8 mmoles) de 2-amino-N-metil-benzamida en DMF (300 ml) se añaden 2,4,5-tricloropirimidina (23,8 g, 130 mmoles) y carbonato potásico (17,9 g, 130 mmoles). La mezcla de reacción se [0131] To a solution of 15.0 g (99.8 mmol) of 2-amino-N-methyl-benzamide in DMF (300 ml) are added 2,4,5-trichloropyrimidine (23.8 g, 130 mmol ) and potassium carbonate (17.9 g, 130 mmol). The reaction mixture is

5 agita durante 5 horas a 75ºC, se enfría a temperatura ambiente y después se vierte en H2O (600 ml). El precipitado resultante se recoge mediante filtración y seguidamente se lava con CH3CN acuoso al 50% (200 ml) y se seca a presión reducida (40ºC, 10 horas) para dar la 2-(2,5-dicloro-pirimidin-4-il-amino)-N-metil-benzamida deseada en forma de un sólido de color marfil (26,4 g, 88,9 mmoles, 89%). RMN (400 MHz, DMSO-d6, δ): 2,81 (d, 3H, J = 4,52 Hz), 7,22 (dd, 1H, J = 8,56, 8,04 Hz), 7,60 (ddd, 1H, J = 8,56, 5 stirred for 5 hours at 75 ° C, cooled to room temperature and then poured into H2O (600 ml). The resulting precipitate is collected by filtration and then washed with 50% aqueous CH3CN (200 ml) and dried under reduced pressure (40 ° C, 10 hours) to give 2- (2,5-dichloro-pyrimidin-4-yl -amino) -N-methyl-benzamide desired in the form of an ivory solid (26.4 g, 88.9 mmol, 89%). NMR (400 MHz, DMSO-d6, δ): 2.81 (d, 3H, J = 4.52 Hz), 7.22 (dd, 1H, J = 8.56, 8.04 Hz), 7, 60 (ddd, 1H, J = 8.56,

10 8,56, 1,0 Hz), 7,81 (dd, 1H, J = 8,04, 1,0 Hz), 8,48 (s, 1H), 8,52 (d, 1H, J = 8,56 Hz), 8,80-8,90 (m, 1H), 12,18 (s, 1H). 10 8.56, 1.0 Hz), 7.81 (dd, 1H, J = 8.04, 1.0 Hz), 8.48 (s, 1H), 8.52 (d, 1H, J = 8.56 Hz), 8.80-8.90 (m, 1H), 12.18 (s, 1H).

[0132] Los siguientes compuestos se preparan como se ha descrito anteriormente. [0132] The following compounds are prepared as described above.

36-3 15 2-(5-Bromo-2-cloro-pirimidin-4-ilamino)-N-metil-benzamida 36-3 15 2- (5-Bromo-2-chloro-pyrimidin-4-ylamino) -N-methyl-benzamide

[0133] [0133]

imagen1image 1

20 RMN (400 MHz, DMSO-d6, δ): 2,81 (d, 3H), 7,23 (ddd, 1H, J = 7,54, 7,54, 1,0 Hz), 7,59 (ddd, 1H, J = 7,93, 8,06, 1,52 Hz), 7,79 (dd, 1H, J = 7,8, 1,52 Hz), 8,47 (dd, 1H, J=8,06, 1,0 Hz), 8,55 (s, 1H), 8,81-8,87 (m, 1H), 12,0 (sa, 1H). Rf: 0,46 (n-hexano:AcOEt = 7:3). NMR (400 MHz, DMSO-d6, δ): 2.81 (d, 3H), 7.23 (ddd, 1H, J = 7.54, 7.54, 1.0 Hz), 7.59 ( ddd, 1H, J = 7.93, 8.06, 1.52 Hz), 7.79 (dd, 1H, J = 7.8, 1.52 Hz), 8.47 (dd, 1H, J = 8.06, 1.0 Hz), 8.55 (s, 1H), 8.81-8.87 (m, 1H), 12.0 (sa, 1H). Rf: 0.46 (n-hexane: AcOEt = 7: 3).

25 36-4 25 36-4

2-(2,5-Dicloro-pirimidin-4-ilamino)-N-etil-benzamida 2- (2,5-Dichloro-pyrimidin-4-ylamino) -N-ethyl-benzamide

[0134] [0134]

30 30

imagen1image 1

RMN (400 MHz, CDCl3, δ): 1,28 (t, d=7,04, 3H), 3,48-3,57 (m, 2H), 6,22 (sa, 1H), 7,11-7,17 (m, 1H), 7,51 (dd, J=1,0, 8,04, 1H), 7,53-7,61 (m, 1H), 8,22 (s, 1H), 8,69-8,74 (m, 1H), 11,66 (sa, 1H). Rf: 0,60 (hexano:AcOEt = 1:1). 36-5 Preparación de 2-(5-bromo-2-cloro-pirimidin-4-ilamino)-N-metil-bencenosulfonamida NMR (400 MHz, CDCl3, δ): 1.28 (t, d = 7.04, 3H), 3.48-3.57 (m, 2H), 6.22 (sa, 1H), 7.11 -7.17 (m, 1H), 7.51 (dd, J = 1.0, 8.04, 1H), 7.53-7.61 (m, 1H), 8.22 (s, 1H), 8.69-8.74 (m, 1H), 11.66 (sa, 1H) . Rf: 0.60 (hexane: AcOEt = 1: 1). 36-5 Preparation of 2- (5-Bromo-2-chloro-pyrimidin-4-ylamino) -N-methyl-benzenesulfonamide

[0135] [0135]

imagen1image 1

10 Una suspensión de 5-bromo-2,4-dicloropirimidina (684 mg, 3,0 mmoles) y 2-amino-N-metil-bencenosulfonamida (559 mg, 3,0 mmoles) en N,N-dimetilformamida (10 ml) que contiene carbonato potásico (830 mg, 6,0 mmoles) se agita durante 23 horas a temperatura ambiente. Se añade cloruro de amonio acuoso saturado y la mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con salmuera, se seca mediante sulfato A suspension of 5-bromo-2,4-dichloropyrimidine (684 mg, 3.0 mmol) and 2-amino-N-methyl-benzenesulfonamide (559 mg, 3.0 mmol) in N, N-dimethylformamide (10 ml ) containing potassium carbonate (830 mg, 6.0 mmol) is stirred for 23 hours at room temperature. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with brine, dried by sulfate

15 sódico y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (gradiente de n-hexano-acetato de etilo) para proporcionar el compuesto del título en forma de un sólido amarillento.1H-RMN (CDCl3), δ (ppm): 2,67 (d, 3H), 4,79 (c, 1H), 7,26 (s, 1H), 7,29 (ddd, 1H), 7,66 (ddd, 1H), 7,95 (dd, 1H), 8,37 (s, 1H), 8,48 (d, 1H), 9,52 (s, 1H). Rf (n-hexano: acetato de etilo = 10:3): 0,33. 15 sodium and evaporates in vacuo. The residue is purified by silica gel column chromatography (gradient of n-hexane-ethyl acetate) to provide the title compound as a yellowish solid. 1 H-NMR (CDCl 3), δ (ppm): 2, 67 (d, 3H), 4.79 (c, 1H), 7.26 (s, 1H), 7.29 (ddd, 1H), 7.66 (ddd, 1H), 7.95 (dd, 1H ), 8.37 (s, 1H), 8.48 (d, 1H), 9.52 (s, 1H). Rf (n-hexane: ethyl acetate = 10: 3): 0.33.

20 [0136] El compuesto siguiente se prepara como se ha descrito anteriormente. [0136] The following compound is prepared as described above.

36-6 36-6

2-(2,5-Dicloro-pirimidin-4-ilamino)-N-metil-benceno-sulfonamida 25 2- (2,5-Dichloro-pyrimidin-4-ylamino) -N-methyl-benzene-sulfonamide

[0137] [0137]

imagen1image 1

1H-RMN (400 MHz, CDCl3, δ): 2,67 (d, 3H), 4,97-5,04 (m, 1H), 7,29 (ddd, 1H, J=7,54, 7,54, 1,0 Hz), 7,66 (ddd, 1H, 30 J=7,93, 8,08, 1,48 Hz), 7,94 (dd, 1H, J=8,04, 1,52 Hz), 8,24 (s, 1H), 8,51 (dd, 1H, J=8,06, 1,0 Hz), 9,64 (sa, 1H). Rf: 0,45 (n-hexano:AcOEt = 4:1). 1H-NMR (400 MHz, CDCl3, δ): 2.67 (d, 3H), 4.97-5.04 (m, 1H), 7.29 (ddd, 1H, J = 7.54, 7, 54, 1.0 Hz), 7.66 (ddd, 1H, 30 J = 7.93, 8.08, 1.48 Hz), 7.94 (dd, 1H, J = 8.04, 1.52 Hz), 8.24 (s, 1H), 8.51 (dd, 1H, J = 8.06, 1.0 Hz), 9.64 (sa, 1H). Rf: 0.45 (n-hexane: AcOEt = 4: 1).

36-7 36-7

35 2-(2,5-Dicloro-pirimidin-4-ilamino)-N-isopropil-benceno-sulfonamida 2- (2,5-Dichloro-pyrimidin-4-ylamino) -N-isopropyl-benzene-sulfonamide

[0138] [0138]

imagen1image 1

[0139] A una disolución de 2-amino-N-isopropil-benceno-sulfonamida (16,1 g, 75,1 mmoles) en DMI (150 ml) se añade en porciones hidruro sódico (6,6 g, 165,3 mmoles) a 0ºC. Tras agitar la mezcla durante una hora a [0139] To a solution of 2-amino-N-isopropyl-benzene-sulfonamide (16.1 g, 75.1 mmol) in DMI (150 ml) is added portionwise sodium hydride (6.6 g, 165.3 mmol) at 0 ° C. After stirring the mixture for one hour at

5 temperatura ambiente se añade a 0ºC 2,4,5-tricloropirimidina (20,7 g, 112,7 mmoles). Tras agitar durante otras 5 h a temperatura ambiente se añade agua y la mezcla se extrae tres veces con AcOEt. La fase orgánica se lava con salmuera, se seca mediante sulfato sódico y se evapora a presión reducida. El residuo se purifica mediante cromatografía en columna de gel de sílice (hexano a hexano:AcOEt = 4:1) para proporcionar el compuesto del título en forma de un sólido pardo pálido (10,2 g, 38%).At room temperature, 2,4,5-trichloropyrimidine (20.7 g, 112.7 mmol) is added at 0 ° C. After stirring for another 5 h at room temperature water is added and the mixture is extracted three times with AcOEt. The organic phase is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography (hexane to hexane: AcOEt = 4: 1) to give the title compound as a pale brown solid (10.2 g, 38%).

10 1H-RMN (400 MHz, CDCl3, δ): 1,06 (d, 6H), 3,43-3,53 (m, 1H), 4,38 (d, 1H), 7,29 (dd, 1H), 7,66 (dd, 1H), 7,98 (d, 1H), 8,29 (s, 1H), 8,51 (d, 1H), 9,51 (sa, 1H). Rf: 0,45 (n-hexano:AcOEt = 4:1). 10 1H-NMR (400 MHz, CDCl3, δ): 1.06 (d, 6H), 3.43-3.53 (m, 1H), 4.38 (d, 1H), 7.29 (dd, 1H), 7.66 (dd, 1H), 7.98 (d, 1H), 8.29 (s, 1H), 8.51 (d, 1H), 9.51 (sa, 1H). Rf: 0.45 (n-hexane: AcOEt = 4: 1).

[0140] [0140]

15 fifteen

imagen17image17

Ej. nº Ex. Nº

Rz Rf (disolvente) o EM RMN (400 MHz), δ (ppm) Rz Rf (solvent) or MS NMR (400 MHz), δ (ppm)

36-8 36-8

0,45 (n-hexano:AcOEt = 4:1) DMSO-d6: 0,63 (t, 6H), 0,86 (d, 3H), 1,21-1,31 (m, 2H), 3,02-3,12 (m, 1H), 7,37 (dd, 1H), 7,71 (dd, 1H), 7,85 (d, 1H), 7,89 (d, 1H), 8,20 (d, 1H), 8,56 (d, 1H), 9,51 (sa, 1H) 0.45 (n-hexane: AcOEt = 4: 1) DMSO-d6: 0.63 (t, 6H), 0.86 (d, 3H), 1.21-1.31 (m, 2H), 3.02-3.12 (m, 1H), 7, 37 (dd, 1H), 7.71 (dd, 1H), 7.85 (d, 1H), 7.89 (d, 1H), 8.20 (d, 1H), 8.56 (d, 1H ), 9.51 (sa, 1H)

36-9 36-9

0,46 (n-hexano:AcOEt = 7:3) CDCl3: 0,70 (t, 6H), 1,23-1,45 (m, 4H), 3,033,13 (m, 1H), 4,27 (d, 1H), 7,27 (dd, 1H), 7,65 (dd, 1H), 7,98 (d, 1H), 8,29 (s, 1H), 8,52 (d, 1H), 9,59 (sa, 1H) 0.46 (n-hexane: AcOEt = 7: 3) CDCl3: 0.70 (t, 6H), 1.23-1.45 (m, 4H), 3,033.13 (m, 1H), 4.27 (d, 1H), 7.27 (dd, 1H) , 7.65 (dd, 1H), 7.98 (d, 1H), 8.29 (s, 1H), 8.52 (d, 1H), 9.59 (sa, 1H)

36-10 Preparación de 2-(2-cloro-5-nitro-pirimidin-4-ilamino)-N-metil-bencenosulfonamida: 36-10 Preparation of 2- (2-Chloro-5-nitro-pyrimidin-4-ylamino) -N-methyl-benzenesulfonamide:

20 twenty

[0141] [0141]

imagen1image 1

Se disuelven 2,4-dicloro-5-nitro-pirimidina (1,94 g, 10 mmoles) y 2-amino-N-metil-bencenosulfonamida (1,86 g, 10 mmoles) en CHCl3 (30 ml). La mezcla de reacción se calienta a 61ºC durante 2 h. El disolvente se evapora y el residuo se lava con éter para dar el producto del título. Rf = 0,5 (n-hexano: acetato de etilo = 1:1). 1H-RMN (400 MHz, CDCl3), δ (ppm): 2,67 (d, 3H), 4,6-4,7 (m, 2H), 7,41 (t, 2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10) are dissolved mmol) in CHCl3 (30 ml). The reaction mixture is heated at 61 ° C for 2 h. The solvent evaporates and the residue is washed with ether to give the title product. Rf = 0.5 (n-hexane: ethyl acetate = 1: 1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.67 (d, 3H), 4.6-4.7 (m, 2H), 7.41 (t,

5 1H), 7,7 (t, 1H), 8,04 (d, 1H), 8,15 (d, 1H), 9,21 (s, 1H), 11,2 (s, 1H). 5 1H), 7.7 (t, 1H), 8.04 (d, 1H), 8.15 (d, 1H), 9.21 (s, 1H), 11.2 (s, 1H).

36-11 36-11

Preparación de (2,5-dicloro-pirimidin-4-il)-[2-(propano-1-sulfonil)-fenil]-amina 10 Preparation of (2,5-dichloro-pyrimidin-4-yl) - [2- (propane-1-sulfonyl) -phenyl] -amine 10

[0142] [0142]

imagen1image 1

A una disolución de 2-(propano-1-sulfonil)-fenilamino (3,69 g, 18,5 mmoles) en N,N-dimetilformamida (40 ml) se To a solution of 2- (propane-1-sulfonyl) -phenylamino (3.69 g, 18.5 mmol) in N, N-dimethylformamide (40 ml) is

15 añade en porciones hidruro sódico (1,48 g, 37 mmoles) a 0ºC. Tras agitar se añade 2,4,5-tricloropirimidina (2,1 ml, 18,5 mmoles). La mezcla se agita durante 30 minutos a 0ºC y se sigue agitando durante 7 h a temperatura ambiente. Tras añadir cloruro de amonio acuoso saturado, la mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con salmuera, se seca mediante sulfato sódico y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (gradiente de n-hexano-acetato de etilo) para 15 add portionwise sodium hydride (1.48 g, 37 mmol) at 0 ° C. After stirring, 2,4,5-trichloropyrimidine (2.1 ml, 18.5 mmol) is added. The mixture is stirred for 30 minutes at 0 ° C and stirring is continued for 7 h at room temperature. After adding saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient of n-hexane-ethyl acetate) to

20 proporcionar el compuesto del título en forma de sólidos incoloros.1H-RMN (CDCl3), δ (ppm): 0,99 (t, 3H), 1,77 (d, 2H), 3,07-3,11 (m, 2H), 7,26 (s, 1H), 7,32 (ddd, 1H), 7,73 (ddd, 1H), 7,95 (dd, 1H), 8,31 (s, 1H), 8,61 (dd, 1H), 9,94 (sa, 1H). Rf (n-hexano: acetato de etilo = 3:1): 0,63 20 to provide the title compound as colorless solids. 1 H-NMR (CDCl 3), δ (ppm): 0.99 (t, 3H), 1.77 (d, 2H), 3.07-3.11 ( m, 2H), 7.26 (s, 1H), 7.32 (ddd, 1H), 7.73 (ddd, 1H), 7.95 (dd, 1H), 8.31 (s, 1H), 8.61 (dd, 1H), 9.94 (sa, 1H). Rf (n-hexane: ethyl acetate = 3: 1): 0.63

[0143] [0143]

25 25

imagen17image17

Ej. nº Ex. Nº

Rx Identificación Rx ID

36-12 36-12

1H-RMN (CDCl3), δ (ppm): 1,35 (d, 6H), 3,18-3,24 (m, 1H), 7,30-7,34 (m, 1H), 7,70-7,75 (m, 1H), 7,92 (dd, 1H), 8,30 (s, 1H), 8,63 (d, 1H), 10,06 (s, 1H). Rf 0,70 (AcOEt) 1H-NMR (CDCl3), δ (ppm): 1.35 (d, 6H), 3.18-3.24 (m, 1H), 7.30-7.34 (m, 1H), 7.70 -7.75 (m, 1H), 7.92 (dd, 1H), 8.30 (s, 1H), 8.63 (d, 1H), 10.06 (s, 1H). Rf 0.70 (AcOEt)

36-13 36-13

RMN (400 MHz) en CDCl3, δ (ppm): 1,29 (t, 3H), 3,15 (c, 1H), 7,31-7,35 (m, 1H), 7,71-7,75 (m, 1H), 7,96 (dd, 1H), 8,31 (s, 1H), 8,60 (d, 1H), 9,92 (s, 1H). Rf: 0,67 (AcOEt) NMR (400 MHz) in CDCl3, δ (ppm): 1.29 (t, 3H), 3.15 (c, 1H), 7.31-7.35 (m, 1H), 7.71-7, 75 (m, 1H), 7.96 (dd, 1H), 8.31 (s, 1H), 8.60 (d, 1H), 9.92 (s, 1H). Rf: 0.67 (AcOEt)

36-14 36-14

1,01-1,06 (m, 2H), 1,32-1,37 (m, 2H), 2,49-2,55 (m, 1H), 7,29-7,33 (m, 1H), 7,69-7,73 (m, 1H), 7,91 (dd, 1H), 8,31 (s, 1H), 8,58 (d, 1H), 9,90 (s, 1H). Rf =,69 (AcOEt) 1.01-1.06 (m, 2H), 1.32-1.37 (m, 2H), 2.49-2.55 (m, 1H), 7.29-7.33 (m, 1H ), 7.69-7.73 (m, 1H), 7.91 (dd, 1H), 8.31 (s, 1H), 8.58 (d, 1H), 9.90 (s, 1H) . Rf =, 69 (AcOEt)

36-15 36-15

0,99 (t, 6H), 1,72-1,90 (m, 4H), 2,76-2,82 (m, 1H), 7,26-7,34 (m, 1H), 7,697,74 (m, 1H), 7,92 (dd, 1H), 8,30 (s, 1H), 8,62 (d, 1H), 10,02 (s, 1H). Rf: 0,73 (AcOEt) 0.99 (t, 6H), 1.72-1.90 (m, 4H), 2.76-2.82 (m, 1H), 7.26-7.34 (m, 1H), 7.697, 74 (m, 1H), 7.92 (dd, 1H), 8.30 (s, 1H), 8.62 (d, 1H), 10.02 (s, 1H). Rf: 0.73 (AcOEt)

Ejemplo 36-16 Example 36-16

Síntesis de aminas sustituidas no disponibles en el mercado: 5 Preparación de 3-amino-4’-metoxi-4-metilbifenilo Synthesis of substituted amines not available in the market: 5 Preparation of 3-amino-4’-methoxy-4-methylbiphenyl

[0144] A una disolución de ácido 4-metoxifenilbórico (500 mg, 3,29 mmoles) en tolueno (5,2 ml) y etanol (1,3 ml) se añaden carbonato potásico (910 mg, 6,58 mmoles), tetrakis-(trifenilfosfina)-paladio (228,1 mg, 0,099 mmoles) [0144] To a solution of 4-methoxyphenylboric acid (500 mg, 3.29 mmol) in toluene (5.2 ml) and ethanol (1.3 ml) are added potassium carbonate (910 mg, 6.58 mmol), tetrakis- (triphenylphosphine) -palladium (228.1 mg, 0.099 mmol)

10 y 4-bromo-1-metil-2-nitrobenceno (711 mg, 3,29 mmoles) y se agita durante 7 horas a 100ºC.La mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) para proporcionar 4’-metoxi-4-metil-3-nitrobifenilo en forma de un sólido amarillo. 10 and 4-Bromo-1-methyl-2-nitrobenzene (711 mg, 3.29 mmol) and stir for 7 hours at 100 ° C. The mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with water and then with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to provide 4’-methoxy-4-methyl-3-nitrobiphenyl as a yellow solid.

15 1H-RMN (δ, ppm): 2,62 (s, 3H), 3,86 (s, 3H), 7,02-6,98 (m, 2H), 7,37 (d, 1H), 7,54 (dd, 2H), 7,68 (dd, 1H), 8,18 (d, 1H). Rf (hexano: acetato de etilo = 3:1): 0,40. Una suspensión de 4’-metoxi-4-metil-3-nitrobifenilo (630 mg, 2,95 mmoles) y 10% de paladio sobre carbón (63 mg, 0,059 mmoles) en metanol (6 ml) se agita durante 12 horas bajo una atmósfera de hidrógeno. El catalizador de paladio se elimina por filtración y la disolución resultante se evapora al vacío para proporcionar el compuesto del 1 H-NMR (δ, ppm): 2.62 (s, 3H), 3.86 (s, 3H), 7.02-6.98 (m, 2H), 7.37 (d, 1H), 7.54 (dd, 2H), 7.68 (dd, 1H), 8.18 (d, 1H). Rf (hexane: ethyl acetate = 3: 1): 0.40. A suspension of 4'-methoxy-4-methyl-3-nitrobiphenyl (630 mg, 2.95 mmol) and 10% palladium on carbon (63 mg, 0.059 mmol) in methanol (6 ml) is stirred for 12 hours under An atmosphere of hydrogen. The palladium catalyst is removed by filtration and the resulting solution is evaporated in vacuo to provide the compound of the

20 título. 1H-RMN (δ, ppm): 2,20 (s, 3H), 3,84 (s, 3H), 6,87 (d, 1H), 6,89 (dd, 1H), 6,95 (d, 2H), 7,09 (d, 1H), 7,48 (d, 2H). Rf (n-hexano: acetato de etilo = 1:1): 0,50. 20 title. 1H-NMR (δ, ppm): 2.20 (s, 3H), 3.84 (s, 3H), 6.87 (d, 1H), 6.89 (dd, 1H), 6.95 (d , 2H), 7.09 (d, 1H), 7.48 (d, 2H). Rf (n-hexane: ethyl acetate = 1: 1): 0.50.

Preparación de éster terc-butílico del ácido 4-(3-amino-4-metilbenzoil)-piperazin-1-carboxílico Preparation of 4- (3-amino-4-methylbenzoyl) -piperazin-1-carboxylic acid tert-butyl ester

25 [0145] A una disolución de ácido 4-metil-3-nitrobenzoico (300 mg, 2,76 mmoles) y N-butoxicarbonilpiperazina (340 mg, 1,83 mmoles) en DMF (3,0 ml) se añaden trietilamina (300 μl, 3,59 mmoles), TBTU (800 mg, 2,49 mmoles) y HOAt (270,5 mg, 1,99 mmoles) y se agita durante 24 horas a temperatura ambiente. La mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca [0145] To a solution of 4-methyl-3-nitrobenzoic acid (300 mg, 2.76 mmol) and N-butoxycarbonylpiperazine (340 mg, 1.83 mmol) in DMF (3.0 ml) are added triethylamine ( 300 μl, 3.59 mmol), TBTU (800 mg, 2.49 mmol) and HOAt (270.5 mg, 1.99 mmol) and stir for 24 hours at room temperature. The mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with water and then with brine, dried

30 mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) para proporcionar éster terc-butílico del ácido 4-(4-metil-3nitrobenzoil)-piperazin-1-carboxílico en forma de un sólido incoloro.1H-RMN (δ, ppm): 1,47 (s, 9H), 2,64 (s, 3H), 3,28-3,88 (m, 8H), 7,42 (d, 1H), 7,56 (dd, 1H), 8,03 (d, 1H). Rf (hexano: acetato de etilo = 10:1): 0,13. 30 by magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to provide 4- (4-methyl-3-nitrobenzoyl) -piperazin-1-carboxylic acid tert-butyl ester of a colorless solid. 1 H-NMR (δ, ppm): 1.47 (s, 9H), 2.64 (s, 3H), 3.28-3.88 (m, 8H), 7.42 (d , 1H), 7.56 (dd, 1H), 8.03 (d, 1H). Rf (hexane: ethyl acetate = 10: 1): 0.13.

35 Preparación de 4-(3-amino-4-metilfenil)-morfolina Preparation of 4- (3-amino-4-methylphenyl) -morpholine

[0146] A una disolución de 4-bromo-1-metil-2-nitrobenceno (225 mg, 1,04 mmoles), morfolina (125 μl, 1,25 mmoles) y carbonato de cesio (474,4 mg, 1,46 mmoles) en tolueno se añaden diacetato de paladio (31,2 mg, 0,139 [0146] To a solution of 4-bromo-1-methyl-2-nitrobenzene (225 mg, 1.04 mmol), morpholine (125 μl, 1.25 mmol) and cesium carbonate (474.4 mg, 1, 46 mmol) in toluene are added palladium diacetate (31.2 mg, 0.139

40 mmoles) y 2-(di-t-butilfosfino)bifenilo (125 mg, 0,403 mmoles) y se agita durante 5 horas a 100ºC. Una vez enfriada, la mezcla se filtra para eliminar el material insoluble. El filtrado se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) para proporcionar 4-(4-metil-3-nitrofenil)-morfolina en forma de un sólido amarillo.40 mmol) and 2- (di-t-butylphosphino) biphenyl (125 mg, 0.403 mmol) and stir for 5 hours at 100 ° C. Once cooled, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted twice with ethyl acetate. The organic phase is washed with water and then with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to provide 4- (4-methyl-3-nitrophenyl) -morpholine as a yellow solid.

45 1H-RMN (δ, ppm): 2,50 (s, 3H), 3,17-3,19 (m, 4H), 3,86-3,88 (m, 4H), 7,04 (dd, 1H), 7,21 (d, 1H), 7,47 (d, 1H). Rf (hexano: acetato de etilo = 5:1): 0,20. El compuesto del título se obtiene por reducción con hidrógeno sobre 10% de paladio sobre carbón en una disolución metanólica. 1 H-NMR (δ, ppm): 2.50 (s, 3H), 3.17-3.19 (m, 4H), 3.86-3.88 (m, 4H), 7.04 (dd , 1H), 7.21 (d, 1H), 7.47 (d, 1H). Rf (hexane: ethyl acetate = 5: 1): 0.20. The title compound is obtained by reduction with hydrogen over 10% palladium on carbon in a methanolic solution.

50 Ejemplo 37: Síntesis de aminas sustituidas no disponibles en el mercado. 50 Example 37: Synthesis of substituted amines not commercially available.

37-1 37-1

Preparación de 1-(3-metoxi-4-nitrofenil)-piperidin-4-ol Preparation of 1- (3-methoxy-4-nitrophenyl) -piperidin-4-ol

[0147] [0147]

imagen1image 1

5 [0148] A una suspensión de piperidin-4-ol (2,79 g, 28 mmoles) y carbonato potásico (3,88 g, 28 mmoles) en N,N-dimetilformamida (40 ml) se añade 4-fluoro-2-metoxi-1-nitrobenceno (4,0 g, 23 mmoles) y se agita durante 24 horas a temperatura ambiente. La mezcla se vierte en agua y el precipitado se recoge por filtración. El sólido resultante se seca al vacío a 50ºC para proporcionar 1-(3-metoxi-4-nitrofenil)-piperidin-4-ol (5,23 g) en forma de sólidos amarillos con un rendimiento del 89%. [0148] To a suspension of piperidin-4-ol (2.79 g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) in N, N-dimethylformamide (40 ml) is added 4-fluoro- 2-Methoxy-1-nitrobenzene (4.0 g, 23 mmol) and stirred for 24 hours at room temperature. The mixture is poured into water and the precipitate is collected by filtration. The resulting solid is dried under vacuum at 50 ° C to provide 1- (3-methoxy-4-nitrophenyl) -piperidin-4-ol (5.23 g) as yellow solids in a yield of 89%.

10 1H-RMN (400 MHz, CDCl3, δ, ppm): 1,54 (d, 1H), 1,62-1,71 (m, 2H), 1,98-2,04 (m, 2H), 3,22 (ddd, 4H), 3,73-3,80 (m, 2H), 3,95 (s, 3H), 3,98-4,02 (m, 1H), 6,33 (d, 1H), 6,43 (dd, 1H), 8,00 (d, 1H). 10 1 H-NMR (400 MHz, CDCl 3, δ, ppm): 1.54 (d, 1 H), 1.62-1.71 (m, 2 H), 1.98-2.04 (m, 2 H), 3.22 (ddd, 4H), 3.73-3.80 (m, 2H), 3.95 (s, 3H), 3.98-4.02 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H).

[0149] Por repetición de los procedimientos antes descritos usando materiales de partida y condiciones apropiados se obtienen los compuestos siguientes. [0149] By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained.

15 fifteen

Ej. nº Ex. Nº

Rx Identificación Rx ID

37-2 37-2

1H-RMN (400 MHz, CDCl3, δ, ppm) 1,53-1,72 (m, 2H), 1,80-1,83 (m, 4H), 1,99-2,04 (m, 2H), 2,24-2,31 (m, 1H), 2,54-2,67 (m, 4H), 3,03 (dt, 2H), 3,84-3,89 (m, 2H), 3,95 (s, 3H), 6,31 (d, 1H), 6,42 (dd, 1H), 8,01 (d, 1H). Rf 0,54 (AcOEt) 1H-NMR (400 MHz, CDCl3, δ, ppm) 1.53-1.72 (m, 2H), 1.80-1.83 (m, 4H), 1.99-2.04 (m, 2H ), 2.24-2.31 (m, 1H), 2.54-2.67 (m, 4H), 3.03 (dt, 2H), 3.84-3.89 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.01 (d, 1H). Rf 0.54 (AcOEt)

37-3 37-3

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,81-1,91 (m, 2H), 1,99-2,04 (m, 2H), 2,38-2,48 (m, 1H), 3,03 (ddd, 2H), 3,91-3,96 (m, 2H), 3,95 (s, 3H), 5,22-5,41 (m, 1H), 5,40-5,53 (m, 1H), 6,36 (d, 1H), 6,43 (dd, 1H), 8,00 (d, 1H). Rf 0,15 (AcOEt) 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.81-1.91 (m, 2H), 1.99-2.04 (m, 2H), 2.38-2.48 (m, 1H), 3.03 (ddd, 2H), 3.91-3.96 (m, 2H), 3.95 (s, 3H), 5.22-5.41 (m, 1H), 5.40 -5.53 (m, 1H), 6.36 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H). Rf 0.15 (AcOEt)

37-4 37-4

Etil-[1-(3-metoxi-4-nitrofenil-pirrolidin3-il]-amina 1H-RMN (400 MHz, CDCl3, δ, ppm); 1,15 (t, 3H), 1,88-1,96 (m, 1H), 2,22-2,30 (m, 1H), 2,68-2,77 (m, 2H), 3,15-3,18 (m, 1H), 3,38-3,44 (m, 1H), 3,52-3,62 (m, 2H), 3,93 (s, 3H), 5,92 (d, 1H), 6,07-6,10 (m, 1H), 8,00-8,02 (m, 1H). Rf 0,65 (n-hexano:AcOEt = 1:1) Ethyl- [1- (3-methoxy-4-nitrophenyl-pyrrolidin3-yl] -amine 1 H-NMR (400 MHz, CDCl 3, δ, ppm); 1.15 (t, 3H), 1.88-1.96 (m, 1H), 2.22-2.30 (m, 1H), 2.68-2.77 (m, 2H), 3, 15-3.18 (m, 1H), 3.38-3.44 (m, 1H), 3.52-3.62 (m, 2H), 3.93 (s, 3H), 5.92 ( d, 1H), 6.07-6.10 (m, 1H), 8.00-8.02 (m, 1H). Rf 0.65 (n-hexane: AcOEt = 1: 1)

37-5 37-5

1-(3-Metoxi-4-nitro-fenil)-4-metilpiperazina 1H-RMN (400 MHz, CDCl3, δ, ppm): 2,36 (s, 3H), 2,52-2,57 (m, 4H), 3,40-3,43 (m, 4H), 3,95 (s, 3H), 6,32 (d, 1H, J=2,52 Hz), 6,43 (dd, 1H, J=9,56, 2,52 Hz), 7,99 (d, 1H, J=9,08 Hz). Rf 0,60 (MeOH:CH2Cl2 = 4:1) 1- (3-Methoxy-4-nitro-phenyl) -4-methylpiperazine 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.36 (s, 3H), 2.52-2.57 (m, 4H), 3.40-3.43 (m, 4H), 3 , 95 (s, 3H), 6.32 (d, 1H, J = 2.52 Hz), 6.43 (dd, 1H, J = 9.56, 2.52 Hz), 7.99 (d, 1H, J = 9.08 Hz). Rf 0.60 (MeOH: CH2Cl2 = 4: 1)

37-6 37-6

3-(3-Metoxi-4-nitro-fenoximetil-1metil-piperidina 1H-RMN (400 MHz, CDCl3, δ, ppm): 1,10-1,19 (m, 1H), 1,59-2,18 (m, 6H), 2,28 (s, 3H), 2,71-2,74 (m, 1H), 2,88-2,91 (m, 1H), 3,863,95 (m, 5H), 6,47-6,52 (m, 2H), 7,97-8,00 (m, 1H). Rf 0,65 (nhexano:AcOEt = 1:1) 3- (3-Methoxy-4-nitro-phenoxymethyl-1methyl-piperidine 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.10-1.19 (m, 1H), 1.59-2.18 (m, 6H), 2.28 (s, 3H), 2 , 71-2.74 (m, 1H), 2.88-2.91 (m, 1H), 3.863.95 (m, 5H), 6.47-6.52 (m, 2H), 7.97 -8.00 (m, 1 H). Rf 0.65 (nhexane: AcOEt = 1: 1)

37-7 37-7

1H-RMN (400 MHz, CDCl3, δ, ppm): 4,08 (s, 3H), 7,30 (dd, 1H), 7,58 (d, 1H), 8,05 (d, 1H), 8,15 (s, 1H), 8,67 (s, 1H). Rf =,42 (AcOEt) 1H-NMR (400 MHz, CDCl3, δ, ppm): 4.08 (s, 3H), 7.30 (dd, 1H), 7.58 (d, 1H), 8.05 (d, 1H), 8.15 (s, 1 H), 8.67 (s, 1 H). Rf =, 42 (AcOEt)

37-8 37-8

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,40-1,50 (m, 2H), 1,55-1,69 (m, 6H), 1,90-1,96 (m, 2H), 2,45-2,53 (m, 5H), 2,90-2,99 (m, 2H), 3,90-4,00 (m, 2H), 3,94 (s, 3H), 6,30 (d, 1H, J=2,5 Hz), 6,41 (dd, 1H, J=9,0, 2,5 Hz), 7,99 (d, 1H, J=9,0 Hz) 1 H-NMR (400 MHz, CDCl 3, δ, ppm): 1.40-1.50 (m, 2H), 1.55-1.69 (m, 6H), 1.90-1.96 (m, 2H), 2.45-2.53 (m, 5H), 2.90-2.99 (m, 2H), 3.90-4.00 (m, 2H), 3.94 (s, 3H) , 6.30 (d, 1H, J = 2.5 Hz), 6.41 (dd, 1H, J = 9.0, 2.5 Hz), 7.99 (d, 1H, J = 9.0 Hz)

37-9 37-9

1H-RMN (400 MHz, DMSO-d6, δ, ppm): 1,95-1,82 (m, 2H), 2,152,06 (m, 1H), 2,30 (s, 3H), 3,17 (dd, 1H), 3,32-3,23 (m, 1H), 3,563,34 (m, 3H), 3,96 (s, 1H), 6,09 (d, 1H), 6,21 (dd, 1H), 7,91 (d, 1H) 1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.95-1.82 (m, 2H), 2,152.06 (m, 1H), 2.30 (s, 3H), 3.17 (dd, 1H), 3.32-3.23 (m, 1H), 3,563.34 (m, 3H), 3.96 (s, 1H), 6.09 (d, 1H), 6.21 ( dd, 1H), 7.91 (d, 1H)

37-10 37-10

1H-RMN (400 MHz, CDCl3, δ, ppm): 2,30-2,48 (m, 3H), 2,59-2,66 (m, 1H), 2,70-2,76 (m, 1H), 2,85-2,92 (m, 1H), 3,09-3,17 (m, 1H), 3,30-3,34 (m, 1H), 3,52-3,58 (m, 1H), 3,68-3,84 (m, 3H), 3,873,91 (m, 1H), 3,96 (s, 3H), 6,32 (d, 1H, J=2,5Hz), 6,42 (dd, 1H, J=9,6, 2,5 Hz), 8,00 (d, 1H, J=9,6 Hz) 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.30-2.48 (m, 3H), 2.59-2.66 (m, 1H), 2.70-2.76 (m, 1H), 2.85-2.92 (m, 1H), 3.09-3.17 (m, 1H), 3.30-3.34 (m, 1H), 3.52-3.58 ( m, 1H), 3.68-3.84 (m, 3H), 3,873.91 (m, 1H), 3.96 (s, 3H), 6.32 (d, 1H, J = 2.5Hz) , 6.42 (dd, 1H, J = 9.6, 2.5 Hz), 8.00 (d, 1H, J = 9.6 Hz)

37-11 37-11

1H-RMN (400 MHz, DMSO-d6, CDCl3, δ, ppm): 1,90-1,79 (m, 1H), 2,25-2,15 (m, 1H), 2,21 (s, 3H), 2,87-2,77 (m, 1H), 3,16 (dd, 1H), 3,42-3,32 (m, 1H), 3,59-3,52 (m, 1H), 3,67-3,61 (m, 1H), 3,91 (s, 3H), 6,13 (d, 1H), 6,24 (dd, 1H), 7,91 (dd, 1H) 1H-NMR (400 MHz, DMSO-d6, CDCl3, δ, ppm): 1.90-1.79 (m, 1H), 2.25-2.15 (m, 1H), 2.21 (s, 3H), 2.87-2.77 (m, 1H), 3.16 (dd, 1H), 3.42-3.32 (m, 1H), 3.59-3.52 (m, 1H) , 3.67-3.61 (m, 1H), 3.91 (s, 3H), 6.13 (d, 1H), 6.24 (dd, 1H), 7.91 (dd, 1H)

37-12 37-12

1H-RMN (400 MHz, CDCl3): 1,43-1,00 (m, 2H), 1,95-1,81 (m, 2H), 2,94-2,17 (m, 2H), 2,96 (s, 3H), 3,27 (d, 2H), 3,35 (s, 3H), 3,97-3,90 (m, 2H), 3,95 (s, 3H), 6,30 (d, 1H), 6,42 (dd, 1H), 8,00 (d, 1H). Rf: 0,25 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.43-1.00 (m, 2H), 1.95-1.81 (m, 2H), 2.94-2.17 (m, 2H), 2 , 96 (s, 3H), 3.27 (d, 2H), 3.35 (s, 3H), 3.97-3.90 (m, 2H), 3.95 (s, 3H), 6, 30 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf: 0.25 (AcOEt)

37-13 37-13

1H-RMN (400 MHz, CDCl3): 1,14 (t, 3H), 2,48 (dd, 2H), 2,59 (t, 4H), 3,42 (t, 4H), 3,95 (s, 3H), 6,32 (d, 1H), 6,43 (dd, 1H), 8,01 (d, 1H). Rf 0,15 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.14 (t, 3H), 2.48 (dd, 2H), 2.59 (t, 4H), 3.42 (t, 4H), 3.95 ( s, 3H), 6.32 (d, 1H), 6.43 (dd, 1H), 8.01 (d, 1H). Rf 0.15 (AcOEt)

37-14 37-14

1H-RMN (400 MHz, CDCl3): 1,02-0,89 (m, 2H), 2,01-1,94 (m, 2H), 2,52-2,38 (m, 1H), 2,65-2,53 (m, 4H), 3,04-2,94 (m, 2H), 3,79-3,69 (m, 4H), 3,97-3,88 (m, 2H), 3,95 (s, 3H), 6,32 (d, 1H), 6,42 (dd, 1H), 8,00 (d, 1H). Rf 0,10 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.02-0.89 (m, 2H), 2.01-1.94 (m, 2H), 2.52-2.38 (m, 1H), 2 , 65-2.53 (m, 4H), 3.04-2.94 (m, 2H), 3.79-3.69 (m, 4H), 3.97-3.88 (m, 2H) , 3.95 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.10 (AcOEt)

37-15 37-15

1H-RMN (400 MHz, CDCl3): 1,08 (s, 3H), 1,09 (s, 3H), 2,66 (t, 4H), 2,74 (sept, 1H), 3,41 (t, 4H), 3,95 (s, 3H), 6,32 (d, 1H), 6,42 (dd, 1H), 8,00 (d, 1H). Rf 0,15 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.08 (s, 3H), 1.09 (s, 3H), 2.66 (t, 4H), 2.74 (sept, 1H), 3.41 ( t, 4H), 3.95 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.15 (AcOEt)

37-16 37-16

1H-RMN (400 MHz, CDCl3): 1,91-1,81 (m, 2H), 2,06-1,97 (m, 2H), 2,48-2,40 (m, 1H), 3,07-2,98 (m, 2H), 3,97-3,93 (m, 2H), 3,93 (s, 3H), 5,37-5,30 (m, 1H), 5,55-5,43 (m, 1H), 6,33 (d, 1H), 6,43 (dd, 1H), 8,00 (d, 1H). Rf 0,10 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.91-1.81 (m, 2H), 2.06-1.97 (m, 2H), 2.48-2.40 (m, 1H), 3 , 07-2.98 (m, 2H), 3.97-3.93 (m, 2H), 3.93 (s, 3H), 5.37-5.30 (m, 1H), 5.55 -5.43 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H). Rf 0.10 (AcOEt)

37-17 37-17

1H-RMN (400 MHz, CDCl3): 2,18-2,07 (m, 1H), 2,30-2,22 (m, 1H), 3,38 (s, 3H), 3,56-3,44 (m, 4H), 3,95 (s, 3H), 4,13 (ddd, 1H), 5,96 (d, 1H), 6,12 (dd, 1H), 8,03 (d, 1H). Rf 0,30 (AcOEt) 1H-NMR (400 MHz, CDCl3): 2.18-2.07 (m, 1H), 2.30-2.22 (m, 1H), 3.38 (s, 3H), 3.56-3 , 44 (m, 4H), 3.95 (s, 3H), 4.13 (ddd, 1H), 5.96 (d, 1H), 6.12 (dd, 1H), 8.03 (d, 1 HOUR). Rf 0.30 (AcOEt)

37-18 37-18

1H-RMN (400 MHz, CDCl3): 1,46 (s, 9H), 1,81-1,68 (m, 4H), 2,73 (sa, 3H), 3,07-2,97 (m, 2H), 3,95 (s, 3H), 4,03-3,94 (m, 2H), 6,32 (d, 1H), 6,43 (dd, 1H), 8,00 (d, 1H). Rf 0,55 (hexano:AcOEt) 1H-NMR (400 MHz, CDCl3): 1.46 (s, 9H), 1.81-1.68 (m, 4H), 2.73 (sa, 3H), 3.07-2.97 (m , 2H), 3.95 (s, 3H), 4.03-3.94 (m, 2H), 6.32 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1 HOUR). Rf 0.55 (hexane: AcOEt)

37-19 37-19

1H-RMN (400 MHz, CDCl3): 3,60-3,57 (m, 2H), 3,68-3,65 (m, 2H), 3,97 (s, 3H), 4,07 (s, 2H), 6,17 (sa, 1H), 6,26 (d, 1H), 6,39 (dd, 1H), 8,04 (d, 1H). Rf 0,85 (AcOEt) 1 H-NMR (400 MHz, CDCl 3): 3.60-3.57 (m, 2H), 3.68-3.65 (m, 2H), 3.97 (s, 3H), 4.07 (s , 2H), 6.17 (sa, 1H), 6.26 (d, 1H), 6.39 (dd, 1H), 8.04 (d, 1H). Rf 0.85 (AcOEt)

37-20 37-20

1H-RMN (400 MHz, CDCl3): 3,08 (s, 3H), 3,54 (dd, 2H), 3,67 (dd, 2H), 3,96 (s, 3H), 4,05 (s, 2H), 6,25 (d, 1H), 6,38 (dd, 1H), 8,03 (d, 1H). Rf 0,30 (AcOEt) 1H-NMR (400 MHz, CDCl3): 3.08 (s, 3H), 3.54 (dd, 2H), 3.67 (dd, 2H), 3.96 (s, 3H), 4.05 ( s, 2H), 6.25 (d, 1H), 6.38 (dd, 1H), 8.03 (d, 1H). Rf 0.30 (AcOEt)

37-21 37-21

1H-RMN (400 MHz, CDCl3): 1,73-1,55 (m, 2H), 1,99-1,91 (m, 2H), 2,09 (s, 3H), 2,61-2,49 (m, 5H), 3,47 (t, 2H), 3,63 (t, 2H), 3,99-3,89 (m, 3H), 3,95 (s, 3H), 6,32 (d, 1H), 6,42 (dd, 1H), 8,01 (d, 1H). Rf 0,10 (AcOEt:MeOH = 4:1) 1H-NMR (400 MHz, CDCl3): 1.73-1.55 (m, 2H), 1.99-1.91 (m, 2H), 2.09 (s, 3H), 2.61-2 , 49 (m, 5H), 3.47 (t, 2H), 3.63 (t, 2H), 3.99-3.89 (m, 3H), 3.95 (s, 3H), 6, 32 (d, 1H), 6.42 (dd, 1H), 8.01 (d, 1H). Rf 0.10 (AcOEt: MeOH = 4: 1)

37-22 37-22

1H-RMN (400 MHz, CDCl3): 3,90 (s, 3H), 3,98 (s, 3H), 3,98 (s, 3H), 6,56 (s, 1H), 7,59 (s, 1H). Rf 0,605 (AcOEt) 1H-NMR (400 MHz, CDCl3): 3.90 (s, 3H), 3.98 (s, 3H), 3.98 (s, 3H), 6.56 (s, 1H), 7.59 ( s, 1H). Rf 0.605 (AcOEt)

37-23 37-23

1H-RMN (400 MHz, CDCl3): 3,25-3,22 (m, 4H), 3,90-3,87 (m, 4H), 3,95 (s, 3H), 6,48 (s, 1H), 7,57 (s, 1H). Rf 0,060 (hexano:AcOEt = 5:1) 1 H-NMR (400 MHz, CDCl 3): 3.25-3.22 (m, 4H), 3.90-3.87 (m, 4H), 3.95 (s, 3H), 6.48 (s , 1H), 7.57 (s, 1H). Rf 0.060 (hexane: AcOEt = 5: 1)

37-24 37-24

1H-RMN (400 MHz, CDCl3): 2,37 (s, 3H), 2,61 (sa, 4H), 3,27 (sa, 4H), 3,88 (s, 3H), 3,95 (s, 3H), 6,48 (s, 1H), 7,56 (s, 1H). Rf 0,10 (AcOEt:MeOH = 5:1 1H-NMR (400 MHz, CDCl3): 2.37 (s, 3H), 2.61 (sa, 4H), 3.27 (sa, 4H), 3.88 (s, 3H), 3.95 ( s, 3H), 6.48 (s, 1H), 7.56 (s, 1H). Rf 0.10 (AcOEt: MeOH = 5: 1

37-25 37-25

1H-RMN (400 MHz, CDCl3): 1,09 (t, 3H), 1,89 (dd, 2H), 2,36 (s, 3H), 2,55 (t, 4H), 3,39 (t, 4H), 4,03 (t, 2H), 6,32 (d, 1H), 6,42 (dd, 1H), 7,98 (d, 1H). Rf 0,12 (AcOEt:MeOH = 9:1) 1H-NMR (400 MHz, CDCl3): 1.09 (t, 3H), 1.89 (dd, 2H), 2.36 (s, 3H), 2.55 (t, 4H), 3.39 ( t, 4H), 4.03 (t, 2H), 6.32 (d, 1H), 6.42 (dd, 1H), 7.98 (d, 1H). Rf 0.12 (AcOEt: MeOH = 9: 1)

37-26 37-26

1H-RMN (400 MHz, CDCl3): 1,36 (s, 3H), 1,38 (s, 3H), 2,10 (s, 2H), 2,17 (s, 3H), 3,27-2,96 (m, 2H), 3,71 (d, 2H), 3,96 (s, 3H), 6,33 (s, 1H), 6,43 (dd, 1H), 8,02 (d, 1H). Rf 0,10 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.36 (s, 3H), 1.38 (s, 3H), 2.10 (s, 2H), 2.17 (s, 3H), 3.27- 2.96 (m, 2H), 3.71 (d, 2H), 3.96 (s, 3H), 6.33 (s, 1H), 6.43 (dd, 1H), 8.02 (d , 1 HOUR). Rf 0.10 (AcOEt)

37-27 37-27

1H-RMN (400 MHz, CDCl3): 1,16 (s, 3H), 1,18 (s, 3H), 2,50 (dd, 2H), 3,02-2,47 (m, 2H), 3,69 (dd, 2H), 3,96 (s, 3H), 6,31 (d, 1H), 6,43 (dd, 1H), 8,00 (d, 1H). Rf 0,070 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.16 (s, 3H), 1.18 (s, 3H), 2.50 (dd, 2H), 3.02-2.47 (m, 2H), 3.69 (dd, 2H), 3.96 (s, 3H), 6.31 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H). Rf 0.070 (AcOEt)

37-28 37-28

1H-RMN (400 MHz, CDCl3): 1,16 (d, 3H), 2,57 (dd, 1H), 3,00-2,89 (m, 4H), 3,18-3,11 (m, 1H), 3,75-3,68 (m, 2H), 3,96 (s, 3H), 6,31 (d, 1H), 6,43 (dd, 1H), 8,01 (d, 1H). Rf 0,070 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.16 (d, 3H), 2.57 (dd, 1H), 3.00-2.89 (m, 4H), 3.18-3.11 (m , 1H), 3.75-3.68 (m, 2H), 3.96 (s, 3H), 6.31 (d, 1H), 6.43 (dd, 1H), 8.01 (d, 1 HOUR). Rf 0.070 (AcOEt)

37-29 37-29

1H-RMN (400 MHz, CDCl3): 1,18 (t, 3H), 2,40 (dd, 2H), 3,47-3,38 (m, 4H), 3,71-3,63 (m, 2H), 3,85-3,79 (m, 2H), 3,96 (s, 3H), 6,32 (d, 1H), 6,42 (dd, 1H), 8,01 (d, 1H). Rf 0,20 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.18 (t, 3H), 2.40 (dd, 2H), 3.47-3.38 (m, 4H), 3.71-3.63 (m , 2H), 3.85-3.79 (m, 2H), 3.96 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H), 8.01 (d, 1 HOUR). Rf 0.20 (AcOEt)

37-30 37-30

1H-RMN (400 MHz, CDCl3): 1,16 (s, 3H), 1,18 (s, 3H), 2,82 (sept, 1H), 3,50-3,37 (m, 4H), 3,77-3,65 (m, 2H), 3,86-3,78 (m, 2H), 3,96 (s, 3H), 6,33 (d, 1H), 6,43 (dd, 1H), 8,01 (d, 1H). Rf 0,48 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.16 (s, 3H), 1.18 (s, 3H), 2.82 (sept, 1H), 3.50-3.37 (m, 4H), 3.77-3.65 (m, 2H), 3.86-3.78 (m, 2H), 3.96 (s, 3H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.01 (d, 1H). Rf 0.48 (AcOEt)

37-31 37-31

1H-RMN (400 MHz, CDCl3): 2,86 (d, 3H), 3,48-3,45 (m, 4H), 3,61-3,58 (m, 4H), 3,96 (s, 3H), 4,48-4,37 (m, 1H), 6,29 (d, 1H), 6,40 (dd, 1H), 8,01 (d, 1H). Rf 0,20 (AcOEt) 1H-NMR (400 MHz, CDCl3): 2.86 (d, 3H), 3.48-3.45 (m, 4H), 3.61-3.58 (m, 4H), 3.96 (s , 3H), 4.48-4.37 (m, 1H), 6.29 (d, 1H), 6.40 (dd, 1H), 8.01 (d, 1H). Rf 0.20 (AcOEt)

37-32 37-32

1H-RMN (400 MHz, CDCl3): 1,72-1,60 (m, 2H), 2,06-1,97 (m, 2H), 3,25-3,17 (d, 3H), 3,78-3,70 (m, 2H), 3,95 (s, 3H), 4,04-3,99 (m, 1H), 6,33 (d, 1H), 6,43 (dd, 1H), 8,00 (d, 1H). Rf 0,20 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.72-1.60 (m, 2H), 2.06-1.97 (m, 2H), 3.25-3.17 (d, 3H), 3 , 78-3.70 (m, 2H), 3.95 (s, 3H), 4.04-3.99 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H ), 8.00 (d, 1 H). Rf 0.20 (AcOEt)

37-33 37-33

1H-RMN (400 MHz, CDCl3): 1,53 (s, 6H), 2,14 (s, 3H), 3,50 (s, 2H), 3,61-3,58 (m, 2H), 3,97-3,81 (m, 2H), 3,97 (s, 3H), 6,10 (d, 1H), 6,26 (dd, 1H), 8,05 (d, 1H). Rf 0,030 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.53 (s, 6H), 2.14 (s, 3H), 3.50 (s, 2H), 3.61-3.58 (m, 2H), 3.97-3.81 (m, 2H), 3.97 (s, 3H), 6.10 (d, 1H), 6.26 (dd, 1H), 8.05 (d, 1H). Rf 0.030 (AcOEt)

37-34 37-34

1H-RMN (400 MHz, CDCl3): 2,54-2,23 (m, 4H), 2,67 (t, 2H), 3,293,23 (m, 2H), 3,74 (t, 4H), 3,94 (s, 3H), 6,07 (d, 1H), 6,16 (dd, 1H), 8,00 (d, 1H). Rf 0,15 (AcOEt) 1H-NMR (400 MHz, CDCl3): 2.54-2.23 (m, 4H), 2.67 (t, 2H), 3,293.23 (m, 2H), 3.74 (t, 4H), 3.94 (s, 3H), 6.07 (d, 1H), 6.16 (dd, 1H), 8.00 (d, 1H). Rf 0.15 (AcOEt)

37-35 37-35

1H-RMN (400 MHz, CDCl3): 2,10-2,02 (m, 2H), 2,41 (t, 2H), 3,56 (dd, 2H), 3,71 (t, 2H), 3,95 (s, 3H), 4,19 (t, 2H), 6,49 (dd, 1H), 6,55 (d, 1H), 7,99 (d, 1H). Rf 0,10 (AcOEt) 1H-NMR (400 MHz, CDCl3): 2.10-2.02 (m, 2H), 2.41 (t, 2H), 3.56 (dd, 2H), 3.71 (t, 2H), 3.95 (s, 3H), 4.19 (t, 2H), 6.49 (dd, 1H), 6.55 (d, 1H), 7.99 (d, 1H). Rf 0.10 (AcOEt)

37-36 37-36

1H-RMN (400 MHz, CDCl3): 2,14 (s, 3H), 3,87-3,34 (m, 8H), 3,99 (s, 3H), 7,01 (dd, 1H), 7,16 (d, 1H), 7,88 (d, 1H). Rf 0,25 (AcOEt) 1H-NMR (400 MHz, CDCl3): 2.14 (s, 3H), 3.87-3.34 (m, 8H), 3.99 (s, 3H), 7.01 (dd, 1H), 7.16 (d, 1H), 7.88 (d, 1H). Rf 0.25 (AcOEt)

37-37 37-37

1H-RMN (400 MHz, CDCl3): 3,49-3,37 (m, 2H), 3,88-3,55 (m, 6H), 3,99 (s, 3H), 7,00 (dd, 1H), 7,16 (d, 1H), 7,87 (d, 1H). Rf 0,50 (AcOEt) 1H-NMR (400 MHz, CDCl3): 3.49-3.37 (m, 2H), 3.88-3.55 (m, 6H), 3.99 (s, 3H), 7.00 (dd , 1H), 7.16 (d, 1H), 7.87 (d, 1H). Rf 0.50 (AcOEt)

37-38 37-38

1H-RMN (400 MHz, CDCl3): 1,17 (s, 3H), 1,19 (s, 3H), 2,69 (t, 4H), 3,06 (s, 2H), 3,42 (t, 4H), 3,96 (s, 3H), 4,13 (sept, 1H), 6,34 (d, 1H), 6,44 (dd, 1H), 6,90-6,79 (m, 1H), 8,00 (d, 1H). Rf 0,20 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.17 (s, 3H), 1.19 (s, 3H), 2.69 (t, 4H), 3.06 (s, 2H), 3.42 ( t, 4H), 3.96 (s, 3H), 4.13 (sept, 1H), 6.34 (d, 1H), 6.44 (dd, 1H), 6.90-6.79 (m , 1H), 8.00 (d, 1H). Rf 0.20 (AcOEt)

37-39 37-39

1H-RMN (400 MHz, CDCl3): 1,44-1,34 (m, 2H), 1,84-1,77 (m, 1H), 1,94-1,85 (m, 2H), 3,04-2,94 (m, 2H), 3,55 (t, 2H), 3,96-3,57 (m, 2H), 3,95 (s, 3H), 6,31 (d, 1H), 6,42 (dd, 1H), 8,00 (d, 1H). Rf 0,30 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.44-1.34 (m, 2H), 1.84-1.77 (m, 1H), 1.94-1.85 (m, 2H), 3 , 04-2.94 (m, 2H), 3.55 (t, 2H), 3.96-3.57 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H ), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.30 (AcOEt)

37-40 37-40

1H-RMN (400 MHz, CDCl3): 1,44-1,34 (m, 2H), 1,84-1,77 (m, 1H), 1,94-1,85 (m, 2H), 3,04-2,94 (m, 2H), 3,55 (t, 2H), 3,96-3,57 (m, 2H), 3,95 (s, 3H), 6,31 (d, 1H), 6,42 (dd, 1H), 8,04 (d, 1H). Rf 0,45 (AcOEt) 1H-NMR (400 MHz, CDCl3): 1.44-1.34 (m, 2H), 1.84-1.77 (m, 1H), 1.94-1.85 (m, 2H), 3 , 04-2.94 (m, 2H), 3.55 (t, 2H), 3.96-3.57 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H ), 6.42 (dd, 1H), 8.04 (d, 1H). Rf 0.45 (AcOEt)

37-41 37-41

1H-RMN (400 MHz, CDCl3): 4,05 (s, 3H), 7,07 (d, 1H), 7,08 (d, 1H), 7,27-7,26 (m, 1H), 7,33 (t, 1H), 7,92 (s, 1H), 8,04 (d, 1H). Rf: 0,20 (AcOEt) 1H-NMR (400 MHz, CDCl3): 4.05 (s, 3H), 7.07 (d, 1H), 7.08 (d, 1H), 7.27-7.26 (m, 1H), 7.33 (t, 1H), 7.92 (s, 1H), 8.04 (d, 1H). Rf: 0.20 (AcOEt)

37-42 37-42

1H-RMN (400 MHz, CDCl3): 2,34 (s, 3H), 2,55-2,37 (m, 4H), 3,863,38 (m, 4), 4,00 (s, 3H), 7,13 (d, 1H), 7,66 (dd, 1H), 7,93 (d, 1H). Rf: 0,30 (AcOEt:MeOH = 4:1) 1H-NMR (400 MHz, CDCl3): 2.34 (s, 3H), 2.55-2.37 (m, 4H), 3.863.38 (m, 4), 4.00 (s, 3H), 7.13 (d, 1H), 7.66 (dd, 1H), 7.93 (d, 1H). Rf: 0.30 (AcOEt: MeOH = 4: 1)

37-43 37-43

1H-RMN (400 MHz, CDCl3): 2,43 (s, 3H), 2,74 (s, 6H), 7,91 (dd, 1H), 7,23 (d, 1H), 7,24 (d, 1H), 7,46 (dd, 1H), Rf: 0,70 (hexano:AcOEt = 5:1) 1H-NMR (400 MHz, CDCl3): 2.43 (s, 3H), 2.74 (s, 6H), 7.91 (dd, 1H), 7.23 (d, 1H), 7.24 ( d, 1H), 7.46 (dd, 1H), Rf: 0.70 (hexane: AcOEt = 5: 1)

37-44 37-44

1H-RMN (400 MHz, CDCl3): 2,15 (s, 3H), 3,80-3,48 (m, 2H), 6,87 (dd, 1H), 6,92 (dd, 1H), 7,09 (d, 1H), 7,40 (dd, 2H), 8,54 (dd, 2H) 1H-NMR (400 MHz, CDCl3): 2.15 (s, 3H), 3.80-3.48 (m, 2H), 6.87 (dd, 1H), 6.92 (dd, 1H), 7.09 (d, 1H), 7.40 (dd, 2H), 8.54 (dd, 2H)

37-45 37-45

1H-RMN (400 MHz, CDCl3): 3,86 (s, 3H), 4,00 (s, 3H), 6,78 (d, 1H), 6,99 (dd, 2H), 7,14 (d, 1H), 7,48 (dd, 2H), 7,71 (dd, 1H), 8,03 (d, 1H). Rf: 0,30 (hexano:AcOEt = 3:1) 1H-NMR (400 MHz, CDCl3): 3.86 (s, 3H), 4.00 (s, 3H), 6.78 (d, 1H), 6.99 (dd, 2H), 7.14 ( d, 1H), 7.48 (dd, 2H), 7.71 (dd, 1H), 8.03 (d, 1H). Rf: 0.30 (hexane: AcOEt = 3: 1)

37-46 37-46

1H-RMN (400 MHz, CDCl3): 1,44 (t, 3H), 3,10 (t, 4H), 3,86 (t, 4H), 4,13 (c, 2H), 7,01 (dd, 1H), 7,08 (dd, 1H), 7,35 (d, 1H). Rf: 0,25 (hexano:AcOEt = 3:1) 1 H-NMR (400 MHz, CDCl 3): 1.44 (t, 3H), 3.10 (t, 4H), 3.86 (t, 4H), 4.13 (c, 2H), 7.01 ( dd, 1H), 7.08 (dd, 1H), 7.35 (d, 1H). Rf: 0.25 (hexane: AcOEt = 3: 1)

37-47 37-47

1H-RMN (400 MHz, CDCl3): 1,26 (t, 3H), 3,32 (t, 4H), 3,85 (t, 4H), 4,15 (c, 2H), 6,34 (d, 1H), 6,42 (dd, 1H), 7,98 (d, 1H). Rf: 0,45 (hexano:AcOEt = 5:1) 1 H-NMR (400 MHz, CDCl 3): 1.26 (t, 3H), 3.32 (t, 4H), 3.85 (t, 4H), 4.15 (c, 2H), 6.34 ( d, 1H), 6.42 (dd, 1H), 7.98 (d, 1H). Rf: 0.45 (hexane: AcOEt = 5: 1)

37-48 37-48

1H-RMN (400 MHz, CDCl3): 3,45 (s, 3H), 3,77 (dd, 2H), 3,81 (s, 3H), 4,06 (t, 2H), 7,08-7,08 (m, 2H), 7,37 (t, 1H). Rf: 0,45 (hexano:AcOEt = 3:1) 1H-NMR (400 MHz, CDCl3): 3.45 (s, 3H), 3.77 (dd, 2H), 3.81 (s, 3H), 4.06 (t, 2H), 7.08- 7.08 (m, 2H), 7.37 (t, 1H). Rf: 0.45 (hexane: AcOEt = 3: 1)

37-49 37-49

1H-RMN (400 MHz, CDCl3): 2,44 (t, 1H), 3,83 (s, 3H), 3,96 (ddd, 2H), 4,20 (t, 2H), 7,06 (d, 1H), 7,12 (dd, 1H), 7,40 (d, 1H). Rf: 0,10 (hexano:AcOEt = 3:1) 1 H-NMR (400 MHz, CDCl 3): 2.44 (t, 1 H), 3.83 (s, 3 H), 3.96 (ddd, 2 H), 4.20 (t, 2 H), 7.06 ( d, 1H), 7.12 (dd, 1H), 7.40 (d, 1H). Rf: 0.10 (hexane: AcOEt = 3: 1)

37-50 37-50

1H-RMN (400 MHz, CDCl3): 1,45 (t, 3H), 3,81 (s, 3H), 4,13 (c, 2H), 7,01 (d, 1H), 7,12 (dd, 1H), 7,40 (d, 1H). Rf: 0,10 (hexano:AcOEt = 3:1). 1H-NMR (400 MHz, CDCl3): 1.45 (t, 3H), 3.81 (s, 3H), 4.13 (c, 2H), 7.01 (d, 1H), 7.12 ( dd, 1H), 7.40 (d, 1H). Rf: 0.10 (hexane: AcOEt = 3: 1).

37-51 37-51

1H-RMN (400 MHz, CDCl3): 1,35 (s, 3H), 1,36 (s, 3H), 4,52 (sept, 1H), 7,08-7,01 (m, 2H), 7,31 (d, 1H). Rf: 0,30 (hexano:AcOEt = 3:1) 1H-NMR (400 MHz, CDCl3): 1.35 (s, 3H), 1.36 (s, 3H), 4.52 (sept, 1H), 7.08-7.01 (m, 2H), 7.31 (d, 1 H). Rf: 0.30 (hexane: AcOEt = 3: 1)

37-52 37-52

1H-RMN (400 MHz, CDCl3): 1,05 (t, 3H), 1,83 (ddd, 2H), 3,81 (s, 3H), 4,01 (t, 2H), 7,01 (d, 1H), 7,08 (dd, 1H), 7,36 (d, 1H). Rf: 0,35 (hexano:AcOEt = 3:1) 1H-NMR (400 MHz, CDCl3): 1.05 (t, 3H), 1.83 (ddd, 2H), 3.81 (s, 3H), 4.01 (t, 2H), 7.01 ( d, 1H), 7.08 (dd, 1H), 7.36 (d, 1H). Rf: 0.35 (hexane: AcOEt = 3: 1)

37-53 37-53

1H-RMN (400 MHz, CDCl3): 3,86 (s, 6H), 3,79 (s, 3H), 6,91 (dd, 1H), 7,00 (d, 1H), 7,18 (d, 1H). Rf: 0,5 (hexano:AcOEt = 9:1) 1H-NMR (400 MHz, CDCl3): 3.86 (s, 6H), 3.79 (s, 3H), 6.91 (dd, 1H), 7.00 (d, 1H), 7.18 ( d, 1H). Rf: 0.5 (hexane: AcOEt = 9: 1)

37-54 37-54

1H-RMN (400 MHz, CDCl3): 4,04 (s, 3H), 7,22 (d, 1H), 7,48 (dd, 2H), 7,83 (dd, 1H), 8,16 (d, 1H), 8,69 (dd, 2H). Rf: 0,12 (hexano:AcOEt = 1:1) 1H-NMR (400 MHz, CDCl3): 4.04 (s, 3H), 7.22 (d, 1H), 7.48 (dd, 2H), 7.83 (dd, 1H), 8.16 ( d, 1H), 8.69 (dd, 2H). Rf: 0.12 (hexane: AcOEt = 1: 1)

37-55 37-55

1H-RMN (400 MHz, CDCl3): 4,02 (s, 3H), 7,22 (d, 1H), 7,39 (ddd, 1H), 7,77 (dd, 1H), 7,85 (ddd, 1H), 8,08 (d, 1H), 8,63 (dd, 1H), 8,83 (d, 1H). Rf: 0,55 (hexano:AcOEt = 2:1) 1H-NMR (400 MHz, CDCl3): 4.02 (s, 3H), 7.22 (d, 1H), 7.39 (ddd, 1H), 7.77 (dd, 1H), 7.85 ( ddd, 1H), 8.08 (d, 1H), 8.63 (dd, 1H), 8.83 (d, 1H). Rf: 0.55 (hexane: AcOEt = 2: 1)

37-56 37-56

1H-RMN (400 MHz, CDCl3): 4,03 (s, 3H), 7,19 (d, 1H), 7,28-7,24 (m, 1H), 7,72 (dd, 1H), 7,80-7,76 (m, 1H), 8,25 (dd, 1H), 8,52 (d, 1H), 8,69 (ddd, 1H). Rf: 0,55 (hexano:AcOEt = 2:1) 1H-NMR (400 MHz, CDCl3): 4.03 (s, 3H), 7.19 (d, 1H), 7.28-7.24 (m, 1H), 7.72 (dd, 1H), 7.80-7.76 (m, 1H), 8.25 (dd, 1H), 8.52 (d, 1H), 8.69 (ddd, 1H). Rf: 0.55 (hexane: AcOEt = 2: 1)

37-57 37-57

p.f. 90,7ºC; 1H-RMN (400 MHz, CDCl3) δ (ppm): 1,68 (m, 2H), 2,00 (m, 2H), 2,36 (s, 1H), 2,62 (sa, 4H), 2,72 (m, 2H), 3,62 (m, 2H), 3,78 (sa, 4H), 3,90 (s, 3H), 6,99 (d, 1H), 7,13 (dd, 1H), 7,26 (s, 1H), 7,40 (s, 1H) m.p. 90.7 ° C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.68 (m, 2H), 2.00 (m, 2H), 2.36 (s, 1H), 2.62 (sa, 4H), 2.72 (m, 2H), 3.62 (m, 2H), 3.78 (sa, 4H), 3.90 (s, 3H), 6.99 (d, 1H), 7.13 (dd , 1H), 7.26 (s, 1H), 7.40 (s, 1H)

38 Preparación de 1-[4-(4-metoxi-3-nitrofenil)-piperazin-1-il]-etanona 38 Preparation of 1- [4- (4-Methoxy-3-nitrophenyl) -piperazin-1-yl] -ethanone

5 5

104 104

[0150] [0150]

imagen1image 1

[0151] A una disolución de 5-bromo-1-metoxi-2-nitrobenceno (300 mg, 1,29 mmoles) en dioxano se añaden [0151] To a solution of 5-bromo-1-methoxy-2-nitrobenzene (300 mg, 1.29 mmol) in dioxane are added

5 1-acetil-piperazina (400 mg, 3,12 mmoles), carbonato de cesio (1,0 g, 3,07 mmoles), diacetato de paladio (29,0 mg, 0,129 mmoles) y 2-(di-t-butilfosfino)bifenilo (77 mg, 0,258 mmoles) y se agita durante 8 horas a 100ºC. Una vez enfriada, la mezcla se filtra para eliminar el material insoluble. El filtrado se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (gradiente de n5 1-acetyl-piperazine (400 mg, 3.12 mmol), cesium carbonate (1.0 g, 3.07 mmol), palladium diacetate (29.0 mg, 0.129 mmol) and 2- (di-t -butylphosphino) biphenyl (77 mg, 0.258 mmol) and stirred for 8 hours at 100 ° C. Once cooled, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted twice with ethyl acetate. The organic phase is washed with water and then with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient of n

10 hexano: acetato de etilo) para proporcionar 1-[4-(4-metoxi-3-nitrofenil)-piperazin-1-il]-etanona (319 mg, 44%) en forma de sólidos amarillos. 1H-RMN (400 MHz, CDCl3, δ, ppm): 2,14 (s, 3H), 3,63 (ddd, 4H), 3,63 (t, 2H), 3,78 (t, 2H), 3,92 (s, 3H), 7,03 (d, 1H), 7,12 (d, 1H), 7,41 (d, 1H). Rf (acetato de etilo: 0,18 10 hexane: ethyl acetate) to provide 1- [4- (4-methoxy-3-nitrophenyl) -piperazin-1-yl] -ethanone (319 mg, 44%) as yellow solids. 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.14 (s, 3H), 3.63 (ddd, 4H), 3.63 (t, 2H), 3.78 (t, 2H), 3.92 (s, 3H), 7.03 (d, 1H), 7.12 (d, 1H), 7.41 (d, 1H). Rf (ethyl acetate: 0.18

39 39

15 Preparación de 1-(3-metoxi-4-nitrofenil)-piperidin-4-ona Preparation of 1- (3-methoxy-4-nitrophenyl) -piperidin-4-one

[0152] [0152]

imagen1image 1

20 [0153] A una disolución de clorhidrato de 4-piperidona monohidrato (10,0 g, 0,065 moles) en DMF (80 ml) se añaden 4-fluoro-2-metoxi-1-nitrobenceno (10,0 g, 0,058 moles) y carbonato potásico (20,2 g) y la mezcla se agita durante 20 h a 70ºC. Tras una filtración, el filtrado se vierte en H2O (aproximadamente 300 ml) y los precipitados resultantes se recogen por filtración y, seguidamente, se lavan varias veces con H2O para dar el compuesto del título [0153] To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065 mol) in DMF (80 ml) are added 4-fluoro-2-methoxy-1-nitrobenzene (10.0 g, 0.058 mol ) and potassium carbonate (20.2 g) and the mixture is stirred for 20 h at 70 ° C. After filtration, the filtrate is poured into H2O (approximately 300 ml) and the resulting precipitates are collected by filtration and then washed several times with H2O to give the title compound.

25 (8,98 g) con un rendimiento del 61%. Sólido naranja. 1H-RMN (400 MHz, CDCl3, δ): 2,65-2,62 (4H, m), 3,81-3,78 (4H, m), 3,98 (3H, s), 6,34 (1H, d), 6,45 (1H, dd), 8,05 (1H, d). 25 (8.98 g) with a yield of 61%. Solid orange. 1 H-NMR (400 MHz, CDCl 3, δ): 2.65-2.62 (4H, m), 3.81-3.78 (4H, m), 3.98 (3H, s), 6.34 (1H, d), 6.45 (1H, dd), 8.05 (1H, d).

40 40

30 Preparación de 1-[1-(3-metoxi-4-nitrofenil)-piperidin-4-il]-4-metil-piperazina Preparation of 1- [1- (3-Methoxy-4-nitrophenyl) -piperidin-4-yl] -4-methyl-piperazine

[0154] [0154]

imagen1image 1

[0155] A una disolución de 1-(3-metoxi-4-nitrofenil)-piperidin-4-ona (4,96 g, 0,020 moles) en dicloroetano (50 ml) se añade N-metilpiperazina (2,7 ml, 0,024 moles) a 0ºC y la mezcla se agita a temperatura ambiente. Al cabo de 5 4 h se añade triacetoxi-borohidruro sódico (5,04 g, 0,024 moles) y la mezcla se sigue agitando durante 24 h a temperatura ambiente. Tras añadir hidróxido de sodio 1N a 0ºC, la mezcla se vierte en agua y se extrae tres veces con diclorometano. La fase orgánica se combina y se extrae tres veces con clorhidrato 1N. La fase acuosa se basifica con hidróxido de sodio 2N y se extrae tres veces con diclorometano. La fase orgánica se lava con salmuera, se seca mediante sulfato sódico y se evapora al vacío para dar el compuesto del título en forma de sólidos amarillos [0155] To a solution of 1- (3-methoxy-4-nitrophenyl) -piperidin-4-one (4.96 g, 0.020 mol) in dichloroethane (50 ml) is added N-methylpiperazine (2.7 ml, 0.024 mol) at 0 ° C and the mixture is stirred at room temperature. After 5 4 h, sodium triacetoxy borohydride (5.04 g, 0.024 mol) is added and the mixture is stirred for 24 h at room temperature. After adding 1N sodium hydroxide at 0 ° C, the mixture is poured into water and extracted three times with dichloromethane. The organic phase is combined and extracted three times with 1N hydrochloride. The aqueous phase is basified with 2N sodium hydroxide and extracted three times with dichloromethane. The organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo to give the title compound as yellow solids.

10 (6,04 g) con un rendimiento del 91%.1H-RMN (400 MHz, CDCl3, δ): 1,70-1,57 (2H, m), 2,03-1,93 (2H, m), 2,29 (3H, s), 2,55-2,38 (5H, m), 2,70-2,56 (4H, m), 2,97 (2H, ddd), 3,97-3,92 (2H, m), 3,95 (3H, s), 6,31 (1H, d), 6,42 (1H, dd), 8,00 (1H, d). 10 (6.04 g) with a yield of 91% .1H-NMR (400 MHz, CDCl3, δ): 1.70-1.57 (2H, m), 2.03-1.93 (2H, m ), 2.29 (3H, s), 2.55-2.38 (5H, m), 2.70-2.56 (4H, m), 2.97 (2H, ddd), 3.97- 3.92 (2H, m), 3.95 (3H, s), 6.31 (1H, d), 6.42 (1H, dd), 8.00 (1H, d).

41 15 Preparación de 4’-metoxi-4-metil-3-nitrobifenilo 41 15 Preparation of 4’-methoxy-4-methyl-3-nitrobiphenyl

[0156] [0156]

imagen1image 1

20 [0157] A una disolución de ácido 4-metoxifenil-bórico (500 mg, 3,29 mmoles) en tolueno (5,2 ml) y etanol (1,3 ml) se añaden carbonato potásico (910 mg, 6,58 mmoles), tetrakis(trifenilfosfina)-paladio (228,1 mg, 0,099 mmoles) y 4-bromo-1-metil-2-nitrobenceno (711 mg, 3,29 (mmoles) y se agitan durante 7 horas a 100ºC. La mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se [0157] To a solution of 4-methoxyphenyl boric acid (500 mg, 3.29 mmol) in toluene (5.2 ml) and ethanol (1.3 ml) are added potassium carbonate (910 mg, 6.58 mmol), tetrakis (triphenylphosphine) -palladium (228.1 mg, 0.099 mmol) and 4-bromo-1-methyl-2-nitrobenzene (711 mg, 3.29 (mmol) and stir for 7 hours at 100 ° C. The mixture is poured into water and extracted twice with ethyl acetate.The organic phase is washed with water and then with brine.

25 seca mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) para proporcionar 4’-metoxi-4-metil-3-nitrobifenilo (630 mg, 79%) en forma de un sólido amarillo. 1H-RMN (400 MHz, CDCl3, δ): 2,62 (s, 3H), 3,86 (s, 3H), 7,02-6,98 (m, 2H), 7,37 (d, 1H), 7,54 (dd, 2H), 7,68 (dd, 1H), 8,18 (d, 1H). Rf (hexano: acetato de etilo = 3:1): 0,40. 25 dried by magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to provide 4'-methoxy-4-methyl-3-nitrobiphenyl (630 mg, 79%) as a yellow solid 1H-NMR (400 MHz, CDCl3, δ): 2.62 (s, 3H), 3.86 (s, 3H), 7.02-6.98 (m, 2H), 7.37 (d, 1H ), 7.54 (dd, 2H), 7.68 (dd, 1H), 8.18 (d, 1H). Rf (hexane: ethyl acetate = 3: 1): 0.40.

30 42 30 42

Preparación de 4-(2-etoxi-etoxi)-1-(3-metoxi-4-nitro-fenil)-piperidina Preparation of 4- (2-ethoxy-ethoxy) -1- (3-methoxy-4-nitro-phenyl) -piperidine

35 [0158] 35 [0158]

imagen1image 1

[0159] A una disolución de 1-(3-metoxi-4-nitro-fenil)-piperidin-4-ol (300 mg, 1,2 mmoles) en N,Ndimetilformamida (3,0 ml) se añade hidruro sódico (1,52 g, 3,8 mmoles). Tras agitar se añade éter 2-bromoetil[0159] To a solution of 1- (3-methoxy-4-nitro-phenyl) -piperidin-4-ol (300 mg, 1.2 mmol) in N, N-dimethylformamide (3.0 ml) is added sodium hydride ( 1.52 g, 3.8 mmol). After stirring, 2-bromoethyl ether is added

5 metílico (150 μl, 1,6 mmoles) y la mezcla se sigue agitando durante 15 horas a 70ºC. Tras añadir cloruro de amonio acuoso saturado, la mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con salmuera, se seca mediante sulfato sódico y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (gradiente de n-hexano-acetato de etilo) para proporcionar 4-(2-metoxi-etoxi)-1-(3metoxi-4-nitro-fenil)-piperidina (111 mg, 29%) en forma de un aceite amarillo.5 methyl (150 μl, 1.6 mmol) and the mixture is stirred for 15 hours at 70 ° C. After adding saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient of n-hexane-ethyl acetate) to provide 4- (2-methoxy-ethoxy) -1- (3methoxy-4-nitro-phenyl) -piperidine (111 mg, 29%) in the form of a yellow oil.

10 1H-RMN (400 MHz, CDCl3, δ, ppm): 1,52 (t, 3H), 1,95-2,00 (m, 2H), 1,70-1,79 (m, 2H), 3,23 (ddd, 2H), 3,58-3,64 (m, 2H), 3,65-3,68 (m, 2H), 3,64-3,72 (m, 2H), 3,95 (s, 3H), 6,31 (d, 1H), 6,42 (dd, 1H), 8,00 (d, 1H). Rf 0,53 (nhexano:AcOEt = 1:1). 10 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.52 (t, 3H), 1.95-2.00 (m, 2H), 1.70-1.79 (m, 2H), 3.23 (ddd, 2H), 3.58-3.64 (m, 2H), 3.65-3.68 (m, 2H), 3.64-3.72 (m, 2H), 3, 95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.53 (nhexane: AcOEt = 1: 1).

[0160] Los compuestos siguientes se preparan de acuerdo con el procedimiento antes descrito usando los 15 haluros de alquilo apropiados. [0160] The following compounds are prepared according to the procedure described above using the appropriate alkyl halides.

Ej. nº Ex. Nº

Rx Identificación Rx ID

42-1 42-1

1H-RMN (400 MHz, CDCl3, δ, ppm): 2,04-2,21 (m, 1H), 2,63 (t, 2H), 2,68 (t, 2H), 3,42 (t, 4H), 3,87 (t, 4H), 3,96 (s, 3H), 6,33 (d, 1H), 6,44 (dd, 1H), 8,02 (d, 1H). Rf 0,09 (AcOEt) 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.04-2.21 (m, 1H), 2.63 (t, 2H), 2.68 (t, 2H), 3.42 (t , 4H), 3.87 (t, 4H), 3.96 (s, 3H), 6.33 (d, 1H), 6.44 (dd, 1H), 8.02 (d, 1H). Rf 0.09 (AcOEt)

42-2 42-2

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,71-1,79 (m, 2H), 1,95-2,02 (m, 2H), 3,22 (ddd, 2H), 3,40 (s, 3H), 3,55-3,57 (m, 2H), 3,59-3,73 (m, 3H), 3,65-3,67 (m, 2H), 3,95 (s, 3H), 6,31 (d, 1H), 6,42 (dd, 1H), 8,00 (d, 1H). Rf 0,35 (n-hexano:AcOEt = 1:1) 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.71-1.79 (m, 2H), 1.95-2.02 (m, 2H), 3.22 (ddd, 2H), 3 , 40 (s, 3H), 3.55-3.57 (m, 2H), 3.59-3.73 (m, 3H), 3.65-3.67 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.35 (n-hexane: AcOEt = 1: 1)

Ejemplo 43 20 2-Metoxi-4-(1-metil-piperidin-4-iloxi)-fenilamino-4-(3-metoxi-4-nitrofenoxi)-1-metilpiperidina
Example 43 2-Methoxy-4- (1-methyl-piperidin-4-yloxy) -phenylamino-4- (3-methoxy-4-nitrophenoxy) -1-methylpiperidine

107 107

[0161] [0161]

imagen1image 1

[0162] A una disolución de 4-fluoro-2-metoxi-1-nitrobenceno (10,3 g, 60 mmoles) en tolueno (50 ml) y KOH [0162] To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (10.3 g, 60 mmol) in toluene (50 ml) and KOH

5 ac. al 25% (50 ml) se añaden a temperatura ambiente 4-hidroxi-1-metilpiperidina (13,8 g, 120 mmoles) y bromuro de tetra-n-butilamonio (3,87 g, 12 mmoles). La mezcla se calienta a 60ºC durante 1 día. La mezcla de reacción se enfría a temperatura ambiente, se vierte en agua helada y se extrae dos veces con acetato de etilo. La fase orgánica se lava sucesivamente con HCl dil. y salmuera, se seca mediante sulfato sódico y se evapora al vacío para proporcionar el compuesto bruto con un rendimiento cuantitativo (13,4 g). 5 ac. 25% (50 ml) 4-hydroxy-1-methylpiperidine (13.8 g, 120 mmol) and tetra-n-butylammonium bromide (3.87 g, 12 mmol) are added at room temperature. The mixture is heated at 60 ° C for 1 day. The reaction mixture is cooled to room temperature, poured into ice water and extracted twice with ethyl acetate. The organic phase is washed successively with dil HCl. and brine, dried over sodium sulfate and evaporated in vacuo to provide the crude compound with a quantitative yield (13.4 g).

10 Rf = 0,22 (metanol: diclorometano = 1:4). 1H-RMN (400 MHz, CDCl3, δ, ppm): 1,84-1,92 (m, 2H), 2,0-2,1 (m, 2H), 2,3-2,4 (m, 2H), 2,33 (s, 3H), 2,65-2,75 (m, 2H), 3,94 (s, 3H), 4,39-4,46 (m, 1H), 6,49 (dd, 1H), 6,99 (d, 1H), 6,54 (d, 1H), 7,99 (d, 1H). 10 Rf = 0.22 (methanol: dichloromethane = 1: 4). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.84-1.92 (m, 2H), 2.0-2.1 (m, 2H), 2.3-2.4 (m, 2H), 2.33 (s, 3H), 2.65-2.75 (m, 2H), 3.94 (s, 3H), 4.39-4.46 (m, 1H), 6.49 (dd, 1H), 6.99 (d, 1H), 6.54 (d, 1H), 7.99 (d, 1H).

Ejemplo 44 Example 44

15 2-Metoxi-4-(2-morfolin-4-il-etoxi)-fenilamina 15 2-Methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamine

3-Metoxi-4-nitro-fenol 3-Methoxy-4-nitro-phenol

imagen18image18

[0164] A una disolución de 3-fluoro-4-nitrofenol (15,7 g, 100 mmoles) en THF (300 ml) se añade a 0ºC KOMe al 30% en metanol (49 ml, 210 mmoles). La mezcla se calienta a reflujo suave durante 18 horas. 25 4-[2-(3-Metoxi-4-nitrofenoxi)-etil]-morfolina [0164] To a solution of 3-fluoro-4-nitrophenol (15.7 g, 100 mmol) in THF (300 ml) is added at 0 ° C 30% KOMe in methanol (49 ml, 210 mmol). The mixture is heated at gentle reflux for 18 hours. 25 4- [2- (3-Methoxy-4-nitrophenoxy) -ethyl] -morpholine

[0165] [0165]

imagen1image 1

[0166] A una disolución de 3-metoxi-4-nitrofenol (1,69 g, 10 mmoles) en DMF (25 ml) se añaden a temperatura ambiente clorhidrato de 4-(2-cloroetil)morfolina (2,05 g, 11 mmoles) y KI (332 mg, 2 mmoles). La mezcla [0166] To a solution of 3-methoxy-4-nitrophenol (1.69 g, 10 mmol) in DMF (25 ml) are added at room temperature 4- (2-chloroethyl) morpholine hydrochloride (2.05 g, 11 mmol) and KI (332 mg, 2 mmol). Mix

5 se calienta a reflujo suave durante 4 horas. La mezcla de reacción se enfría a temperatura ambiente y se inactiva con agua. La mezcla resultante se extrae dos veces con acetato de etilo, y la fase orgánica se lava después sucesivamente con agua y salmuera, se seca mediante sulfato sódico, se filtra y se evapora al vacío para proporcionar el compuesto bruto con un rendimiento del 90% (2,55 g). Rf = 0,11 (AcOEt solo). 1H-RMN (400 MHz, CDCl3, δ, ppm): 2,56-2,61 (m, 4H), 2,83 (t). La mezcla de reacción se 5 is heated at gentle reflux for 4 hours. The reaction mixture is cooled to room temperature and quenched with water. The resulting mixture is extracted twice with ethyl acetate, and the organic phase is then washed successively with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to provide the crude compound in 90% yield ( 2.55 g). Rf = 0.11 (AcOEt only). 1 H-NMR (400 MHz, CDCl 3, δ, ppm): 2.56-2.61 (m, 4H), 2.83 (t). The reaction mixture is

10 enfría a temperatura ambiente y se inactiva lentamente con HCl ac. 1N a 0ºC. La mezcla resultante se extrae dos veces con acetato de etilo, y la fase orgánica sucesivamente se lava con salmuera, se seca mediante sulfato sódico, se filtra y se evapora al vacío para proporcionar el compuesto bruto con un rendimiento del 94% (15,9 g). Rf = 0,22 (metanol: diclorometano = 1:4). 1H-RMN (400 MHz, CDCl3), δ (ppm): 3,95 (s, 3H), 5,49 (s, 1H), 6,44 (dd, 1H, J=8,8, 2,52 Hz), 6,54 (d, 1H, J=2,52 Hz), 7,96 (d, 1H, J=8,6 Hz). 10 cools to room temperature and slowly quenches with ac HCl. 1N at 0 ° C. The resulting mixture is extracted twice with ethyl acetate, and the organic phase is successively washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to provide the crude compound in 94% yield (15.9 g). Rf = 0.22 (methanol: dichloromethane = 1: 4). 1H-NMR (400 MHz, CDCl3), δ (ppm): 3.95 (s, 3H), 5.49 (s, 1H), 6.44 (dd, 1H, J = 8.8, 2.52 Hz), 6.54 (d, 1H, J = 2.52 Hz), 7.96 (d, 1H, J = 8.6 Hz).

15 3,72-3,76 (m, 4H), 3,94 (s, 3H), 4,18 (t, 2H), 6,51 (dd, 1H, J=9,08, 2,52 Hz), 6,56 (d, 1H, J=2,48 Hz), 8,00 (d, 1H, J=9,08 Hz). 15 3.72-3.76 (m, 4H), 3.94 (s, 3H), 4.18 (t, 2H), 6.51 (dd, 1H, J = 9.08, 2.52 Hz ), 6.56 (d, 1H, J = 2.48 Hz), 8.00 (d, 1H, J = 9.08 Hz).

Ejemplo 45 Example 45

20 2-Metoxi-4-(2-morfolin-4-il-etoxi)-fenilamina 20 2-Methoxy-4- (2-morpholin-4-yl-ethoxy) -phenylamine

Éster 4-metoxi-3-nitrofenílico del ácido acético Acetic acid 4-methoxy-3-nitrophenyl ester

imagen19image19

[0168] A una disolución de 4-metoxifenol (12,4 g, 100 mmoles) en AcOH (50 ml) se añade Ac2O (50 ml) a temperatura ambiente. La mezcla se calienta a reflujo suave durante 1,5 horas. La mezcla de reacción se enfría a temperatura ambiente y se añade lentamente HNO3 c. (d=1,38, 10 ml) a 0ºC. La mezcla se calienta a 55ºC durante [0168] To a solution of 4-methoxyphenol (12.4 g, 100 mmol) in AcOH (50 ml) is added Ac2O (50 ml) at room temperature. The mixture is heated at gentle reflux for 1.5 hours. The reaction mixture is cooled to room temperature and HNO3 c is added slowly. (d = 1.38, 10 ml) at 0 ° C. The mixture is heated at 55 ° C for

30 1,5 h. La mezcla de reacción se enfría a temperatura ambiente y se inactiva con agua a 0ºC. El sólido resultante se filtra a través de un embudo de Buchner para proporcionar el compuesto bruto con un rendimiento del 76% (16,0 g). Rf = 0,59 (AcOEt:n-hexano = 3:7). 1H-RMN (400 MHz, CDCl3), δ (ppm): 2,31 (s, 3H), 3,96 (s, 3H), 7,08 (d, 1H, J=9,04 Hz), 7,31 (dd, 1H, J=9,04, 3,04 Hz), 7,96 (d, 1H, J=3,04 Hz). 30 1.5 h. The reaction mixture is cooled to room temperature and quenched with water at 0 ° C. The resulting solid is filtered through a Buchner funnel to provide the crude compound in a yield of 76% (16.0 g). Rf = 0.59 (AcOEt: n-hexane = 3: 7). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.31 (s, 3H), 3.96 (s, 3H), 7.08 (d, 1H, J = 9.04 Hz), 7 , 31 (dd, 1H, J = 9.04, 3.04 Hz), 7.96 (d, 1H, J = 3.04 Hz).

35 4-Metoxi-3-nitrofenol 35 4-Methoxy-3-nitrophenol

[0169] [0169]

imagen1image 1

[0170] A una disolución de éster 4-metoxi-3-nitrofenílico del ácido acético (1,06 g, 5 mmoles) en EtOH (20 ml) se añade NaOH ac. 1N (5,5 ml) a 0ºC. La mezcla se agita durante 2 horas a temperatura ambiente. La mezcla de [0170] To a solution of 4-methoxy-3-nitrophenyl ester of acetic acid (1.06 g, 5 mmol) in EtOH (20 ml) is added aq NaOH. 1N (5.5 ml) at 0 ° C. The mixture is stirred for 2 hours at room temperature. The mixture of

5 reacción se inactiva con AcOH y se extrae dos veces con acetato de etilo. La fase orgánica se lava sucesivamente con agua y salmuera, se seca mediante sulfato sódico, se filtra y se evapora al vacío para proporcionar el compuesto bruto con un rendimiento cuantitativo (840 mg). Rf = 0,59 (AcOEt:n-hexano = 3:7). 1H-RMN (400 MHz, CDCl3), δ (ppm): 3,91 (s, 3H), 6,99 (d, 1H, J=9,04 Hz), 7,17 (dd, 1H, J=9,04, 3,00 Hz), 7,38 (d, 1H, J=3,04 Hz). The reaction is quenched with AcOH and extracted twice with ethyl acetate. The organic phase is washed successively with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to provide the crude compound with a quantitative yield (840 mg). Rf = 0.59 (AcOEt: n-hexane = 3: 7). 1H-NMR (400 MHz, CDCl3), δ (ppm): 3.91 (s, 3H), 6.99 (d, 1H, J = 9.04 Hz), 7.17 (dd, 1H, J = 9.04, 3.00 Hz), 7.38 (d, 1H, J = 3.04 Hz).

10 4-[2-(4-metoxi-3-nitrofenoxi)-etil]-morfolina 10 4- [2- (4-Methoxy-3-nitrophenoxy) -ethyl] -morpholine

[0171] [0171]

imagen1image 1

15 [0172] A una disolución de 4-metoxi-3-nitrofenol (1,01 g, 6 mmoles) en DMF (15 ml) se añaden a temperatura ambiente clorhidrato de 4-(2-cloroetil)morfolina (1,34 g, 7,2 mmoles), K2CO3 (2,49 g, 18 mmoles), KI (2,99 g, 18 mmoles). La mezcla se calienta a 80ºC durante 4 horas. La mezcla de reacción se enfría a temperatura ambiente y se inactiva con una disolución saturada de NH4Cl en agua. La mezcla resultante se extrae dos veces con acetato de [0172] To a solution of 4-methoxy-3-nitrophenol (1.01 g, 6 mmol) in DMF (15 ml) are added at room temperature 4- (2-chloroethyl) morpholine hydrochloride (1.34 g , 7.2 mmol), K2CO3 (2.49 g, 18 mmol), KI (2.99 g, 18 mmol). The mixture is heated at 80 ° C for 4 hours. The reaction mixture is cooled to room temperature and quenched with a saturated solution of NH4Cl in water. The resulting mixture is extracted twice with acetate

20 etilo, y la fase orgánica se lava después sucesivamente con agua y salmuera, se seca mediante sulfato sódico, se filtra y se evapora al vacío para proporcionar el compuesto bruto con un rendimiento cuantitativo (1,70 g). Rf = 0,14 (AcOEt solo). 1H-RMN (400 MHz, DSMO, δ, ppm): 2,36-2,51 (m, 4H), 2,67 (t, J=5,5, 2H), 3,52-3,60 (m, 4H), 3,86 (s, 3H), 4,11 (t, J=6,0, 2H), 7,25-7,29 (m, 2H), 7,46-7,49 (m, 1H). Ethyl, and the organic phase is then washed successively with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to provide the crude compound with a quantitative yield (1.70 g). Rf = 0.14 (AcOEt only). 1 H-NMR (400 MHz, DSMO, δ, ppm): 2.36-2.51 (m, 4H), 2.67 (t, J = 5.5, 2H), 3.52-3.60 ( m, 4H), 3.86 (s, 3H), 4.11 (t, J = 6.0, 2H), 7.25-7.29 (m, 2H), 7.46-7.49 ( m, 1H).

25 Preparación de 2-metoxi-4-(1-metil-piperidin-4-iloxi)-fenilamina: [0174] A una disolución de 4-(3-metoxi-4-nitrofenoxi)-1-metil-piperidina (3,0 g, 11,3 mmoles) en etanol (50 ml) se añade 5% de paladio sobre carbono bajo una atmósfera de nitrógeno. El recipiente de reacción se equipa con un adaptador para balones, se carga con hidrógeno y se evacua tres veces hasta que la reacción se encuentre bajo una atmósfera de hidrógeno. La reacción se deja agitando durante la noche. La mezcla de reacción se filtra a través Preparation of 2-methoxy-4- (1-methyl-piperidin-4-yloxy) -phenylamine: [0174] To a solution of 4- (3-methoxy-4-nitrophenoxy) -1-methyl-piperidine (3, 0 g, 11.3 mmol) in ethanol (50 ml) 5% palladium on carbon is added under a nitrogen atmosphere. The reaction vessel is equipped with a balloon adapter, charged with hydrogen and evacuated three times until the reaction is under a hydrogen atmosphere. The reaction is allowed to stir overnight. The reaction mixture is filtered through

imagen20image20

5 de una almohadilla de Celite y se lava con metanol. El filtrado se concentra al vacío para proporcionar 2-metoxi-4-(1metilpiperidin-4-iloxi)-fenilamina con un rendimiento cuantitativo (2,7 g). Rf = 0,41 (metanol: diclorometano = 1:1). 1H-RMN (400 MHz, CDCl3), δ (ppm): 1,75-1,86 (m, 2H), 1,92-2,05 (m, 2H), 2,2-2,32 (m, 2H), 2,30 (s, 3H), 3,4-3,7 (sa, 2H), 3,82 (s, 3H), 4,1-4,2 (m, 1H), 6,37 (dd, 1H), 6,46 (d, 1H), 6,61 (d, 1H). 5 of a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo to provide 2-methoxy-4- (1-methylpiperidin-4-yloxy) -phenylamine in quantitative yield (2.7 g). Rf = 0.41 (methanol: dichloromethane = 1: 1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 1.75-1.86 (m, 2H), 1.92-2.05 (m, 2H), 2.2-2.32 (m , 2H), 2.30 (s, 3H), 3.4-3.7 (sa, 2H), 3.82 (s, 3H), 4.1-4.2 (m, 1H), 6, 37 (dd, 1H), 6.46 (d, 1H), 6.61 (d, 1H).

10 [0175] Por repetición de los procedimientos antes descritos usando materiales de partida y condiciones apropiados se obtienen los compuestos siguientes. [0175] By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained.

Ej. nº Ex. Nº

Rx Identificación Rx ID

46-1 46-1

1H-RMN (400 MHz, CDCl3, δ, ppm): 3,92 (s, 3H), 3,97 (a, 2H), 6,75 (d, 1H), 7,00 (dd, 1H), 7,12 (d, 1H), 8,06 (s, 1H), 8,41 (s, 1H). Rf 0,32 (AcOEt) 1H-NMR (400 MHz, CDCl3, δ, ppm): 3.92 (s, 3H), 3.97 (a, 2H), 6.75 (d, 1H), 7.00 (dd, 1H), 7.12 (d, 1H), 8.06 (s, 1H), 8.41 (s, 1H). Rf 0.32 (AcOEt)

46-2 46-2

[1-(4-Amino-3-metoxifenil)-pirimidin-3il]-etilamina 1H-RMN (400 MHz, CDCl3, δ, ppm): 1,13 (t, 3H), 1,77-1,86 (m, 1H), 2,19-2,27 (m, 1H), 2,67-2,75 (m, 2H), 3,01-3,06 (m, 1H), 3,20-3,26 (m, 1H), 3,33-3,38 (m, 1H), 3,42-3,49 (m, 2H), 3,84 (s, 3H), 6,04-6,07 (m, 1H), 6,14-6,15 (m, 1H), 6,64-6,66 (m, 1H). Rf 0,2 (AcOEt solo) [1- (4-Amino-3-methoxyphenyl) -pyrimidin-3-yl] -ethylamine 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.13 (t, 3H), 1.77-1.86 (m, 1H), 2.19-2.27 (m, 1H), 2 , 67-2.75 (m, 2H), 3.01-3.06 (m, 1H), 3.20-3.26 (m, 1H), 3.33-3.38 (m, 1H) , 3.42-3.49 (m, 2H), 3.84 (s, 3H), 6.04-6.07 (m, 1H), 6.14-6.15 (m, 1H), 6 , 64-6.66 (m, 1 H). Rf 0.2 (AcOEt only)

46-3 46-3

2-Metoxi-4-(4-metil-piperazin-1-il)fenilamina 1H-RMN (400 MHz, CDCl3, δ, ppm): 2,44 (s, 3H), 2,70-2,73 (m, 4H), 3,13-3,17 (m, 4H), 3,48 (sa, 2H), 3,84 (s, 3H), 6,41 (dd, 1H, J=8,5, 2,52 Hz), 6,51 (d, 1H, J=2,52 Hz), 6,64 (d, 1H, J=8,5 Hz). Rf 0,2 (AcOEt solo) 2-Methoxy-4- (4-methyl-piperazin-1-yl) phenylamine 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.44 (s, 3H), 2.70-2.73 (m, 4H), 3.13-3.17 (m, 4H), 3 , 48 (sa, 2H), 3.84 (s, 3H), 6.41 (dd, 1H, J = 8.5, 2.52 Hz), 6.51 (d, 1H, J = 2.52 Hz), 6.64 (d, 1H, J = 8.5 Hz). Rf 0.2 (AcOEt only)

46-4 46-4

2-Metoxi-4-(1-metil-piperidin-3dimetoxi)-fenilamina 1H-RMN (400 MHz, CDCl3, δ, ppm): 1,01-1,12 (m, 1H), 1,572,13 (m, 6H), 2,26 (s, 3H), 2,74-2,77 (m, 1H), 2,93-2,96 (m, 1H), 3,47 (sa, 2H), 3,70-3,80 (m, 2H), 3,82 (s, 3H), 6,31-6,34 (m, 1H), 6,44-6,45 (m, 1H), 6,60-6,62 (m, 1H). Rf 0,2 (AcOEt solo) 2-Methoxy-4- (1-methyl-piperidin-3dimethoxy) -phenylamine 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.01-1.12 (m, 1H), 1,572.13 (m, 6H), 2.26 (s, 3H), 2.74-2 , 77 (m, 1H), 2.93-2.96 (m, 1H), 3.47 (sa, 2H), 3.70-3.80 (m, 2H), 3.82 (s, 3H ), 6.31-6.34 (m, 1H), 6.44-6.45 (m, 1H), 6.60-6.62 (m, 1H). Rf 0.2 (AcOEt only)

46-5 46-5

1H-RMN (400 MHz, CDCl3) 1,80-1,67 (2H, m), 1,99-1,90 (2H, m), 2,42-2,27 (1H, m), 2,56-2,43 (4H, m), 2,68-2,58 (2H, m), 2,76-2,58 (4H, m), 3,57-3,48 (2H, m), 3,83 (3H, s), 6,41 (1H, dd), 6,52 (1H, d), 6,63 (1H, d). Rf (hexano/acetona 1:1) 0,44. 1H-NMR (400 MHz, CDCl3) 1.80-1.67 (2H, m), 1.99-1.90 (2H, m), 2.42-2.27 (1H, m), 2, 56-2.43 (4H, m), 2.68-2.58 (2H, m), 2.76-2.58 (4H, m), 3.57-3.48 (2H, m), 3.83 (3H, s), 6.41 (1H, dd), 6.52 (1H, d), 6.63 (1H, d). Rf (hexane / acetone 1: 1) 0.44.

46-6 46-6

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,83-1,95 (m, 2H), 1,972,08 (m, 2H), 2,20-2,31 (m, 1H), 2,60-2,72 (m, 2H), 3,46-3,53 (m, 2H), 3,84 (s, 3H), 5,42-5,60 (m, 1H), 6,43 (dd, 1H), 6,53 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.83-1.95 (m, 2H), 1,972.08 (m, 2H), 2.20-2.31 (m, 1H), 2 , 60-2.72 (m, 2H), 3.46-3.53 (m, 2H), 3.84 (s, 3H), 5.42-5.60 (m, 1H), 6.43 (dd, 1H), 6.53 (d, 1H), 6.64 (d, 1H)

46-7 46-7

1H-RMN (400 MHz, CDCl3, δ, ppm): 2,13 (s, 3H), 3,01-3,05 (m, 4H), 3,59 (t, 2H), 3,75 (t, 2H), 3,81 (s, 3H), 6,30 (dd, 1H), 6,39 (sa, 1H), 6,71 (d, 1H) 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.13 (s, 3H), 3.01-3.05 (m, 4H), 3.59 (t, 2H), 3.75 (t , 2H), 3.81 (s, 3H), 6.30 (dd, 1H), 6.39 (sa, 1H), 6.71 (d, 1H)

46-8 46-8

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,84-1,97 (m, 2H), 1,982,07 (m, 2H), 2,20-2,32 (m, 1H), 2,61-2,72 (m, 2H), 3,47-3,55 (m, 2H), 3,95 (s, 3H), 5,20-5,38 (m, 1H), 5,40-5,56 (m, 2H), 6,43 (d, 1H), 6,53 (sa, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.84-1.97 (m, 2H), 1,982.07 (m, 2H), 2.20-2.32 (m, 1H), 2 , 61-2.72 (m, 2H), 3.47-3.55 (m, 2H), 3.95 (s, 3H), 5.20-5.38 (m, 1H), 5.40 -5.56 (m, 2H), 6.43 (d, 1H), 6.53 (sa, 1H), 6.64 (d, 1H)

46-9 46-9

1H-RMN (400 MHz, CDCl3, δ, ppm): 2,59-2,67 (m, 2H), 2,772,68 (m, 4H), 3,08-3,15 (m, 4H), 3,49-3,56 (m, 1H), 3,67-3,77 (m, 2H), 3,98 (s, 3H), 6,41-6,43 (m, 1H), 6,52 (sa, 1H), 6,65 (d, 1H) 1 H-NMR (400 MHz, CDCl 3, δ, ppm): 2.59-2.67 (m, 2H), 2,772.68 (m, 4H), 3.08-3.15 (m, 4H), 3 , 49-3.56 (m, 1H), 3.67-3.77 (m, 2H), 3.98 (s, 3H), 6.41-6.43 (m, 1H), 6.52 (sa, 1H), 6.65 (d, 1H)

46-10 46-10

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,72-1,96 (m, 2H), 1,982,10 (m, 2H), 2,63 (s, 3H), 2,73-2,84 (m, 2H), 3,40 (s, 3H), 3,34-3,42 (m, 2H), 3,44-3,49 (m, 1H), 3,55-3,57 (m, 2H), 3,64-3,66 (m, 2H), 3,83 (s, 3H), 6,41-6,43 (m, 1H), 6,53 (sa, 1H), 6,63 (d, 1H) 1 H-NMR (400 MHz, CDCl 3, δ, ppm): 1.72-1.96 (m, 2H), 1,982.10 (m, 2H), 2.63 (s, 3H), 2.73-2 , 84 (m, 2H), 3.40 (s, 3H), 3.34-3.42 (m, 2H), 3.44-3.49 (m, 1H), 3.55-3.57 (m, 2H), 3.64-3.66 (m, 2H), 3.83 (s, 3H), 6.41-6.43 (m, 1H), 6.53 (sa, 1H), 6.63 (d, 1 H)

46-11 46-11

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,22 (t, 3H), 1,72-1,84 (m, 2H), 2,00-2,10 (m, 2H), 2,72-2,82 (m, 2H), 3,33-3,38 (m, 2H), 3,43-3,49 (m, 1H), 3,55 (c, 2H), 3,58-3,61 (m, 2H), 3,643,66 (m, 2H), 3,83 (s, 3H), 6,41-6,43 (m, 1H), 6,53 (sa, 1H), 6,63 (d, 1H) 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.22 (t, 3H), 1.72-1.84 (m, 2H), 2.00-2.10 (m, 2H), 2 , 72-2.82 (m, 2H), 3.33-3.38 (m, 2H), 3.43-3.49 (m, 1H), 3.55 (c, 2H), 3.58 -3.61 (m, 2H), 3,643.66 (m, 2H), 3.83 (s, 3H), 6.41-6.43 (m, 1H), 6.53 (sa, 1H), 6.63 (d, 1 H)

46-12 46-12

1H-RMN (400 MHz, CDCl3, δ, ppm): 2,20 (s, 3H), 3,84 (s, 3H), 6,87 (d, 1H), 6,89 (dd, 1H), 6,95 (d, 2H), 7,09 (d, 1H), 7,48 (d, 2H). Rf (n-hexano:acetato de etilo = 1:1): 0,50 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.20 (s, 3H), 3.84 (s, 3H), 6.87 (d, 1H), 6.89 (dd, 1H), 6.95 (d, 2H), 7.09 (d, 1H), 7.48 (d, 2H). Rf (n-hexane: ethyl acetate = 1: 1): 0.50

46-13 46-13

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,49-1,59 (m, 3H), 1,701,95 (m, 6H), 2,00-2,20 (m, 2H), 2,60-2,90 (m, 7H), 3,50-3,60 (m, 3H), 3,83 (s, 3H), 3,85-3,91 (m, 1H), 6,41 (dd, 1H, J=8,0, 2,5 Hz), 6,50 (d, 1H, J=2,5 Hz), 6,63 (d, 1H, J=8,0 Hz) 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.49-1.59 (m, 3H), 1,701.95 (m, 6H), 2.00-2.20 (m, 2H), 2 , 60-2.90 (m, 7H), 3.50-3.60 (m, 3H), 3.83 (s, 3H), 3.85-3.91 (m, 1H), 6.41 (dd, 1H, J = 8.0, 2.5 Hz), 6.50 (d, 1H, J = 2.5 Hz), 6.63 (d, 1H, J = 8.0 Hz)

46-14 46-14

1H-RMN (400 MHz, DMSO-d6, δ, ppm): 1,87-1,79 (m, 1H), 2,22 (ddd, 1H), 2,48 (s, 3H), 3,05 (dd, 1H), 3,28-3,21 (m, 1H), 3,40-3,32 (m, 2H), 3,45 (dd, 1H), 3,84 (s, 3H), 6,06 (dd, 1H), 6,15 (d, 1H), 6,66 (d, 1H) 1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.87-1.79 (m, 1H), 2.22 (ddd, 1H), 2.48 (s, 3H), 3.05 (dd, 1H), 3.28-3.21 (m, 1H), 3.40-3.32 (m, 2H), 3.45 (dd, 1H), 3.84 (s, 3H), 6.06 (dd, 1H), 6.15 (d, 1H), 6.66 (d, 1H)

46-15 46-15

1H-RMN (400 MHz, CDCl3, δ, ppm): 2,35-2,73 (m, 4H), 2,682,75 (m, 1H), 2,82-2,93 (m, 2H), 3,14-3,19 (m, 1H), 3,29-3,40 (m, 2H), 3,50-3,60 (sa, 2H), 3,69-3,78 (m, 2H), 3,84 (s, 3H), 3,85-3,91 (m, 1H), 6,40 (dd, 1H, J=8,0, 2,5 Hz), 6,50 (d, 1H, J=2,5 Hz), 6,64 (d, 1H, J=8,0 Hz) 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.35-2.73 (m, 4H), 2.682.75 (m, 1H), 2.82-2.93 (m, 2H), 3 , 14-3.19 (m, 1H), 3.29-3.40 (m, 2H), 3.50-3.60 (sa, 2H), 3.69-3.78 (m, 2H) , 3.84 (s, 3H), 3.85-3.91 (m, 1H), 6.40 (dd, 1H, J = 8.0, 2.5 Hz), 6.50 (d, 1H , J = 2.5 Hz), 6.64 (d, 1H, J = 8.0 Hz)

46-16 46-16

1H-RMN (400 MHz, DMSO-d6, δ, ppm): 1,95-1,85 (m, 1H), 2,22-2,14 (m, 1H), 2,31 (s, 3H), 2,89-2,79 (m, 1H), 3,10 (t, 1H), 3,39-3,25 (m, 3H), 3,42 (t, 1H), 3,85 (s, 3H), 6,05 (dd, 1H), 6,14 (d, 1H), 6,67 (d, 1H) 1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.95-1.85 (m, 1H), 2.22-2.14 (m, 1H), 2.31 (s, 3H) , 2.89-2.79 (m, 1H), 3.10 (t, 1H), 3.39-3.25 (m, 3H), 3.42 (t, 1H), 3.85 (s , 3H), 6.05 (dd, 1H), 6.14 (d, 1H), 6.67 (d, 1H)

46-17 46-17

1H-RMN (400 MHz, CDCl3, δ, ppm): 1,68-1,81 (m, 2H), 1,972,09 (m, 2H), 2,74-2,87 (m, 2H), 3,39-3,41 (m, 2H), 3,77-3,88 (m, 1H), 3,84 (s, 3H), 6,40-6,48 (m, 1H), 6,65 (sa, 1H), 6,64 (d, 1H) 1 H-NMR (400 MHz, CDCl 3, δ, ppm): 1.68-1.81 (m, 2H), 1,972.09 (m, 2H), 2.74-2.87 (m, 2H), 3 , 39-3.41 (m, 2H), 3.77-3.88 (m, 1H), 3.84 (s, 3H), 6.40-6.48 (m, 1H), 6.65 (sa, 1H), 6.64 (d, 1H)

46-18 46-18

1H-RMN (400 MHz, CDCl3), δ (ppm): 2,55-2,61 (m, 4H), 2,80 (t, 2H), 3,72-3,77 (m, 4H), 3,81 (s, 3H), 4,05 (t, 2H), 6,24 (dd, 1H, J=8,56, 2,52 Hz), 6,34 (d, 1H, J=2,52 Hz), 6,68 (d, 1H, J=8,56). Rf = 0,31 (metanol: diclorometano = 1:9) 1 H-NMR (400 MHz, CDCl 3), δ (ppm): 2.55-2.61 (m, 4H), 2.80 (t, 2H), 3.72-3.77 (m, 4H), 3.81 (s, 3H), 4.05 (t, 2H), 6.24 (dd, 1H, J = 8.56, 2.52 Hz), 6.34 (d, 1H, J = 2, 52 Hz), 6.68 (d, 1H, J = 8.56). Rf = 0.31 (methanol: dichloromethane = 1: 9)

46-19 46-19

1H-RMN (400 MHz, CDCl3), δ (ppm): 2,55-2,61 (m, 4H), 2,78 (t, 2H), 3,72-3,77 (m, 4H), 3,82 (s, 3H), 4,05 (t, 2H), 6,35 (dd, 1H, J=8,56, 2,52 Hz), 6,47 (d, 1H, J=2,52 Hz), 6,63 (d, 1H, J=8,56 Hz). Rf = 0,61 (metanol: diclorometano = 1:4) 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.55-2.61 (m, 4H), 2.78 (t, 2H), 3.72-3.77 (m, 4H), 3.82 (s, 3H), 4.05 (t, 2H), 6.35 (dd, 1H, J = 8.56, 2.52 Hz), 6.47 (d, 1H, J = 2, 52 Hz), 6.63 (d, 1H, J = 8.56 Hz). Rf = 0.61 (methanol: dichloromethane = 1: 4)

46-20 46-20

1H-RMN (DMSO), δ (ppm): 3,84 (s, 3H), 6,95-7,00 (m, 1H), 7,08-7,12 (m, 2H) 1H-NMR (DMSO), δ (ppm): 3.84 (s, 3H), 6.95-7.00 (m, 1H), 7.08-7.12 (m, 2H)

46-21 46-21

1H-RMN (400 MHz, CDCl3): 1,47-1,34 (m, 2H), 1,75-1,63 (m, 1H), 1,86-1,79 (m, 2H), 2,64-2,58 (m, 2H), 3,28 (d, 2H), 3,61 (d, 3H), 3,87 (s, 3H), 3,36 (s, 1H), 3,49-3,45 (m, 2H), 3,84 (s, 3H), 6,43 (dd, 1H), 6,53 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.47-1.34 (m, 2H), 1.75-1.63 (m, 1H), 1.86-1.79 (m, 2H), 2 , 64-2.58 (m, 2H), 3.28 (d, 2H), 3.61 (d, 3H), 3.87 (s, 3H), 3.36 (s, 1H), 3, 49-3.45 (m, 2H), 3.84 (s, 3H), 6.43 (dd, 1H), 6.53 (d, 1H), 6.64 (d, 1H)

46-22 46-22

1H-RMN (400 MHz, CDCl3): 1,13 (t, 3H), 2,49 (dd, 2H), 2,682,59 (m, 4H), 3,10 (t, 4H), 3,84 (s, 3H), 6,43 (dd, 1H), 6,53 (d, 1H), 6,65 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.13 (t, 3H), 2.49 (dd, 2H), 2,682.59 (m, 4H), 3.10 (t, 4H), 3.84 ( s, 3H), 6.43 (dd, 1H), 6.53 (d, 1H), 6.65 (d, 1H)

46-23 46-23

1H-RMN (400 MHz, CDCl3): 1,78-1,68 (m, 2H), 1,99-1,89 (m, 2H), 2,36-2,20 (m, 1H), 2,67-2,50 (m, 6H), 3,56-3,48 (m, 2H), 3,79-3,69 (m, 4H), 3,84 (s, 3H), 6,42 (dd, 1H), 6,52 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.78-1.68 (m, 2H), 1.99-1.89 (m, 2H), 2.36-2.20 (m, 1H), 2 , 67-2.50 (m, 6H), 3.56-3.48 (m, 2H), 3.79-3.69 (m, 4H), 3.84 (s, 3H), 6.42 (dd, 1H), 6.52 (d, 1H), 6.64 (d, 1H)

46-24 46-24

1H-RMN (400 MHz, CDCl3): 1,08 (s, 3H), 1,10 (s, 3H), 2,69 (t, 4H), 2,72-2,68 (m, 1H), 3,08 (t, 4H), 3,83 (s, 3H), 6,42 (dd, 1H), 6,53 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.08 (s, 3H), 1.10 (s, 3H), 2.69 (t, 4H), 2.72-2.68 (m, 1H), 3.08 (t, 4H), 3.83 (s, 3H), 6.42 (dd, 1H), 6.53 (d, 1H), 6.64 (d, 1H)

46-25 46-25

1H-RMN (400 MHz, CDCl3): 1,96-1,84 (m, 2H), 2,07-1,99 (m, 2H), 2,32-2,28 (m, 1H), 2,70-2,60 (m, 2H), 3,54-3,47 (m, 2H), 3,84 (s, 3H), 5,35-5,24 (m, 1H), 5,50-5,45 (m, 1H), 6,42 (dd, 1H), 6,52 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.96-1.84 (m, 2H), 2.07-1.99 (m, 2H), 2.32-2.28 (m, 1H), 2 , 70-2.60 (m, 2H), 3.54-3.47 (m, 2H), 3.84 (s, 3H), 5.35-5.24 (m, 1H), 5.50 -5.45 (m, 1H), 6.42 (dd, 1H), 6.52 (d, 1H), 6.64 (d, 1H)

46-26 46-26

1H-RMN (400 MHz, CDCl3): 2,18-2,03 (m, 2H), 3,28-3,19 (m, 2H), 3,39-3,31 (m, 1H), 3,36 (s, 3H), 3,49-3,42 (m, 1H), 3,85 (s, 3H), 6,07 (dd, 1H), 6,16 (d, 1H), 6,66 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.18-2.03 (m, 2H), 3.28-3.19 (m, 2H), 3.39-3.31 (m, 1H), 3 , 36 (s, 3H), 3.49-3.42 (m, 1H), 3.85 (s, 3H), 6.07 (dd, 1H), 6.16 (d, 1H), 6, 66 (d, 1 H)

46-27 46-27

1H-RMN (400 MHz, CDCl3): 1,48 (s, 9H), 1,88-1,71 (m, 2H), 1,97-1,82 (m, 2H), 2,78 (s, 3H), 2,84-2,64 (m, 2H), 3,55-3,48 (m, 2H), 3,95 (s, 3H), 3,84 (s, 3H), 6,43 (d, 1H), 6,52 (sa, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.48 (s, 9H), 1.88-1.71 (m, 2H), 1.97-1.82 (m, 2H), 2.78 (s , 3H), 2.84-2.64 (m, 2H), 3.55-3.48 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 6, 43 (d, 1H), 6.52 (sa, 1H), 6.64 (d, 1H)

46-28 46-28

1H-RMN (400 MHz, CDCl3): 3,02 (s, 3H), 3,33 (dd, 2H), 3,44 (t, 2H), 3,74 (s, 2H), 3,83 (s, 3H), 6,38 (dd, 1H), 6,47 (d, 1H), 6,66 (d, 1H) 1H-NMR (400 MHz, CDCl3): 3.02 (s, 3H), 3.33 (dd, 2H), 3.44 (t, 2H), 3.74 (s, 2H), 3.83 ( s, 3H), 6.38 (dd, 1H), 6.47 (d, 1H), 6.66 (d, 1H)

46-29 46-29

1H-RMN (400 MHz, CDCl3): 1,78-1,38 (m, 2H), 1,96-1,89 (m, 2H), 2,30 (s, 3H), 2,39-2,31 (m, 1H), 2,55-2,42 (m, 4H), 2,712,56 (m, 6H), 3,35-3,49 (m, 2H), 3,83 (s, 3H), 6,41 (dd, 1H), 6,52 (d, 1H), 6,63 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.78-1.38 (m, 2H), 1.96-1.89 (m, 2H), 2.30 (s, 3H), 2.39-2 , 31 (m, 1H), 2.55-2.42 (m, 4H), 2,712.56 (m, 6H), 3.35-3.49 (m, 2H), 3.83 (s, 3H ), 6.41 (dd, 1H), 6.52 (d, 1H), 6.63 (d, 1H)

46-30 46-30

1H-RMN (400 MHz, CDCl3): 3,80 (s, 3H), 3,82 (s, 3H), 3,82 (s, 3H), 6,40 (s, 1H), 6,54 (s, 1H) 1H-NMR (400 MHz, CDCl3): 3.80 (s, 3H), 3.82 (s, 3H), 3.82 (s, 3H), 6.40 (s, 1H), 6.54 ( s, 1H)

46-31 46-31

1H-RMN (400 MHz, CDCl3): 3,20 (t, 2H), 4,57 (t, 2H), 6,55 (dd, 1H), 6,70-6,65 (m, 1H), 6,68 (d, 1H). Rf 0,40 (AcOEt) 1H-NMR (400 MHz, CDCl3): 3.20 (t, 2H), 4.57 (t, 2H), 6.55 (dd, 1H), 6.70-6.65 (m, 1H), 6.68 (d, 1 H). Rf 0.40 (AcOEt)

46-32 46-32

1H-RMN (400 MHz, CDCl3): 2,98 (t, 4H), 3,62 (sa, 2H), 3,79 (s, 3H), 3,81 (s, 3H), 3,87 (t, 4H), 6,36 (s, 1H), 6,53 (s, 1H) 1H-NMR (400 MHz, CDCl3): 2.98 (t, 4H), 3.62 (sa, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 3.87 ( t, 4H), 6.36 (s, 1H), 6.53 (s, 1H)

46-33 46-33

1H-RMN (400 MHz, CDCl3): 2,37 (s, 3H), 2,61 (t, 4H), 3,27 (t, 4H), 3,88 (s, 3H), 3,95 (s, 3H), 6,48 (s, 1H), 7,56 (s, 1H) 1 H-NMR (400 MHz, CDCl 3): 2.37 (s, 3H), 2.61 (t, 4H), 3.27 (t, 4H), 3.88 (s, 3H), 3.95 ( s, 3H), 6.48 (s, 1H), 7.56 (s, 1H)

46-34 46-34

1H-RMN (400 MHz, CDCl3): 1,05 (t, 3H), 1,83 (ddd, 2H), 2,35 (s, 3H), 2,58 (t, 4H), 3,07 (t, 4H), 3,94 (t, 2H), 6,41 (dd, 1H), 6,51 (d, 1H), 6,65 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.05 (t, 3H), 1.83 (ddd, 2H), 2.35 (s, 3H), 2.58 (t, 4H), 3.07 ( t, 4H), 3.94 (t, 2H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65 (d, 1H)

46-35 46-35

1H-RMN (400 MHz, CDCl3): 1,28 (s, 3H), 1,30 (s, 3H), 2,04 (s, 2H), 2,17 (s, 3H), 2,84-2,72 (m, 2H), 3,20 (d, 2H), 3,86 (s, 3H), 6,41 (d, 1H), 6,46 (dd, 1H), 6,66 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.28 (s, 3H), 1.30 (s, 3H), 2.04 (s, 2H), 2.17 (s, 3H), 2.84- 2.72 (m, 2H), 3.20 (d, 2H), 3.86 (s, 3H), 6.41 (d, 1H), 6.46 (dd, 1H), 6.66 (d , 1 HOUR)

46-36 46-36

1H-RMN (400 MHz, CDCl3): 1,18 (t, 3H), 2,39 (dd, 2H), 3,072,98 (m, 4H), 3,61 (t, 2H), 3,78 (t, 2H), 3,88 (s, 3H), 6,41 (dd, 1H), 6,51 (d, 1H), 6,65 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.18 (t, 3H), 2.39 (dd, 2H), 3,072.98 (m, 4H), 3.61 (t, 2H), 3.78 ( t, 2H), 3.88 (s, 3H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65 (d, 1H)

46-37 46-37

1H-RMN (400 MHz, CDCl3): 1,15 (s, 3H), 1,16 (s, 3H), 2,83 (sept, 1H), 3,07-2,98 (m, 4H), 3,73-3,64 (m, 2H), 3,83-3,76 (m, 2H), 3,84 (s, 3H), 6,41 (dd, 1H), 6,51 (d, 1H), 6,65 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.15 (s, 3H), 1.16 (s, 3H), 2.83 (sept, 1H), 3.07-2.98 (m, 4H), 3.73-3.64 (m, 2H), 3.83-3.76 (m, 2H), 3.84 (s, 3H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65 (d, 1H)

46-38 46-38

1H-RMN (400 MHz, CDCl3): 2,84 (d, 3H), 3,02 (t, 4H), 3,51 (t, 4H), 3,84 (s, 3H), 4,48-4,38 (m, 1H), 6,41 (dd, 1H), 6,51 (d, 1H), 6,65 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.84 (d, 3H), 3.02 (t, 4H), 3.51 (t, 4H), 3.84 (s, 3H), 4.48- 4.38 (m, 1H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65 (d, 1H)

46-39 46-39

1H-RMN (400 MHz, CDCl3): 1,99-1,81 (m, 2H), 2,23-2,12 (m, 2H), 2,69-2,58 (m, 2H), 2,84 (d, 3H), 3,54-3,45 (m, 2H), 3,84 (s, 3H), 5,55-5,45 (m, 1H), 6,42 (dd, 1H), 6,52 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.99-1.81 (m, 2H), 2.23-2.12 (m, 2H), 2.69-2.58 (m, 2H), 2 , 84 (d, 3H), 3.54-3.45 (m, 2H), 3.84 (s, 3H), 5.55-5.45 (m, 1H), 6.42 (dd, 1H ), 6.52 (d, 1H), 6.64 (d, 1H)

46-40 46-40

1H-RMN (400 MHz, CDCl3): 1,53 (s, 6H), 2,11 (s, 3H), 3,05 (s, 2H), 3,28 (t, 2H), 3,64 (t, 2H), 3,86 (s, 3H), 6,26 (dd, 1H), 6,33 (d, 1H), 6,67 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.53 (s, 6H), 2.11 (s, 3H), 3.05 (s, 2H), 3.28 (t, 2H), 3.64 ( t, 2H), 3.86 (s, 3H), 6.26 (dd, 1H), 6.33 (d, 1H), 6.67 (d, 1H)

46-41 46-41

1H-RMN (400 MHz, CDCl3): 2,55-2,41 (m, 4H), 2,63 (t, 2H), 3,13 (t, 2H), 3,77-3,68 (m, 4H), 3,83 (s, 3H), 6,15 (dd, 1H), 6,25 (d, 1H), 6,62 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.55-2.41 (m, 4H), 2.63 (t, 2H), 3.13 (t, 2H), 3.77-3.68 (m , 4H), 3.83 (s, 3H), 6.15 (dd, 1H), 6.25 (d, 1H), 6.62 (d, 1H)

46-42 46-42

1H-RMN (400 MHz, CDCl3): 2,05-2,00 (m, 2H), 2,39 (t, 2H), 3,57 (t, 2H), 3,64 (t, 2H), 3,83 (s, 3H), 4,04 (t, 2H), 6,32 (dd, 1H), 6,44 (d, 1H), 6,63 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.05-2.00 (m, 2H), 2.39 (t, 2H), 3.57 (t, 2H), 3.64 (t, 2H), 3.83 (s, 3H), 4.04 (t, 2H), 6.32 (dd, 1H), 6.44 (d, 1H), 6.63 (d, 1H)

46-43 46-43

1H-RMN (400 MHz, CDCl3): 2,13 (s, 3H), 3,53-3,46 (m, 2H), 3,65-3,55 (m, 4H), 3,71-3,66 (m, 2H), 3,88 (s, 3H), 6,67 (d, 1H), 6,87 (dd, 1H), 6,95 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.13 (s, 3H), 3.53-3.46 (m, 2H), 3.65-3.55 (m, 4H), 3.71-3 , 66 (m, 2H), 3.88 (s, 3H), 6.67 (d, 1H), 6.87 (dd, 1H), 6.95 (d, 1H)

46-44 46-44

1H-RMN (400 MHz, CDCl3): 3,73-3,61 (m, 8H), 3,87 (s, 3H), 6,65 (d, 1H), 6,86 (dd, 1H), 6,95 (d, 1H) 1H-NMR (400 MHz, CDCl3): 3.73-3.61 (m, 8H), 3.87 (s, 3H), 6.65 (d, 1H), 6.86 (dd, 1H), 6.95 (d, 1 H)

46-46 46-46

1H-RMN (400 MHz, CDCl3): 1,17 (s, 3H), 1,19 (s, 3H), 2,69 (t, 4H), 3,04 (s, 2H), 3,08 (t, 4H), 4,15-4,07 (m, 1H), 6,41 (dd, 1H), 6,51 (d, 1H), 6,65 (d, 1H), 7,01-6,94 (m, 1H) 1H-NMR (400 MHz, CDCl3): 1.17 (s, 3H), 1.19 (s, 3H), 2.69 (t, 4H), 3.04 (s, 2H), 3.08 ( t, 4H), 4.15-4.07 (m, 1H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65 (d, 1H), 7.01-6 , 94 (m, 1 H)

46-47 46-47

1H-RMN (400 MHz, CDCl3): 3,35-3,28 (m, 2H), 3,53-3,46 (m, 2H), 3,76 (s, 2H), 3,84 (s, 3H), 5,92-5,83 (m, 1H), 6,40 (dd, 1H), 6,48 (d, 1H), 6,67 (d, 1H) 1H-NMR (400 MHz, CDCl3): 3.35-3.28 (m, 2H), 3.53-3.46 (m, 2H), 3.76 (s, 2H), 3.84 (s , 3H), 5.92-5.83 (m, 1H), 6.40 (dd, 1H), 6.48 (d, 1H), 6.67 (d, 1H)

46-48 46-48

1H-RMN (400 MHz, CDCl3): 2,09-2,00 (m, 2H), 2,25-2,15 (m, 2H), 3,29-3,20 (m, 2H), 3,51-3,40 (m, 4H), 3,85 (s, 3H), 4,624,55 (m, 1H), 6,08 (d, 1H), 6,18 (d, 1H), 6,67 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.09-2.00 (m, 2H), 2.25-2.15 (m, 2H), 3.29-3.20 (m, 2H), 3 , 51-3.40 (m, 4H), 3.85 (s, 3H), 4,624.55 (m, 1H), 6.08 (d, 1H), 6.18 (d, 1H), 6, 67 (d, 1 H)

46-49 46-49

1H-RMN (400 MHz, CDCl3): 1,52-1,40 (m, 2H), 1,90-1,84 (m, 2H), 2,68-2,59 (m, 2H), 3,51-3,45 (m, 2H), 3,84 (s, 3H), 6,44 (dd, 1H), 6,54 (d, 1H), 6,64 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.52-1.40 (m, 2H), 1.90-1.84 (m, 2H), 2.68-2.59 (m, 2H), 3 , 51-3.45 (m, 2H), 3.84 (s, 3H), 6.44 (dd, 1H), 6.54 (d, 1H), 6.64 (d, 1H)

46-50 46-50

1H-RMN (400 MHz, CDCl3): 2,14 (s, 3H), 2,66 (s, 6H), 6,44 (d, 1H), 6,54 (d, 9H), 6,98 (t, 1H) 1H-NMR (400 MHz, CDCl3): 2.14 (s, 3H), 2.66 (s, 6H), 6.44 (d, 1H), 6.54 (d, 9H), 6.98 ( t, 1H)

46-51 46-51

1H-RMN (400 MHz, CDCl3): 2,63 (s, 3H), 7,49-7,45 (m, 1H), 7,74-7,62 (m, 2H), 7,76 (dd, 1H), 8,24 (d, 1H), 8,77-8,64 (m, 2H) 1H-NMR (400 MHz, CDCl3): 2.63 (s, 3H), 7.49-7.45 (m, 1H), 7.74-7.62 (m, 2H), 7.76 (dd , 1H), 8.24 (d, 1H), 8.77-8.64 (m, 2H)

46-52 46-52

1H-RMN (400 MHz, CDCl3): 3,84 (s, 3H), 3,88 (s, 3H), 6,78 (d, 1H), 6,83 (d, 1H), 7,00-6,89 (m, 3H), 7,45 (d, 1H) 1H-NMR (400 MHz, CDCl3): 3.84 (s, 3H), 3.88 (s, 3H), 6.78 (d, 1H), 6.83 (d, 1H), 7.00- 6.89 (m, 3H), 7.45 (d, 1H)

46-53 46-53

1H-RMN (400 MHz, CDCl3): 1,40 (t, 3H), 3,03 (t, 4H), 3,84 (t, 4H), 4,00 (c, 2H), 6,27 (dd, 1H), 6,38 (d, 1H), 6,71 (dd, 1H) 1H-NMR (400 MHz, CDCl3): 1.40 (t, 3H), 3.03 (t, 4H), 3.84 (t, 4H), 4.00 (c, 2H), 6.27 ( dd, 1H), 6.38 (d, 1H), 6.71 (dd, 1H)

46-54 46-54

1H-RMN (400 MHz, CDCl3): 1,26 (t, 3H), 3,02 (t, 4H), 3,85 (t, 4H), 4,05 (c, 2H), 6,40 (dd, 1H), 6,49 (d, 1H), 6,66 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.26 (t, 3H), 3.02 (t, 4H), 3.85 (t, 4H), 4.05 (c, 2H), 6.40 ( dd, 1H), 6.49 (d, 1H), 6.66 (d, 1H)

46-55 46-55

1H-RMN (400 MHz, CDCl3): 3,44 (s, 3H), 3,73 (s, 3H), 3,743,68 (m, 2H), 3,95-3,85 (m, 2H), 4,10-4,05 (m, 2H), 6,21 (dd, 1H), 6,32 (d, 1H), 6,75 (d, 1H) 1H-NMR (400 MHz, CDCl3): 3.44 (s, 3H), 3.73 (s, 3H), 3,743.68 (m, 2H), 3.95-3.85 (m, 2H), 4.10-4.05 (m, 2H), 6.21 (dd, 1H), 6.32 (d, 1H), 6.75 (d, 1H)

46-56 46-56

1H-RMN (400 MHz, CDCl3): 2,35-2,26 (m, 1H), 3,74 (s, 3H), 3,93-3,86 (m, 2H), 4,09-4,07 (m, 2H), 6,25 (dd, 1H), 6,34 (d, 1H), 6,76 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.35-2.26 (m, 1H), 3.74 (s, 3H), 3.93-3.86 (m, 2H), 4.09-4 , 07 (m, 2H), 6.25 (dd, 1H), 6.34 (d, 1H), 6.76 (d, 1H)

46-57 46-57

1H-RMN (400 MHz, CDCl3): 1,40 (t, 3H), 3,71 (s, 3H), 4,00 (c, 2H), 6,22 (dd, 1H), 6,33 (d, 1H), 6,69 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.40 (t, 3H), 3.71 (s, 3H), 4.00 (c, 2H), 6.22 (dd, 1H), 6.33 ( d, 1H), 6.69 (d, 1H)

46-58 46-58

1H-RMN (400 MHz, CDCl3): 1,32 (d, 6H), 3,73 (s, 3H), 3,853,71 (m, 2H), 4,37 (sept, 1H), 6,22 (dd, 1H), 6,32 (d, 1H), 6,72 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.32 (d, 6H), 3.73 (s, 3H), 3,853.71 (m, 2H), 4.37 (sept, 1H), 6.22 ( dd, 1H), 6.32 (d, 1H), 6.72 (d, 1H)

46-59 46-59

1H-RMN (400 MHz, CDCl3): 1,04 (t, 3H), 1,80 (ddd, 2H), 3,72 (s, 3H), 3,85-3,75 (m, 2H), 3,90 (t, 2H), 6,22 (dd, 1H), 6,33 (d, 1H), 6,69 (d, 1H) 1H-NMR (400 MHz, CDCl3): 1.04 (t, 3H), 1.80 (ddd, 2H), 3.72 (s, 3H), 3.85-3.75 (m, 2H), 3.90 (t, 2H), 6.22 (dd, 1H), 6.33 (d, 1H), 6.69 (d, 1H)

46-60 46-60

1H-RMN (400 MHz, CDCl3): 2,94 (s, 6H), 3,89 (s, 3H), 6,16 (dd, 1H), 6,25 (d, 1H), 8,72 (d, 1H) 1H-NMR (400 MHz, CDCl3): 2.94 (s, 6H), 3.89 (s, 3H), 6.16 (dd, 1H), 6.25 (d, 1H), 8.72 ( d, 1H)

46-61 46-61

1H-RMN (400 MHz, CDCl3): 3,91 (s, 3H), 6,87 (d, 1H), 7,02 (dd, 1H), 7,05 (d, 1H), 7,44 (dd, 2H), 8,59 (dd, 2H) 1H-NMR (400 MHz, CDCl3): 3.91 (s, 3H), 6.87 (d, 1H), 7.02 (dd, 1H), 7.05 (d, 1H), 7.44 ( dd, 2H), 8.59 (dd, 2H)

46-62 46-62

1H-RMN (400 MHz, CDCl3): 3,91 (s, 3H), 6,88 (d, 1H), 6,966,93 (m, 1H), 7,31 (ddd, 1H), 7,83-7,80 (m, 1H), 8,51 (dd, 1H), 8,78 (dd, 1H) 1H-NMR (400 MHz, CDCl3): 3.91 (s, 3H), 6.88 (d, 1H), 6.966.93 (m, 1H), 7.31 (ddd, 1H), 7.83- 7.80 (m, 1H), 8.51 (dd, 1H), 8.78 (dd, 1H)

46-63 46-63

1H-RMN (400 MHz, CDCl3): 3,91 (s, 3H), 6,87 (dd, 1H), 7,16 (ddd, 1H), 7,34 (dd, 1H), 7,43 (d, 1H), 7,72-7,64 (m, 2H), 8,63-8,61 (m, 1H) 1H-NMR (400 MHz, CDCl3): 3.91 (s, 3H), 6.87 (dd, 1H), 7.16 (ddd, 1H), 7.34 (dd, 1H), 7.43 ( d, 1H), 7.72-7.64 (m, 2H), 8.63-8.61 (m, 1H)

46-64 46-64

p.f. 148,6ºC; 1H-RMN (500 MHz, CDCl3) δ (ppm): 1,63 (m, 2H), 1,99 (m, 2H), 2,27 (m, 1H), 2,60 (m, 6H), 3,52 (m, 2H), 3,71 (m, 4H), 3,78 (s, 3H), 6,36 (dd, 1H), 6,52 (d, 1H), 6,73 (d, 1H) m.p. 148.6 ° C; 1H-NMR (500 MHz, CDCl3) δ (ppm): 1.63 (m, 2H), 1.99 (m, 2H), 2.27 (m, 1H), 2.60 (m, 6H), 3.52 (m, 2H), 3.71 (m, 4H), 3.78 (s, 3H), 6.36 (dd, 1H), 6.52 (d, 1H), 6.73 (d , 1 HOUR)

47 Preparación de éster terc-butílico del ácido 4-(3-amino-4-metilbenzoil)-piperazin-1-carboxílico 47 Preparation of 4- (3-amino-4-methylbenzoyl) -piperazin-1-carboxylic acid tert-butyl ester

5 5

[0176] [0176]

imagen1image 1

[0177] A una disolución de ácido 4-metil-3-nitrobenzoico (300 mg, 2,76 mmoles) y N[0177] To a solution of 4-methyl-3-nitrobenzoic acid (300 mg, 2.76 mmol) and N

10 butoxicarbonilpiperazina (340 mg, 1,83 mmoles) en DMF (3,0 ml) se añaden trietilamina (300 μl, 3,59 mmoles), TBTU (800 mg, 2,49 mmoles) y HOAt (270,5 mg, 1,99 mmoles) y se agita durante 24 horas a temperatura ambiente. La mezcla se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) para proporcionar éster terc-butílico del 10 butoxycarbonylpiperazine (340 mg, 1.83 mmol) in DMF (3.0 ml) are added triethylamine (300 μl, 3.59 mmol), TBTU (800 mg, 2.49 mmol) and HOAt (270.5 mg, 1.99 mmol) and stir for 24 hours at room temperature. The mixture is poured into water and extracted twice with ethyl acetate. The organic phase is washed with water and then with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to provide tert-butyl ester of the

15 ácido 4-(4-metil-3-nitrobenzoil)-piperazin-1-carboxílico en forma de un sólido incoloro.1H-RMN (δ, ppm): 1,47 (s, 9H), 2,64 (s, 3H), 3,88-3,28 (m, 8H), 7,42 (d, 1H), 7,56 (dd, 1H), 8,03 (d, 1H). Rf (hexano: acetato de etilo = 10:1): 0,13. El compuesto del título se obtiene por reducción con hidrógeno sobre 10% de paladio sobre carbón en disolución metanólica. 4- (4-Methyl-3-nitrobenzoyl) -piperazin-1-carboxylic acid in the form of a colorless solid. 1 H-NMR (δ, ppm): 1.47 (s, 9H), 2.64 (s, 3H), 3.88-3.28 (m, 8H), 7.42 (d, 1H), 7.56 (dd, 1H), 8.03 (d, 1H). Rf (hexane: ethyl acetate = 10: 1): 0.13. The title compound is obtained by reduction with hydrogen over 10% palladium on carbon in methanolic solution.

20 48 Preparación de 4-(3-amino-4-metilfenil)-morfolina 20 48 Preparation of 4- (3-amino-4-methylphenyl) -morpholine

[0178] [0178]

5 5

imagen1image 1

[0179] A una disolución de 4-bromo-1-metil-2-nitrobenceno (225 mg, 1,04 mmoles), morfolina (125 μl, 1,25 mmoles) y carbonato de cesio (474,4 mg, 146 mmoles) en tolueno se añaden diacetato de paladio (31,2 mg, 0,139 mmoles) y 2-(di-t-butilfosfino)-bifenilo (125 mg, 0,403 mmoles) y se agita durante 5 horas a 100ºC. Una vez [0179] To a solution of 4-bromo-1-methyl-2-nitrobenzene (225 mg, 1.04 mmol), morpholine (125 µl, 1.25 mmol) and cesium carbonate (474.4 mg, 146 mmol ) in toluene, palladium diacetate (31.2 mg, 0.139 mmol) and 2- (di-t-butylphosphino) -biphenyl (125 mg, 0.403 mmol) are added and stirred for 5 hours at 100 ° C. One time

10 enfriada, la mezcla se filtra para eliminar el material insoluble. El filtrado se vierte en agua y se extrae dos veces con acetato de etilo. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato de magnesio y se evapora al vacío. El residuo se purifica mediante cromatografía en columna de gel de sílice (n-hexano: acetato de etilo = 5:1) para proporcionar 4-(4-metil-3-nitrofenil)-morfolina en forma de un sólido amarillo.1H-RMN (δ, ppm): 2,50 (s, 3H), 3,19-3,17 (m, 4H), 3,88-3,86 (m, 4H), 7,04 (dd, 1H), 7,21 (d, 1H), 7,47 (d, 1H). Rf 10 cooled, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted twice with ethyl acetate. The organic phase is washed with water and then with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to provide 4- (4-methyl-3-nitrophenyl) -morpholine as a yellow solid. 1 H-NMR (δ, ppm): 2.50 (s, 3H), 3.19-3.17 (m, 4H), 3.88-3.86 (m, 4H), 7.04 (dd, 1H), 7.21 (d, 1H), 7.47 (d, 1H). Rf

15 (hexano: acetato de etilo = 5:1): 0,20. El compuesto del título se obtiene por reducción con hidrógeno sobre 10% de paladio sobre carbón en disolución metanólica. 15 (hexane: ethyl acetate = 5: 1): 0.20. The title compound is obtained by reduction with hydrogen over 10% palladium on carbon in methanolic solution.

49 20 Preparación de ácido 2-[5-cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-benzoico 49 20 Preparation of 2- [5-Chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -benzoic acid

imagen21image21

25 [0181] A una disolución de 1,0 g (3,37 mmoles) de 2-(2,5-dicloropirimidin-4-ilamino)-N-metilbenzamida en 15 ml de ácido acético se añaden dihidrocloruro de 2-metoxi-4-morfolinoanilina (1,9 g, 6,73 mmoles) y 6,0 ml de una disolución etanólica de cloruro de hidrógeno (6,0 mmoles). Después de agitar la mezcla de reacción durante 16 horas a 120ºC y enfriarla a temperatura ambiente se añade una disolución acuosa de NaHCO3 para ajustar la acidez [0181] To a solution of 1.0 g (3.37 mmol) of 2- (2,5-dichloropyrimidin-4-ylamino) -N-methylbenzamide in 15 ml of acetic acid are added 2-methoxy dihydrochloride 4-morpholinoaniline (1.9 g, 6.73 mmol) and 6.0 ml of an ethanolic solution of hydrogen chloride (6.0 mmol). After stirring the reaction mixture for 16 hours at 120 ° C and cooling to room temperature an aqueous NaHCO3 solution is added to adjust the acidity

30 entre pH 5 y pH 6. El precipitado resultante se recoge por filtración y se seca a presión reducida para dar ácido 2-[5cloro-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-benzoico (970 mg, 2,12 mmoles, 63%) en forma de un sólido de color marfil. RMN (400 MHz, DMSO-d6, δ): 3,10-3,20 (m, 4H), 3,78 (s, 3H), 3,70-3,80 (m, 4H), 6,52 (dd, 1H, J=8,56, 2,52 Hz), 6,67 (d, 1H, J=2,52 Hz), 7,08 (dd, 1H, J=8,04, 8,04 Hz), 7,39 (d, 1H, J=8,56 Hz), 7,35-7,45 (m, 1H), 7,99 (dd, 1H, 30 between pH 5 and pH 6. The resulting precipitate is collected by filtration and dried under reduced pressure to give 2- [5-chloro-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4 acid -lamino] -benzoic acid (970 mg, 2.12 mmol, 63%) in the form of an ivory solid. NMR (400 MHz, DMSO-d6, δ): 3.10-3.20 (m, 4H), 3.78 (s, 3H), 3.70-3.80 (m, 4H), 6.52 (dd, 1H, J = 8.56, 2.52 Hz), 6.67 (d, 1H, J = 2.52 Hz), 7.08 (dd, 1H, J = 8.04, 8.04 Hz), 7.39 (d, 1H, J = 8.56 Hz), 7.35-7.45 (m, 1H), 7.99 (dd, 1H,

35 J=8,04, 1,52 Hz), 8,14 (s, 1H), 8,28 (s, 1H), 8,70-8,80 (m, 1H). J = 8.04, 1.52 Hz), 8.14 (s, 1H), 8.28 (s, 1H), 8.70-8.80 (m, 1H).

Ejemplo 50: Los restos sulfonamida se preparan de la siguiente manera: Example 50: The sulfonamide moieties are prepared as follows:

Preparación de cloruro de 2-amino-4-cloro-5-metil-benceno-sulfonilo [0182] A una disolución de ácido 2-amino-5-cloro-4-metil-bencenosulfónico (3,0 g, 1,35 mmoles) en dicloroetano (10 ml) se añade cloruro de sulfurilo (4,4 ml, 3,83 mmoles) y se agita a 60ºC. Al cabo de una hora se añade cloruro de tionilo (1,3 ml) y la mezcla se sigue agitando durante 7,0 horas a 100ºC. La mezcla se vierte en Preparation of 2-amino-4-chloro-5-methyl-benzene-sulfonyl chloride [0182] To a solution of 2-amino-5-chloro-4-methyl-benzenesulfonic acid (3.0 g, 1.35 mmol ) in dichloroethane (10 ml) sulfuryl chloride (4.4 ml, 3.83 mmol) is added and stirred at 60 ° C. After one hour, thionyl chloride (1.3 ml) is added and the mixture is stirred for 7.0 hours at 100 ° C. The mixture is poured into

5 agua helada y se extrae tres veces con éter. La fase orgánica se lava con agua y después con salmuera, se seca mediante sulfato sódico y se evapora al vacío. 1H-RMN (δ, ppm): 2,35 (s, 3H), 6,68 (s, 1H), 7,75 (s, 1H). Este cloruro de sulfonilo se hace reaccionar con una amina adecuada. En la reacción con, por ejemplo, metilamina se forma 2-amino-5-cloro-4,N-dimetilbencenosulfonamida. 5 ice water and extracted three times with ether. The organic phase is washed with water and then with brine, dried over sodium sulfate and evaporated in vacuo. 1 H-NMR (δ, ppm): 2.35 (s, 3 H), 6.68 (s, 1 H), 7.75 (s, 1 H). This sulfonyl chloride is reacted with a suitable amine. In the reaction with, for example, methylamine, 2-amino-5-chloro-4, N-dimethylbenzenesulfonamide is formed.

10 Ejemplo de referencia 51 10 Reference example 51

Preparación de 2-[5-bromo-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-N,N-dimetil-bencenosulfonamida Preparation of 2- [5-Bromo-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -N, N-dimethyl-benzenesulfonamide

15 [0183] 15 [0183]

imagen1image 1

[0184] A una disolución de 2-[5-bromo-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-N-metilbencenosulfonamida (ejemplo 3-19) (1,0 g, 1,82 mmoles) en DMF (10 ml) se añaden carbonato potásico (300 mg, [0184] To a solution of 2- [5-bromo-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -N-methylbenzenesulfonamide (example 3-19) (1 , 0 g, 1.82 mmol) in DMF (10 ml) potassium carbonate (300 mg,

20 2,17 mmoles) y yodometano (116 μl, 1,86 mmoles). La suspensión resultante se agita durante 1 h a 50ºC. Se añade agua a la mezcla de reacción y se extrae tres veces con acetato de etilo. La fase orgánica se lava con agua, se seca mediante sulfato sódico y se concentra al vacío. El residuo se purifica mediante cromatografía en columna de óxido de aluminio (AcOEt) para proporcionar el compuesto del título (728 mg, rendimiento 71%). H-RMN (400 MHz, CDCl3, δ): 2,74 (s, 6H), 3,05-3,18 (m, 4H), 3,84-3,93 (m, 4H), 3,88 (s, 3H), 6,43 (dd, 1H), 6,53 (d, 20 2.17 mmol) and iodomethane (116 μl, 1.86 mmol). The resulting suspension is stirred for 1 h at 50 ° C. Water is added to the reaction mixture and extracted three times with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is purified by aluminum oxide column chromatography (AcOEt) to provide the title compound (728 mg, 71% yield). H-NMR (400 MHz, CDCl3, δ): 2.74 (s, 6H), 3.05-3.18 (m, 4H), 3.84-3.93 (m, 4H), 3.88 (s, 3H), 6.43 (dd, 1H), 6.53 (d,

25 1H), 7,24 (m, 1H), 7,31 (s, 1H), 7,56 (m, 1H), 7,87 (dd, 1H), 8,05 (d, 1H), 8,21 (s, 1H), 8,49 (d, 1H), 8,49 (d, 1H), 9,27 (s, 1H). Rf: 0,23 (AcOEt:hexano = 1:1). 1H), 7.24 (m, 1H), 7.31 (s, 1H), 7.56 (m, 1H), 7.87 (dd, 1H), 8.05 (d, 1H), 8 , 21 (s, 1H), 8.49 (d, 1H), 8.49 (d, 1H), 9.27 (s, 1H). Rf: 0.23 (AcOEt: hexane = 1: 1).

Ejemplo de referencia 52 Reference Example 52

30 Preparación de 2-[5-bromo-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-5-fluoro-N-metil-bencenosulfonamida Preparation of 2- [5-bromo-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -5-fluoro-N-methyl-benzenesulfonamide

[0185] [0185]

imagen22image22

Preparación de 7-fluoro-1,1-dioxo-1,4-dihidro-2H-1λ6,s-benzo[1,2,4]tiadiazin-3-ona Preparation of 7-fluoro-1,1-dioxo-1,4-dihydro-2H-1λ6, s-benzo [1,2,4] thiadiazin-3-one

[0186] A una disolución de isocianato de clorosulfonilo (1,2 ml, 13,5 mmoles) en nitroetano (10 ml) se añade gota a gota 4-fluoroanilina (1,0 g, 8,97 mmoles) a 0ºC y la mezcla de reacción se agita durante 30 min. Se añade a la disolución cloruro de aluminio (1,3 g, 9,87 mmoles) a 0ºC y la mezcla se agita durante 1 h a 100ºC. Una vez enfriada a temperatura ambiente se añade agua y la mezcla se extrae dos veces con acetato de etilo. La fase orgánica se lava con salmuera, se seca mediante sulfato sódico y se concentra a presión reducida. Los sólidos resultantes se recogen por filtración y se lavan con éter para dar sólidos grisáceos (803,9 mg, 41%). RMN (400 MHz, DMSO-d6, δ): 7,22-7,28 (m, 1H), 7,45-7,57 (m, 1H), 7,60 (m, 1H), 11,15-11,30 (m, 1H). Rf: 0,43 (MeOH:AcOEt = 1:5). [0186] To a solution of chlorosulfonyl isocyanate (1.2 ml, 13.5 mmol) in nitroethane (10 ml) 4-fluoroaniline (1.0 g, 8.97 mmol) is added dropwise at 0 ° C and the reaction mixture is stirred for 30 min. Aluminum chloride (1.3 g, 9.87 mmol) is added to the solution at 0 ° C and the mixture is stirred for 1 h at 100 ° C. Once cooled to room temperature, water is added and the mixture is extracted twice with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting solids are collected by filtration and washed with ether to give gray solids (803.9 mg, 41%). NMR (400 MHz, DMSO-d6, δ): 7.22-7.28 (m, 1H), 7.45-7.57 (m, 1H), 7.60 (m, 1H), 11.15 -11.30 (m, 1 H). Rf: 0.43 (MeOH: AcOEt = 1: 5).

Preparación de 7-fluoro-2-metil-1,1-dioxo-1,4-dihidro-2H-1λ6-benzo[1,2,4]tiadiazin-3-ona Preparation of 7-fluoro-2-methyl-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo [1,2,4] thiadiazin-3-one

[0187] A una disolución de 7-fluoro-1,1-dioxo-1,4-dihidro-2H-1λ6-benzo[1,2,4]tiadiazin-3-ona (5,19 g, 24,0 mmoles) en DMF (50 ml) se añaden sucesivamente hidruro sódico (1,04 g, 26,0 mmoles) y yodometano (1,5 ml, 24,0 mmoles) y la mezcla se agita durante 1 hora a 70ºC. Una vez enfriada a temperatura ambiente, la mezcla se vierte en agua y el precipitado se recoge por filtración y se lava sucesivamente con agua y hexano para dar sólidos grisáceos (5,38 g, 94%). RMN (400 MHz, DMSO-d6, δ): 3,32 (s, 3H), 7,44 (dd, 1H), 7,75 (ddd, 1H), 7,94 (dd, 1H). Rf (MeOH:AcOEt = 1:5): 0,21. Rf: 0,39 (hexano:AcOEt = 1:1). [0187] To a solution of 7-fluoro-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo [1,2,4] thiadiazin-3-one (5.19 g, 24.0 mmol ) in DMF (50 ml), sodium hydride (1.04 g, 26.0 mmol) and iodomethane (1.5 ml, 24.0 mmol) are successively added and the mixture is stirred for 1 hour at 70 ° C. Once cooled to room temperature, the mixture is poured into water and the precipitate is collected by filtration and washed successively with water and hexane to give gray solids (5.38 g, 94%). NMR (400 MHz, DMSO-d6, δ): 3.32 (s, 3H), 7.44 (dd, 1H), 7.75 (ddd, 1H), 7.94 (dd, 1H). Rf (MeOH: AcOEt = 1: 5): 0.21. Rf: 0.39 (hexane: AcOEt = 1: 1).

Preparación de 2-amino-5-fluoro-N-metil-bencenosulfonamida Preparation of 2-amino-5-fluoro-N-methyl-benzenesulfonamide

[0188] Se disuelven 6,79 g de 7-fluoro-2-metil-1,1-dioxo-1,4-dihidro-2H-1λ6-benzo[1,2,4]tiadiazin-3-ona (29,5 mmoles) en hidróxido de sodio ac. al 20% y la disolución resultante se agita durante 13,5 horas a 100ºC. La mezcla se enfría a temperatura ambiente y se vierte en agua. Se añaden 78 ml de HCl ac. 5 M y el precipitado se recoge por filtración y se lava con agua para proporcionar sólidos ligeramente morados (3,96 g, 65%). RMN (400 MHz, CDCl3, δ): 2,60 (d, 3H), 4,55-4,82 (m, 3H), 6,74 (dd, 1H), 7,05-7,12 (m, 1H), 7,45 (dd, 1H). Rf: 0,41 (hexano:AcOEt = 1:1). [0188] 6.79 g of 7-fluoro-2-methyl-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo [1,2,4] thiadiazin-3-one (29, 5 mmol) in sodium hydroxide ac. at 20% and the resulting solution is stirred for 13.5 hours at 100 ° C. The mixture is cooled to room temperature and poured into water. 78 ml of ac HCl are added. 5 M and the precipitate is collected by filtration and washed with water to provide slightly purple solids (3.96 g, 65%). NMR (400 MHz, CDCl3, δ): 2.60 (d, 3H), 4.55-4.82 (m, 3H), 6.74 (dd, 1H), 7.05-7.12 (m , 1H), 7.45 (dd, 1H). Rf: 0.41 (hexane: AcOEt = 1: 1).

2-(5-Bromo-2-cloro-pirimidin-4-ilamino)-5-fluoro-N-metil-bencenosulfonamida 2- (5-Bromo-2-chloro-pyrimidin-4-ylamino) -5-fluoro-N-methyl-benzenesulfonamide

[0189] La reacción de pirimidina con 2-amino-5-fluoro-N-metil-bencenosulfonamida se realiza como se ha descrito en el ejemplo B. RMN (400 MHz, CDCl3, δ): 2,67 (d, 3H), 4,56 (m, 1H), 7,36-7,45 (m, 1H), 7,68 (dd, 1H), 8,39 (s, 1H), 8,42 (dd, 1H), 9,26 (s, 1H). Rf 0,59 (hexano:AcOEt = 1:1). [0189] The reaction of pyrimidine with 2-amino-5-fluoro-N-methyl-benzenesulfonamide is carried out as has been done described in example B. NMR (400 MHz, CDCl3, δ): 2.67 (d, 3H), 4.56 (m, 1H), 7.36-7.45 (m, 1H), 7.68 (dd, 1H), 8.39 (s, 1H), 8.42 (dd, 1H), 9.26 (s, 1 H). Rf 0.59 (hexane: AcOEt = 1: 1).

2-[5-Bromo-2-(2-metoxi-4-morfolin-4-il-fenilamino)-pirimidin-4-ilamino]-5-fluoro-N-metil-bencenosulfonamida 2- [5-Bromo-2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyrimidin-4-ylamino] -5-fluoro-N-methyl-benzenesulfonamide

[0190] La introducción de anilina sustituida se efectúa como se ha descrito en el ejemplo A. RMN (400 MHz, CDCl3, δ): 2,65 (d, 3H), 3,09-3,16 (m, 4H), 3,87 (s, 3H), 4,50 (c, 1H), 6,41 (dd, 1H), 6,52 (d, 1H), 7,25-7,33 (m, 2H), 7,69 (dd, 1H), 7,95 (d, 1H), 8,20 (s, 1H), 8,37 (dd, 1H), 8,70 (s, 1H). Rf 0,30 (hexano:AcOEt = 1:1) [0190] The introduction of substituted aniline is carried out as described in example A. NMR (400 MHz, CDCl3, δ): 2.65 (d, 3H), 3.09-3.16 (m, 4H), 3.87 (s, 3H), 4.50 (c, 1H), 6.41 (dd, 1H), 6.52 (d, 1H), 7.25-7.33 (m, 2H), 7.69 (dd, 1H), 7.95 (d, 1H), 8.20 (s, 1H), 8.37 (dd, 1H), 8 , 70 (s, 1 H). Rf 0.30 (hexane: AcOEt = 1: 1)

Ejemplo 53: Ensayo de la FAK Example 53: FAK test

[0191] Todos los pasos se realizan en una placa de microvaloración negra de 96 pocillos. El dominio cinasa de la FAK humana recombinante purificado y marcado con hexahistidina se diluye con tampón de dilución (HEPES 50 mM, pH 7,5, 0,01% de ASB, 0,05% de Tween-20 en agua) a una concentración de 94 ng/ml (2,5 nM). La mezcla de reacción se prepara mezclando 10 μl de tampón de cinasa 5x (HEPES 250 mM, pH 7,5, Na3VO4 50 μM, DTT 5 mM, MgCl2 10 mM, MnCl2 50 mM, 0,05% ASB, 0,25% Tween-20 en agua), 20 μl de agua, 5 μl de sustrato peptídico biotinilado 4 μM (Biot-Y397) en disolución acuosa, 5 μl del compuesto de ensayo en DMSO y 5 μl de disolución de enzima recombinante y se incuba durante 30 min a temperatura ambiente. La reacción enzimática se inicia mediante la adición de 5 μl de ATP 5 μM en agua y la mezcla se incuba durante 3 horas a 37ºC. La reacción se termina añadiendo 200 μl de mezcla de detección (Eu-PT66 1 nM, 2,5 μg/ml de SA-(SL)APC, EDTA 6,25 mM en tampón de dilución) y la señal de FRET del europio a la aloficocianina se mide mediante ARVOsx+L (Perkin Elmer) después de 30 min de incubación a temperatura ambiente. Como señal de FRET para el análisis de datos se usa la relación entre las intensidades de fluorescencia a 665 nm y 615 nm con el fin de anular el efecto de extinción del color por un compuesto de ensayo. Los resultados se expresan en porcentaje de inhibición de la actividad enzimática. Como control del 0% y 100% de inhibición se usan DMSO y EDTA 0,5 M, respectivamente. Los valores de CI50 se determinan mediante un análisis de regresión no lineal usando el programa OriginPro 6.1 (OriginLab). [0191] All steps are performed on a black 96-well microtiter plate. The recombinant human FAK kinase domain purified and labeled with hexahistidine is diluted with dilution buffer (50 mM HEPES, pH 7.5, 0.01% ASB, 0.05% Tween-20 in water) at a concentration 94 ng / ml (2.5 nM). The reaction mixture is prepared by mixing 10 μl of 5x kinase buffer (250 mM HEPES, pH 7.5, 50 μM Na3VO4, 5 mM DTT, 10 mM MgCl2, 50 mM MnCl2, 0.05% ASB, 0.25% Tween-20 in water), 20 μl of water, 5 μl of 4 μM biotinylated peptide substrate (Biot-Y397) in aqueous solution, 5 μl of the test compound in DMSO and 5 μl of recombinant enzyme solution and incubate for 30 min at room temperature. The enzymatic reaction is initiated by the addition of 5 μl of 5 μM ATP in water and the mixture is incubated for 3 hours at 37 ° C. The reaction is terminated by adding 200 μl of detection mixture (1 nM Eu-PT66, 2.5 μg / ml of SA- (SL) APC, 6.25 mM EDTA in dilution buffer) and the FRET signal from the europium to allophycocyanin is measured by ARVOsx + L (Perkin Elmer) after 30 min incubation at room temperature. As a FRET signal for data analysis, the relationship between fluorescence intensities at 665 nm and 615 nm is used in order to cancel out the effect of color extinction by a test compound. The results are expressed as a percentage of inhibition of enzymatic activity. DMSO and 0.5 M EDTA, respectively, are used as control of 0% and 100% inhibition. IC50 values are determined by a non-linear regression analysis using the OriginPro 6.1 (OriginLab) program.

[0192] El péptido Biot-Y397 (sal amonio de biotina-SETDDYAEIID) está diseñado de manera que presente la misma secuencia de aminoácidos que la región de S392 a D402 del humano (número de acceso a GenBank L13616) y se prepara mediante procedimientos convencionales. [0192] Biot-Y397 peptide (biotin-SETDDYAEIID ammonium salt) is designed to have the same amino acid sequence as the human S392 to D402 region (GenBank accession number L13616) and is prepared by conventional procedures .

[0193] El dominio cinasa de la FAK humana recombinante purificado y marcado con hexahistidina se obtiene de la siguiente manera: Se aísla ADNc de la FAK humana de longitud completa a partir de ADNc de placenta humana Marathon-ReadyTM (Clontech, nº 7411-1) mediante amplificación por PCR con el cebador de PCR 5’ (ATGGCAGCTGCTTACCTTGAC) y el cebador de PCR 3’ (TCAGTGTGGTCTCGTCTGCCC) y se subclona en un vector pGEM-T (Promega, nº A3600). Tras la digestión con AccIII el fragmento de ADN purificado se trata con el fragmento Klenow. El fragmento de ADNc se digiere con BamHI y se clona en el plásmido pFastBacHTb (Invitrogen Japan K.K., Tokio) cortado previamente con BamHI y StuI. El plásmido resultante, hFAK KD (M384G706)/pFastBacHTb, se secuencia para confirmar su estructura. El ADN resultante codifica una proteína de 364 aminoácidos que contiene una marca de hexahistidina, una región espaciadora y un sitio de escisión para la proteasa rTEV en el extremo N-terminal y el dominio cinasa de la FAK (Met384-Gly706) desde la posición 29 hasta la 351. [0193] The recombinant human FAK kinase domain purified and labeled with hexahistidine is obtained as follows: Full length human FAK cDNA is isolated from Marathon-ReadyTM human placenta cDNA (Clontech, No. 7411-1 ) by PCR amplification with the 5 'PCR primer (ATGGCAGCTGCTTACCTTGAC) and the 3' PCR primer (TCAGTGTGGTCTCGTCTGCCC) and subcloned into a pGEM-T vector (Promega, No. A3600). After digestion with AccIII the purified DNA fragment is treated with the Klenow fragment. The cDNA fragment is digested with BamHI and cloned into plasmid pFastBacHTb (Invitrogen Japan K.K., Tokyo) previously cut with BamHI and StuI. The resulting plasmid, hFAK KD (M384G706) / pFastBacHTb, is sequenced to confirm its structure. The resulting DNA encodes a 364 amino acid protein that contains a hexahistidine brand, a spacer region and a cleavage site for the rTEV protease at the N-terminal end and the FAK kinase domain (Met384-Gly706) from position 29 until 351.

[0194] El plásmido donante se transpone al genoma de baculovirus usando células de E. coli MaxEfficacy DH10Bac. El ADN del Bacmido se prepara mediante un simple protocolo de lisis alcalina descrito en el sistema de expresión de baculovirus Bac-to-Bac® (Invitrogen). Las células de insecto Sf9 se transfectan según el protocolo proporcionado por el suministrador (CellFECTIN®, Invitrogen). La expresión de FAK en cada lisado se analiza mediante electroforesis en gel de poliacrilamida con SDS y transferencia Western con un anticuerpo monoclonal contra la FAK humana (clon nº 77 de Transduction Laboratories). [0194] The donor plasmid is transposed into the baculovirus genome using E. coli MaxEfficacy DH10Bac cells. Bacmido DNA is prepared by a simple alkaline lysis protocol described in the Bac-to-Bac® baculovirus expression system (Invitrogen). Sf9 insect cells are transfected according to the protocol provided by the supplier (CellFECTIN®, Invitrogen). The expression of FAK in each lysate is analyzed by polyacrylamide gel electrophoresis with SDS and Western blotting with a monoclonal antibody against human FAK (clone No. 77 of Transduction Laboratories).

[0195] El clon vírico que muestra la mayor expresión se amplifica adicionalmente por infección de células Sf9. La expresión en células ExpresSF+® (Protein Sciences Corp., Meriden, Connecticut, EE.UU.) proporciona un alto nivel de proteína con poca degradación. Los lisados celulares se aplican en una columna de HiTrapTM Chelating Sepharose HP (Amersham Biosciences) cargada con sulfato de níquel y equilibrada con HEPES 50 mM, pH 7,5, NaCl 0,5 M e imidazol 10 mM. La proteína capturada se eluye con cantidades crecientes de imidazol en tampón HEPES/NaCl y se purifica adicionalmente por diálisis en HEPES 50 mM, pH 7,5, 10% de glicerol y DTT 1 mM. [0195] The viral clone showing the highest expression is further amplified by infection of Sf9 cells. ExpresSF + ® cell expression (Protein Sciences Corp., Meriden, Connecticut, USA) provides a high level of protein with little degradation. Cell lysates are applied on a HiTrapTM Chelating Sepharose HP column (Amersham Biosciences) loaded with nickel sulfate and equilibrated with 50 mM HEPES, pH 7.5, 0.5 M NaCl and 10 mM imidazole. The captured protein is eluted with increasing amounts of imidazole in HEPES / NaCl buffer and further purified by dialysis in 50 mM HEPES, pH 7.5, 10% glycerol and 1 mM DTT.

Ejemplo 54: Ensayo de la cinasa ZAP-70 sin células Example 54: ZAP-70 kinase assay without cells

[0196] El ensayo de la cinasa ZAP-70 se basa en la transferencia de energía por resonancia de fluorescencia a lo largo del tiempo (FRET). En un tubo se polipropileno siliconizado se incuba durante 1 hora a temperatura ambiente ZAP-70 80 nM con Lck 80 nM (proteína tirosina cinasa específica de linfocitos T) y ATP 4 μM en tampón de cinasa ZAP-70 (Tris 20 mM, pH, 7,5, Na3VO4 10 μM, DTT 1 mM, MnCl2 1 mM, 0,01% de ASB, 0,05% de Tween-20). A continuación se añade el inhibidor PP2 (1-terc-butil-3-(4-clorofenil)-1H-pirazolo[3,4-d]pirimidin-4ilamina; Alexis Biochemicals) selectivo de Lck (concentración final 1,2 μM) y se incuba durante otros 10 min. Se mezclan 10 μl de esta disolución con 10 μl del péptido biotinilado LAT-11 (1 μM) como sustrato y 20 μl de diluciones seriadas de inhibidores y se incuban durante 4 horas a temperatura ambiente. La reacción de la cinasa se termina con 10 μl de una disolución de EDTA 10 mM en tampón de detección (Tris 20 mM, pH 7,5, 0,01% de ASB, 0,05% de Tween-20). Se añaden 50 μl de anticuerpo contra fosfotirosina marcado con europio (Eu-PT66; concentración final 0,125 nM) y 50 μl de estreptavidina-aloficocianina (SA-APC; concentración final 40 nM) en tampón de detección. Tras una incubación de 1 hora a temperatura ambiente se mide la fluorescencia en el contador multitécnica Victor2 (Wallac) a 665 nm. Los valores de fondo (control bajo) se obtienen en ausencia de muestras de ensayo y ATP y se restan a todos los valores. Las señales obtenidas en ausencia de muestras de ensayo representan el 100% (control alto). La inhibición obtenida en presencia de los compuestos de ensayo se calcula como porcentaje de inhibición del control alto. La concentración de los compuestos de ensayo que produce una inhibición del 50% (CI50) se determina a partir de las curvas de dosis-respuesta. En este ensayo, los agentes de la invención presentan valores de CI50 comprendidos en el intervalo de 10 nM a 2 μM, preferentemente de 10 nM a 100 nM. [0196] The ZAP-70 kinase assay is based on the transfer of energy by fluorescence resonance over time (FRET). In a tube, siliconized polypropylene is incubated for 1 hour at room temperature ZAP-70 80 nM with 80 nM Lck (T-lymphocyte specific tyrosine kinase protein) and 4 μM ATP in ZAP-70 kinase buffer (20 mM Tris, pH, 7.5, 10 μM Na3VO4, 1 mM DTT, 1 mM MnCl2, 0.01% ASB, 0.05% Tween-20). Next, the PP2 (1-tert-butyl-3- (4-chlorophenyl) -1 H -pyrazolo [3,4-d] pyrimidine-4-ylamine inhibitor; Alexis Biochemicals) selective Lck (final concentration 1.2 μM) is added and incubate for another 10 min. 10 μl of this solution is mixed with 10 μl of the biotinylated peptide LAT-11 (1 μM) as a substrate and 20 μl of serial dilutions of inhibitors and incubated for 4 hours at room temperature. The kinase reaction is terminated with 10 µl of a 10 mM EDTA solution in detection buffer (20 mM Tris, pH 7.5, 0.01% ASB, 0.05% Tween-20). 50 µl of Europium-labeled phosphotyrosine antibody (Eu-PT66; final concentration 0.125 nM) and 50 µl of streptavidin-allophycocyanin (SA-APC; final concentration 40 nM) in detection buffer are added. After an incubation of 1 hour at room temperature the fluorescence is measured in the multi-technical counter Victor2 (Wallac) at 665 nm. Background values (low control) are obtained in the absence of test samples and ATP and are subtracted from all values. The signals obtained in the absence of test samples represent 100% (high control). The inhibition obtained in the presence of test compounds is calculated as a percentage of high control inhibition. The concentration of the test compounds that produces a 50% inhibition (IC50) is determined from the dose-response curves. In this test, the agents of the invention have IC50 values in the range of 10 nM to 2 µM, preferably 10 nM to 100 nM.

[0197] La cinasa ZAP-70 recombinante se obtiene de la siguiente manera: Se amplifica por RT-PCR un ácido nucleico que codifica la ZAP-70 humana de longitud completa (GenBank nº L05148) a partir de una biblioteca de ADNc de células Jurkat y se clona en el vector pBluescript KS (Stratagene, California, EE.UU.). La autenticidad del inserto de ADNc de ZAP-70 se valida mediante un análisis de secuencia completa. Este plásmido donante se usa entonces para construir un vector de transferencia recombinante en baculovirus basado en el plásmido pVL1392 (Pharmingen, California, EE.UU.) que está provisto adicionalmente de una marca de hexahistidina N-terminal. Tras la transfección simultánea con ADN vírico AcNPV se obtienen 10 aislados víricos independientes por purificación a partir de placas que se amplifican a pequeña escala y seguidamente se analizan respecto a la expresión de ZAP-70 recombinante mediante transferencia Western usando un anticuerpo contra ZAP-70 disponible en el mercado (clon 2F3.1, Upstate Biotechnology, Lake Placid, NY, EE.UU.). Tras una amplificación adicional de una placa recombinante positiva se preparan poblaciones de virus titulados que se usan para la infección de células Sf9 cultivadas en medio SF900 II sin suero (Life Technologies, Basilea, Suiza) en condiciones optimizadas definidas. La proteína ZAP-70 se aísla a partir del lisado de células Sf9 infectadas por cromatografía de afinidad en una columna de Ni-NTA (Qiagen, Basilea, Suiza). [0197] Recombinant ZAP-70 kinase is obtained as follows: A nucleic acid encoding the full length human ZAP-70 (GenBank No. L05148) is amplified by RT-PCR from a Jurkat cell cDNA library and is cloned into the pBluescript KS vector (Stratagene, California, USA). The authenticity of the ZAP-70 cDNA insert is validated by a complete sequence analysis. This donor plasmid is then used to construct a recombinant baculovirus transfer vector based on plasmid pVL1392 (Pharmingen, California, USA) which is additionally provided with an N-terminal hexahistidine brand. After simultaneous transfection with AcNPV viral DNA, 10 independent viral isolates are obtained by purification from plates that are amplified on a small scale and then analyzed for the expression of recombinant ZAP-70 by Western blotting using an available anti-ZAP-70 antibody in the market (clone 2F3.1, Upstate Biotechnology, Lake Placid, NY, USA). After further amplification of a positive recombinant plate titrated virus populations are prepared which are used for the infection of Sf9 cells grown in serum-free SF900 II medium (Life Technologies, Basel, Switzerland) under defined optimized conditions. The ZAP-70 protein is isolated from the lysate of Sf9 cells infected by affinity chromatography on a Ni-NTA column (Qiagen, Basel, Switzerland).

También se puede adquirir ZAP-70 recombinante marcada con His de PanVera LLC, Madison, Wisconsin, EE.UU. His-labeled recombinant ZAP-70 can also be purchased from PanVera LLC, Madison, Wisconsin, USA.

[0198] LAT-11 (conector para la activación de linfocitos T): El péptido LAT-11 biotinilado (Biotina-EEGAPDYENLQELN) usado como sustrato en el ensayo de la cinasa ZAP-70 se prepara conforme a procedimientos conocidos de la síntesis peptídica. El grupo N-α Fmoc de Fmoc-Asn(Trt)-oximetil-4-fenoximetilco(poliestireno-1%-divinilbenceno), con un contenido aproximado de Asn de 0,5 mmol/g, se disocia usando piperidina al 20% en DMF. Se acoplan cuatro equivalentes por grupo amino de Fmoc-aminoácido protegido en sus cadenas laterales [Asp(OtBu), Glu(OtBu), Asn(TrT), Gln(Trt) y Tyr(tBu)] usando DIPCDI y HOBt en DMF. Una vez ensamblada por completo la cadena peptídica se elimina el grupo protector Fmoc terminal con piperidina en DMF como anteriormente. Después se acopla ácido L(+)-biotinil-aminohexanoico al grupo amino terminal usando DIPCDI y HOBt en DMF y usando cuatro equivalentes de los reactivos durante cuatro días a TA. El péptido se disocia del soporte de resina, y todos los grupos protectores de la cadena lateral se eliminan simultáneamente usando un reactivo compuesto por 5% de sulfuro de dodecilmetilo y 5% de agua en TFA durante dos horas a TA. Las partículas de resina se eliminan por filtración, se lavan con TFA y el producto se precipita a partir de los filtrados combinados por adición de 10 a 20 volúmenes de éter dietílico, se lava con éter y se seca. El producto se purifica mediante cromatografía en una columna de sílice de poros grandes C-18 usando un gradiente de acetonitrilo en ácido fosfórico acuoso al 2%. Las fracciones que contienen el compuesto puro se recogen, se filtran a través de una resina de intercambio aniónico (Biorad, AG4-X4, forma de acetato) y se liofilizan para dar el compuesto del título. EM: 1958,0 (M-H)-1. [0198] LAT-11 (T lymphocyte activation linker): The biotinylated LAT-11 peptide (Biotin-EEGAPDYENLQELN) used as a substrate in the ZAP-70 kinase assay is prepared according to known peptide synthesis procedures. The N-α Fmoc group of Fmoc-Asn (Trt) -oxymethyl-4-phenoxymethyl (polystyrene-1% -divinylbenzene), with an approximate Asn content of 0.5 mmol / g, is dissociated using 20% piperidine in DMF Four equivalents are coupled per amino group of protected Fmoc-amino acid in their side chains [Asp (OtBu), Glu (OtBu), Asn (TrT), Gln (Trt) and Tyr (tBu)] using DIPCDI and HOBt in DMF. Once the peptide chain is completely assembled, the Fmoc terminal protective group with piperidine in DMF is removed as before. L (+) - Biotinyl aminohexanoic acid is then coupled to the amino terminal group using DIPCDI and HOBt in DMF and using four equivalents of the reagents for four days at RT. The peptide dissociates from the resin support, and all side chain protecting groups are removed simultaneously using a reagent consisting of 5% dodecylmethyl sulfide and 5% water in TFA for two hours at RT. The resin particles are removed by filtration, washed with TFA and the product is precipitated from the combined filtrates by adding 10 to 20 volumes of diethyl ether, washed with ether and dried. The product is purified by chromatography on a C-18 large pore silica column using a gradient of 2% aqueous phosphoric acid acetonitrile. Fractions containing the pure compound are collected, filtered through an anion exchange resin (Biorad, AG4-X4, acetate form) and lyophilized to give the title compound. MS: 1958.0 (M-H) -1.

Ejemplo 55: Niveles de fosforilación de la FAK Example 55: FAK phosphorylation levels

[0199] Los niveles de fosforilación de la FAK en Tyr397 se cuantifican mediante el ELISA sándwich. Se plantan células de carcinoma mamario de ratón 4T1 (1 x 105) en los pocillos de placas de cultivo de 96 pocillos y se incuban durante 1 h con o sin diferentes concentraciones de inhibidores en medio de Eagle modificado por Dulbecco que contiene 0,5% de ASB. El medio se retira y las células se lisan en 200 μl de Tris-HCl 50 mM, pH 7,4, que contiene 1% de NP-40, 0,25% de desoxicolato sódico, NaCl 150 mM, EDTA 1 mM, PMSF 1 mM, Na3VO4 1 mM, NaF 1 mM, 1 μg/ml de aprotinina, 1 μg/ml de leupeptina y 1 μg/ml de pepstatina. Tras la centrifugación, los sobrenadantes se someten a un ELISA sándwich para cuantificar la FAK fosforilada y la FAK total. Los lisados celulares se introducen en placas para ELISA de 96 pocillos de fondo plano recubiertas previamente durante 18 h a 4ºC con 100 μl/pocillo de 4 μg/ml de un anticuerpo monoclonal de ratón contra la FAK (clon 77, Beckton Dickinson Transduction Laboratories) en Tris-HCl 50 mM, pH 9,5, que contiene NaCl 150 mM y se bloquean durante 2 h a temperatura ambiente con 300 μl de BlockAce (Dainippon Pharmaceuticals Co.) diluido 1:4 con H2O. Tras el lavado con TBSN (Tris-HCl 20 mM, pH 8,3, que contiene NaCl 300 mM, 0,1% de SDS y 0,05% de NP-40) se detecta la FAK total con 100 μl de 1 μg/ml de un anticuerpo policlonal contra la FAK (nº 65-6140, Upstate Biology Inc.) y la FAK fosforilada con 100 μl de 0,25 μg/ml de un anticuerpo contra la FAK fosforilada (Y397) (Affinity BioReagents, nº OPA1-03071) en BlockAce diluido 1:10 con H2O. Después de incubarlas durante 1 h a temperatura ambiente las placas se lavan con TBSN y se incuban durante 1 h a temperatura ambiente con 100 μl de un anticuerpo biotinilado contra IgG de conejo (nº 65-6140, Zymed Laboratories Inc.) diluido 1:2.000 con BlockAce diluido 1:10 con H2O. Tras el lavado con TBSN se usa el kit de disolución sustrato ABTS (nº 00-2011, Zymed Laboratories Inc.) para el revelado del color. Después de una incubación de 20 min a temperatura ambiente se mide la absorbancia a 405 nm. Se determina la concentración del compuesto que produce una reducción del 50% en el nivel de fosforilación de la FAK. [0199] FAK phosphorylation levels in Tyr397 are quantified by the sandwich ELISA. 4T1 mouse mammary carcinoma cells (1 x 105) are planted in the wells of 96-well culture plates and incubated for 1 h with or without different concentrations of inhibitors in Dulbecco-modified Eagle medium containing 0.5% of ASB. The medium is removed and the cells are lysed in 200 µl of 50 mM Tris-HCl, pH 7.4, containing 1% NP-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, PMSF 1 mM, 1 mM Na3VO4, 1 mM NaF, 1 μg / ml aprotinin, 1 μg / ml leupeptin and 1 μg / ml pepstatin. After centrifugation, the supernatants are subjected to a sandwich ELISA to quantify phosphorylated FAK and total FAK. Cell lysates are introduced in 96-well flat bottom ELISA plates previously coated for 18 h at 4 ° C with 100 µl / well of 4 µg / ml of a mouse monoclonal antibody against FAK (clone 77, Beckton Dickinson Transduction Laboratories) in 50 mM Tris-HCl, pH 9.5, containing 150 mM NaCl and blocked for 2 h at room temperature with 300 μl of BlockAce (Dainippon Pharmaceuticals Co.) diluted 1: 4 with H2O. After washing with TBSN (20 mM Tris-HCl, pH 8.3, containing 300 mM NaCl, 0.1% SDS and 0.05% NP-40) the total FAK is detected with 100 μl of 1 μg / ml of a polyclonal antibody against FAK (No. 65-6140, Upstate Biology Inc.) and phosphorylated FAK with 100 μl of 0.25 μg / ml of an antibody against phosphorylated FAK (Y397) (Affinity BioReagents, No. OPA1 -03071) in BlockAce diluted 1:10 with H2O. After incubation for 1 h at room temperature the plates are washed with TBSN and incubated for 1 h at room temperature with 100 μl of a biotinylated antibody against rabbit IgG (No. 65-6140, Zymed Laboratories Inc.) diluted 1: 2,000 with BlockAce diluted 1:10 with H2O. After washing with TBSN, the ABTS substrate dissolution kit (No. 00-2011, Zymed Laboratories Inc.) is used for color development. After an incubation of 20 min at room temperature the absorbance at 405 nm is measured. The concentration of the compound that produces a 50% reduction in the level of phosphorylation of FAK is determined.

Ejemplo 56: Ensayo del crecimiento de células tumorales independiente de anclaje Example 56: Anchor independent tumor cell growth assay

[0200] Se plantan células de carcinoma mamario de ratón 4T1 (5 x 103) en placas de 96 pocillos de ultrabaja adhesión (nº 3474, Corning Inc.) en 100 μl de medio de Eagle modificado por Dulbecco que contiene 10% de SBF. Las células se cultivan durante 2 h y los inhibidores se añaden a diferentes concentraciones en una concentración final de DMSO al 0,1%. Transcurridas 48 h se ensaya el crecimiento celular con el kit-8 de recuento celular (Wako Pure Chemical) en el que se usa una sal de tetrazolio hidrosoluble WST8. Se añaden 20 μl del reactivo a cada pocillo y las células se siguen cultivando durante 2 h. Se mide la densidad óptica a 450 nm. Se determina la concentración del compuesto que produce una inhibición del crecimiento del 50%. [0200] 4T1 mouse breast carcinoma cells (5 x 103) are plated in 96-well ultra-low adhesion plates (No. 3474, Corning Inc.) in 100 µl of Dulbecco-modified Eagle's medium containing 10% SBF. The cells are cultured for 2 h and the inhibitors are added at different concentrations in a final concentration of 0.1% DMSO. After 48 hours, cell growth is assayed with the cell count kit-8 (Wako Pure Chemical) in which a water-soluble tetrazolium salt WST8 is used. 20 μl of the reagent is added to each well and the cells are cultured for 2 h. The optical density is measured at 450 nm. The concentration of the compound that produces a 50% growth inhibition is determined.

Ejemplo 57: Ensayo de la migración de linfocitos T in Vitro Example 57: In Vitro T cell migration test

[0201] Las actividades inhibidoras de los inhibidores de la FAK sobre la movilidad de las células inmunológicas se determinan mediante el siguiente estudio in vitro. Es decir, se introducen 1 x 105 células de la línea celular de linfocitos T leucémicos humanos Jurkat en la cámara superior de un Fluoroblok con poros de 8 μm (Beckton Dickinson, RU) y se dejan que migren durante cuatro horas de cultivo a 37ºC bajo 95% de aire y 5% de CO2 dependiendo de un gradiente de concentración de suero bovino fetal (10% de SBF). La movilidad celular se evalúa a partir del número de células que han migrado a la cámara inferior por marcado con calceína-AM (Molecular Probes, Países Bajos) a 8 μg/ml en HBSS durante 1 h. Para la evaluación de los inhibidores de la FAK se añaden a las cámaras superior e inferior diferentes concentraciones de inhibidores de la FAK (0,03 – 1 μM). Los valores de CI50 se calculan a partir de la disminución de la intensidad de fluorescencia en comparación con la del grupo tratado con vehículo, medida con Ascent (ex.: 485 nm, em.: 538 nm). [0201] The inhibitory activities of FAK inhibitors on the mobility of immune cells are determined by the following in vitro study. That is, 1 x 105 Jurkat human leukemic T-cell cells are introduced into the upper chamber of a Fluoroblok with 8 μm pores (Beckton Dickinson, UK) and allowed to migrate for four hours of culture at 37 ° C under 95% air and 5% CO2 depending on a concentration gradient of fetal bovine serum (10% SBF). Cellular mobility is evaluated from the number of cells that have migrated to the lower chamber by labeling with calcein-AM (Molecular Probes, The Netherlands) at 8 μg / ml in HBSS for 1 h. For the evaluation of FAK inhibitors, different concentrations of FAK inhibitors (0.03-1 μM) are added to the upper and lower chambers. IC50 values are calculated from the decrease in fluorescence intensity compared to that of the vehicle treated group, measured with Ascent (ex .: 485 nm, em .: 538 nm).

Ejemplo 58: Ensayo de la actividad frente a la autofosforilación de IGF-IR inducida por IGF-I usando el ensayo celular “ELISA de captura” Example 58: Assay of IGF-I-induced activity against IGF-IR autophosphorylation using the "capture ELISA" cell assay

[0202] El ensayo se realiza de la siguiente manera: Para el ensayo se usan fibroblastos de ratón NIH-3T3 transfectados con ADNc de IGF-IR humano (ADNc de IGF-IR humano completo: nº de acceso a GenBank NM_000875) preparados como se describe en Kato y col., J. Biol. Chem. 268, 2655-61, 1993. Las células que expresan en exceso el IGF-IR humano se cultivan en medio mínimo esencial de Dulbecco (DMEM) que contiene 10% de suero bovino fetal (SBF). Para el ensayo se plantan el día 1 [0202] The assay is performed as follows: For the assay, NIH-3T3 mouse fibroblasts transfected with human IGF-IR cDNA (complete human IGF-IR cDNA: GenBank accession number NM_000875) prepared as prepared are used. described in Kato et al., J. Biol. Chem. 268, 2655-61, 1993. Cells that overexpress human IGF-IR are grown in Dulbecco's essential minimum medium (DMEM) containing 10% bovine serum fetal (SBF). For the trial they are planted on day 1

5.000 células/pocillo en placas de 96 pocillos (Costar nº 3595) en medio de cultivo normal y se incuban durante 2 días a 37ºC en un incubador celular de CO2 convencional. Al tercer día, la densidad de las células no excede del 7080%. El día 3 se desecha el medio y las células se incuban durante 24 h en medio mínimo (DMEM que contiene 0,5% de SBF). Los compuestos de fórmula I se añaden [partiendo de soluciones madre 10 mM en dimetilsulfóxido (DMSO)] de forma que se obtengan concentraciones finales de 0,01, 0,03, 0,1, 0,3, 1, 3 y 10 μM para determinar el valor de CI50. Las células se incuban durante 90 min en presencia de un compuesto de fórmula I. Después, las células se estimulan con 50 μl de IGF-I (concentración final de IGF-I en el pocillo = 10 ng/ml; IGF-I se obtiene de Sigma; código de producto: I 3769) y se incuban durante 10 min a 37ºC. 5,000 cells / well in 96-well plates (Costar No. 3595) in normal culture medium and incubated for 2 days at 37 ° C in a conventional CO2 cell incubator. On the third day, the density of the cells does not exceed 7080%. On day 3 the medium is discarded and the cells are incubated for 24 h in minimal medium (DMEM containing 0.5% SBF). The compounds of formula I are added [starting from 10 mM stock solutions in dimethylsulfoxide (DMSO)] so that final concentrations of 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 µM are obtained to determine the value of IC50. The cells are incubated for 90 min in the presence of a compound of formula I. Then, the cells are stimulated with 50 µl of IGF-I (final concentration of IGF-I in the well = 10 ng / ml; IGF-I is obtained of Sigma; product code: I 3769) and incubate for 10 min at 37 ° C.

[0203] El medio se desecha y las células se lavan dos veces con PBS/O (= disolución salina tamponada con fosfato sin CaCl2) y se lisan durante 15 min en hielo con 50 μl/pocillo de tampón RIPA [Tris-HCl 50 mM, pH=7,2, NaCl 120 mM, EDTA 1 mM, EGTA 6 mM, 1% de NP-40, NaF 20 mM, benzamidina 1 mM, pirofosfato sódico 15 mM, fluoruro de fenilmetilsulfonilo (PMSF) 1 mM y Na3VO4 0,5 mM] y se agitan durante 10 min usando un agitador para placas de 96 pocillos (= extractos celulares). [0203] The medium is discarded and the cells are washed twice with PBS / O (= phosphate buffered saline without CaCl2) and lysed for 15 min on ice with 50 μl / well of RIPA buffer [50 mM Tris-HCl , pH = 7.2, 120 mM NaCl, 1 mM EDTA, 6 mM EGTA, 1% NP-40, 20 mM NaF, 1 mM benzamidine, 15 mM sodium pyrophosphate, 1 mM phenylmethylsulfonyl fluoride (PMSF) and Na3VO4 0 , 5 mM] and stir for 10 min using a 96-well plate shaker (= cell extracts).

[0204] Se recubren durante la noche a 4ºC placas negras HTRF-96 de Packard con 50 μl de un anticuerpo monoclonal (mAB) contra IGF-IR (Santa Cruz; nº de catálogo: SC-462) a una concentración de 5 μg/ml. Las placas se lavan dos veces con 0,05% (v/v) de Tween-20 en disolución salina tamponada con fosfato (PBS) y una vez con H2O nanopura. El bloqueo se realiza durante 2 h a temperatura ambiente (TA) con albúmina de suero bovino (ASB) al 3% en tampón TBS-T (Tris-HCl 20 mM, pH=7,6, NaCl 137 mM, 0,05% de Tween-20). Una vez bloqueadas las placas se lavan una vez con H2O nanopura. [0204] Packard HTRF-96 black plates are coated overnight at 4 ° C with 50 μl of a monoclonal antibody (mAB) against IGF-IR (Santa Cruz; catalog no .: SC-462) at a concentration of 5 μg / ml. The plates are washed twice with 0.05% (v / v) Tween-20 in phosphate buffered saline (PBS) and once with H2O nanopure. Blocking is carried out for 2 h at room temperature (RT) with 3% bovine serum albumin (ASB) in TBS-T buffer (20 mM Tris-HCl, pH = 7.6, 137 mM NaCl, 0.05% Tween-20). Once the plates are blocked, they are washed once with H2O nanopure.

En las placas de Packard recubiertas previamente se pipetean extractos celulares (40 μl/pocillo) junto con 40 μl del mAB de ratón contra fosfotirosina PY-20 conjugado con fosfatasa alcalina (FA) (diluido 1:1.000 en tampón RIPA; el anticuerpo se obtiene de Transduction Labs; nº de catálogo: P11120). Cell extracts (40 μl / well) are pipetted into pre-coated Packard plates together with 40 μl of the mouse mAB against phosphotyrosine PY-20 conjugated to alkaline phosphatase (FA) (diluted 1: 1,000 in RIPA buffer; antibody is obtained of Transduction Labs; catalog no .: P11120).

[0205] Tras incubar los extractos y el anticuerpo secundario durante 2 h a 4ºC se desechan los extractos y las placas se lavan dos veces con 0,05% (v/v) de Tween-20 en PBS y una vez con agua nanopura. A continuación se añaden 90 μl/pocillo de sustrato de la FA (CDP-Star; adquirido en Tropix; nº de catálogo: MS100RY), las placas se incuban durante 45 min a TA en la oscuridad y seguidamente se mide la actividad de la FA en un contador de centelleo para la lectura de microplacas TopCount de Packard. Los valores de CI50 para los compuestos de fórmula I se calculan mediante un análisis de regresión lineal usando el programa GraphPad Instat (GraphPad Software, EE.UU.). Se obtienen valores de CI50 comprendidos en el intervalo de 5 nM a 1 μM, especialmente en el intervalo de 5 nM a 300 nM. [0205] After incubating the extracts and the secondary antibody for 2 h at 4 ° C, the extracts are discarded and the plates are washed twice with 0.05% (v / v) Tween-20 in PBS and once with nanopure water. Next, 90 μl / well of FA substrate (CDP-Star; acquired in Tropix; catalog no .: MS100RY) are added, the plates are incubated for 45 min at RT in the dark and then the activity of the AF is measured in a scintillation counter for reading TopCount microplates from Packard. The IC50 values for the compounds of formula I are calculated by linear regression analysis using the GraphPad Instat program (GraphPad Software, USA). IC50 values are obtained in the range of 5 nM to 1 µM, especially in the range of 5 nM to 300 nM.

[0206] Ejemplo 59: Actividad in vitro en el modelo de xenoinjerto en ratones sin pelo: Se mantienen ratones sin pelo BALB/c hembra o macho (5 a 8 semanas de edad, Charles River Japan Inc., Yokohama, Japón) en condiciones estériles con agua y alimento a voluntad. Se inducen tumores por inyección subcutánea de células tumorales (línea celular epitelial humana MIA PaCa-2; Colección Europea de Cultivos Celulares (ECACC), Salisbury, Wiltshire, RU, número de catálogo 85062806; línea celular de un hombre caucásico de 65 años de edad; línea celular de carcinoma pancreático humano no diferenciado) en el costado izquierdo o derecho de los ratones bajo anestesia con Forene® (Abbott Japan Co., Ltd., Tokio, Japón). El tratamiento con el compuesto de ensayo se inicia cuando los volúmenes tumorales medios alcanzan aproximadamente 100 mm3. El crecimiento tumoral se mide dos veces por semana y 1 día después del último tratamiento determinando la longitud de dos ejes perpendiculares. Los volúmenes tumorales se calculan de acuerdo con procedimientos publicados (véase Evans y col., Brit. J. Cancer 45, 466-8, 1982). La eficacia antitumoral se determina como el incremento medio del volumen tumoral en los animales tratados dividido por el incremento medio del volumen tumoral en los animales no tratados (controles) y, tras multiplicarla por 100, se expresa como delta T/C [%]. La regresión tumoral se define como los cambios medios del volumen tumoral en los animales tratados divididos por el volumen tumoral medio al comienzo del tratamiento y, tras multiplicarla por 100, se expresa como regresión [%]. El compuesto de ensayo se administra diariamente por vía oral con o sin dosificación discontinua. [0206] Example 59: In vitro activity in the xenograft model in hairless mice: Female or male BALB / c hairless mice (5 to 8 weeks old, Charles River Japan Inc., Yokohama, Japan) are maintained under conditions sterile with water and food at will. Tumors are induced by subcutaneous injection of tumor cells (human epithelial cell line MIA PaCa-2; European Cell Culture Collection (ECACC), Salisbury, Wiltshire, UK, catalog number 85062806; cell line of a 65-year-old Caucasian man ; undifferentiated human pancreatic carcinoma cell line) on the left or right side of the mice under anesthesia with Forene® (Abbott Japan Co., Ltd., Tokyo, Japan). Treatment with the test compound begins when the average tumor volumes reach approximately 100 mm 3. Tumor growth is measured twice a week and 1 day after the last treatment by determining the length of two perpendicular axes. Tumor volumes are calculated according to published procedures (see Evans et al., Brit. J. Cancer 45, 466-8, 1982). The antitumor efficacy is determined as the average increase in tumor volume in treated animals divided by the average increase in tumor volume in untreated animals (controls) and, after multiplying by 100, is expressed as delta T / C [%]. Tumor regression is defined as the mean changes in tumor volume in treated animals divided by the mean tumor volume at the beginning of treatment and, after multiplying it by 100, it is expressed as regression [%]. The test compound is administered daily orally with or without discontinuous dosing.

[0207] Como alternativa a la línea celular MIA PaCa-2 también se puede usar del mismo modo otra línea celular, por ejemplo: -la línea celular de carcinoma mamario 4T1 (número ATCC CRL-2539; véase también Cancer 88 (12 supl.), 29792988, 2000) con ratones BALB/c hembra (inyección en el panículo adiposo mamario). [0207] As an alternative to the MIA PaCa-2 cell line, another line can also be used in the same way cell phone, for example: -the 4T1 mammary carcinoma cell line (ATCC number CRL-2539; see also Cancer 88 (12 supl.), 29792988, 2000) with female BALB / c mice (injection into the mammary adipose panicle).

[0208] Según estos estudios, un compuesto de fórmula I de acuerdo con la invención muestra eficacia terapéutica especialmente frente a enfermedades proliferativas que responden a la inhibición de una tirosina cinasa. [0208] According to these studies, a compound of formula I according to the invention shows efficacy therapeutic especially against proliferative diseases that respond to the inhibition of a tyrosine kinase.

Ejemplo 60: Comprimidos Example 60: Tablets

[0209] Se preparan de manera habitual comprimidos que contienen 50 mg del principio activo, por ejemplo de uno de los compuestos de fórmula I descritos en los ejemplos 1 a 131, y que presentan la composición [0209] Tablets containing 50 mg of the active ingredient, for example one of the compounds of formula I described in examples 1 to 131, and having the composition are prepared in a customary manner.

siguiente: next:

Composición: Composition:

[0210] [0210]

Principio activo Almidón de trigo 50 mg 150 mg Active ingredient Wheat starch 50 mg 150 mg

Lactosa Ácido silícico coloidal Lactose Colloidal Silicon Acid

12,5 mg 125 mg 12.5 mg 125 mg

Talco talcum powder

22,5 mg 22.5 mg

Estearato de magnesio 2,5 mg Total: 362,5 mg Magnesium stearate 2.5 mg Total: 362.5 mg

[0211] Preparación: El principio activo se mezcla con una porción del almidón de trigo, la lactosa y el ácido silícico coloidal y la mezcla se fuerza a través de un tamiz. Con otra porción del almidón de trigo se elabora una pasta en un baño de agua con cinco veces la cantidad de agua, y la mezcla de polvos se amasa con la pasta hasta obtener una masa ligeramente plástica. [0211] Preparation: The active substance is mixed with a portion of wheat starch, lactose and colloidal silicic acid and the mixture is forced through a sieve. With another portion of the wheat starch a paste is made in a water bath with five times the amount of water, and the powder mixture is kneaded with the pasta until a slightly plastic dough is obtained.

[0212] La masa plástica se presiona a través de un tamiz con un tamaño de malla de aproximadamente 3 mm y se seca, y los gránulos secos resultantes se vuelven a forzar a través de un tamiz. Después se añaden el resto del almidón de trigo, el talco y el estearato de magnesio y la mezcla se comprime para formar comprimidos con un peso de 145 mg y una muesca de rotura. [0212] The plastic mass is pressed through a screen with a mesh size of approximately 3 mm and dried, and the resulting dried granules are forced back through a sieve. Then the rest of the wheat starch, talc and magnesium stearate are added and the mixture is compressed to form tablets with a weight of 145 mg and a breakage notch.

Ejemplo 61: Cápsulas blandas Example 61: Softgels

[0213] Se preparan de manera habitual 5.000 cápsulas de gelatina blanda que comprenden cada una 50 [0213] 5,000 soft gelatin capsules each comprising 50 are usually prepared

mg del principio activo, por ejemplo de uno de los compuestos de fórmula I descritos en los ejemplos 1 a 131: mg of the active substance, for example one of the compounds of formula I described in examples 1 to 131:

Composición: Composition:

5 [0214] Principio activo 250 mg Lauroglicol ..2 litros 5 [0214] Active substance 250 mg Lauroglycol ..2 liters

[0215] Preparación: El principio activo pulverizado se suspende en Lauroglycol® (laurato de propilenglicol, Gattefossé S.A., Saint Priest, Francia) y se muele en un pulverizador para material húmedo hasta un tamaño de 10 partícula de aproximadamente 1 a 3 μm. Después se reparten porciones de 0,419 g de la mezcla en cápsulas de gelatina blanda usando una máquina llenadora de cápsulas. [0215] Preparation: The powdered active substance is suspended in Lauroglycol® (propylene glycol laurate, Gattefossé S.A., Saint Priest, France) and milled in a spray for wet material up to a particle size of approximately 1 to 3 μm. Then 0.419 g portions of the mixture are distributed in soft gelatin capsules using a capsule filling machine.

Resultados biológicos: Biological results:

[0216] [0216]

Ejemplo Example

CI50 FAK (nM) CI50 Fos (μM) CI50 Crecimiento (μM) CI50 Migración linf. T (μM) CI50 IGF-1R (μM) IC50 FAK (nM) IC50 Fos (μM) IC50 Growth (μM) IC50 Lymph migration. T (μM) IC50 IGF-1R (μM)

1.00 1.00

140 0,7 > 10 140 0.7 > 10

2.00 2.00

13 1,2 13 1.2

3.01 3.01

44 0,34 > 10 44 0.34 > 10

3.02 3.02

36 0,85 4 36 0.85 4

3.03 3.03

9,1 0,14 0,8 9.1 0.14 0.8

3.04 3.04

32 0,53 2 32 0.53 2

3.05 3.05

21 0,17 2 > 10 twenty-one 0.17 2 > 10

3.06 3.06

13 0,11 2 13 0.11 2

3.07 3.07

16 0,45 2 16 0.45 2

3.08 3.08

74 0,3 6 74 0.3 6

3.09 3.09

48 0,5 0,7 48 0.5 0.7

3.10 3.10

52 0,95 > 10 52 0.95 > 10

3.11 3.11

9 0,04 0,3 0,2 9 0.04 0.3 0.2

3.12 3.12

5,4 0,01 1 5.4 0.01 one

3.13 3.13

58 1,7 0,6 0,74 58 1.7 0.6 0.74

3.14 3.14

54 0,4 5 54 0.4 5

3.15 3.15

7 0,02 0,8 0,94 7 0.02 0.8 0.94

3.16 3.16

48 1,1 3 48 1.1 3

3.17 3.17

2,8 0,03 0,2 < 0,08 2.8 0.03 0.2 <0.08

3.18 3.18

130 1,5 9 130 1.5 9

3.19 3.19

6,8 0,35 0,8 0,1 6.8 0.35 0.8 0.1

3.20 3.20

16 0,22 0,3 16 0.22 0.3

3.22 3.22

120 0,9 2 120 0.9 2

3.23 3.23

38 0,39 0,5 38 0.39 0.5

3.24 3.24

64 3,5 5 64 3.5 5

3.25 3.25

22 0,3 0,3 0,81 22 0.3 0.3 0.81

3.26 3.26

50 0,79 2 fifty 0.79 2

3.28 3.28

43 0,71 0,7 43 0.71 0.7

3.29 3.29

89 0,6 > 10 89 0.6 > 10

3.30 3.30

69 0,6 3 69 0.6 3

3.31 3.31

13 1,1 5 13 1.1 5

3.32 3.32

14 0,18 0,49 0,28 0,12 14 0.18 0.49 0.28 0.12

3.33 3.33

2,9 0,03 0,05 0,09 0,13 2.9 0.03 0.05 0.09 0.13

3.34 3.34

7 0,1 0,24 0,13 < 0,08 7 0.1 0.24 0.13 <0.08

3.35 3.35

13 0,02 0,17 0,8 3,55 13 0.02 0.17 0.8 3.55

3.36 3.36

43 1,8 2,8 43 1.8 2.8

3.37 3.37

39 1,1 2,6 39 1.1 2.6

3.38 3.38

64 1,7 3,8 64 1.7 3.8

3.39 3.39

2 0,02 0,03 1 0,09 2 0.02 0.03 one 0.09

3.40 3.40

9 > 10 0,9 9 > 10 0.9

3.41 3.41

22 > 10 0,43 22 > 10 0.43

3.42 3.42

29 0,35 0,3 29 0.35 0.3

3.43 3.43

5,6 0,2 0,11 0,27 5.6 0.2 0.11 0.27

3.44 3.44

11 0,05 0,09 0,09 eleven 0.05 0.09 0.09

3.45 3.45

0,9 0,02 0,02 0.9 0.02 0.02

3.46 3.46

4 0,1 0,18 0,3 4 0.1 0.18 0.3

3.47 3.47

1 0,1 0,06 one 0.1 0.06

3.48 3.48

7 0,07 0,3 0,21 7 0.07 0.3 0.21

3.49 3.49

39 10 0,39 39 10 0.39

3.50 3.50

13 0,12 1 1,19 13 0.12 one 1.19

3.51 3.51

29 0,2 0,4 0,41 29 0.2 0.4 0.41

3.52 3.52

29 0,42 2 29 0.42 2

3.53 3.53

6 0,07 0,21 6 0.07 0.21

3.54 3.54

0,9 0,01 0,07 < 0,08 0.9 0.01 0.07 <0.08

3.55 3.55

34 > 10 3 3. 4 > 10 3

3.56 3.56

28 0,53 0,15 28 0.53 0.15

3.57 3.57

28 0,61 3 28 0.61 3

3.58 3.58

21 0,08 0,3 0,14 twenty-one 0.08 0.3 0.14

3.59 3.59

95 1,2 > 10 95 1.2 > 10

3.60 3.60

90 0,93 2 90 0.93 2

3.61 3.61

12 10 > 10 12 10 > 10

3.62 3.62

63 > 10 > 10 63 > 10 > 10

3.63 3.63

27 > 10 > 10 27 > 10 > 10

3.64 3.64

5 0,13 0,7 0,21 5 0.13 0.7 0.21

3.65 3.65

8 0,08 0,1 0,15 8 0.08 0.1 0.15

3.66 3.66

1 0,08 0,07 0,25 one 0.08 0.07 0.25

3.67 3.67

6 0,38 0,39 6 0.38 0.39

3.68 3.68

5,5 0,2 0,63 1 5.5 0.2 0.63 one

3.69 3.69

4 0,2 0,11 0,58 4 0.2 0.11 0.58

3.70 3.70

3,5 0,02 0,13 3.5 0.02 0.13

3.71 3.71

11 0,05 0,08 eleven 0.05 0.08

3.72 3.72

2,1 0,11 0,06 2.1 0.11 0.06

3.73 3.73

11 0,03 0,29 1,63 eleven 0.03 0.29 1.63

3.74 3.74

15 0,1 0,15 fifteen 0.1 0.15

3.75 3.75

72 0,5 1,3 72 0.5 1.3

3.76 3.76

15 0,29 1,3 0,7 fifteen 0.29 1.3 0.7

3.77 3.77

65 > 10 3 65 > 10 3

3.78 3.78

10 > 10 0,22 10 > 10 0.22

3.79 3.79

5 1,3 0,12 5 1.3 0.12

3.80 3.80

12 0,22 0,45 5 12 0.22 0.45 5

3.81 3.81

21 0,52 0,98 > 10 twenty-one 0.52 0.98 > 10

3.82 3.82

4,8 0,2 0,07 4.8 0.2 0.07

3.83 3.83

20 0,08 0,32 0,68 twenty 0.08 0.32 0.68

3.84 3.84

10 1 0,08 10 one 0.08

6.00 6.00

110 0,35 5 110 0.35 5

7.00 7.00

5,3 0,21 0,47 0,04 0,19 5.3 0.21 0.47 0.04 0.19

7.01 7.01

4,7 0,6 0,54 0,19 4.7 0.6 0.54 0.19

7.02 7.02

7,5 0,1 0,36 0,77 7.5 0.1 0.36 0.77

7.03 7.03

2,9 0,3 0,39 0,27 2.9 0.3 0.39 0.27

7.04 7.04

5,2 1 0,29 5.2 one 0.29

7.05 7.05

6,2 0,3 0,2 0,25 6.2 0.3 0.2 0.25

7.06 7.06

17 0,8 1,09 0,25 17 0.8 1.09 0.25

7.07 7.07

4,1 0,9 0,18 4.1 0.9 0.18

7.08 7.08

8,7 0,8 1 8.7 0.8 one

7.09 7.09

8,2 1 0,85 8.2 one 0.85

7.10 7.10

6,6 1 0,98 6.6 one 0.98

7.11 7.11

2,5 0,6 1,2 0,77 2.5 0.6 1.2 0.77

7.12 7.12

1,9 0,9 1 0,31 0,62 1.9 0.9 one 0.31 0.62

7.13 7.13

5,5 0,8 1,22 5.5 0.8 1.22

7.14 7.14

7,6 0,3 0,36 0,33 7.6 0.3 0.36 0.33

7.15 7.15

4,5 0,06 0,19 0,26 4,5 0.06 0.19 0.26

7.16 7.16

6,4 0,2 0,42 6.4 0.2 0.42

7.17 7.17

4,3 0,7 0,69 4.3 0.7 0.69

7.18 7.18

6,2 0,5 0,7 6.2 0.5 0.7

7.19 7.19

13 0,33 13 0.33

7.20 7.20

2,5 > 10 0,11 2.5 > 10 0.11

7.21 7.21

3,3 > 10 0,46 3.3 > 10 0.46

7.22 7.22

25 0,48 25 0.48

7.23 7.23

1,4 0,25 1.4 0.25

7.24 7.24

5,1 0,09 5.1 0.09

7.25 7.25

13 0,2 0,73 13 0.2 0.73

7.25 7.25

2 > 10 0,57 2 > 10 0.57

7.26 7.26

4,1 0,15 4.1 0.15

7.27 7.27

21 0,5 0,22 twenty-one 0.5 0.22

7.28 7.28

34 1 0,15 3. 4 one 0.15

7.29 7.29

57 2 0,48 57 2 0.48

7.30 7.30

2,1 0,3 1 2.1 0.3 one

8.01 8.01

6,6 0,6 0,33 6.6 0.6 0.33

8.02 8.02

2,4 0,5 0,99 2.4 0.5 0.99

8.03 8.03

13 0,22 1 > 10 13 0.22 one > 10

8.04 8.04

8 > 10 1,1 8 > 10 1.1

9.01 9.01

22 0,36 1 0,6 22 0.36 one 0.6

9.02 9.02

15 0,5 0,81 fifteen 0.5 0.81

9.03 9.03

18 0,1 0,37 18 0.1 0.37

9.04 9.04

13 0,2 0,73 13 0.2 0.73

9.05 9.05

22 0,36 1,6 0,6 22 0.36 1.6 0.6

9.06 9.06

23 3 0,4 0,3 2. 3 3 0.4 0.3

9.07 9.07

17 > 10 0,26 17 > 10 0.26

10.01 10.01

39 1 0,44 39 one 0.44

10.02 10.02

26 0,9 1,06 26 0.9 1.06

10.03 10.03

23 0,9 2,4 2. 3 0.9 2.4

11.01 11.01

9 0,7 0,85 9 0.7 0.85

11.02 11.02

4,1 0,8 0,69 4.1 0.8 0.69

11.03 11.03

26 0,41 0,1 26 0.41 0.1

11.04 11.04

4,3 > 10 3,2 4.3 > 10 3.2

12.01 12.01

2,5 0,09 0,4 0,22 2.5 0.09 0.4 0.22

12.02 12.02

1,6 0,05 1.6 0.05

12.03 12.03

2,3 0,25 2.3 0.25

12.04 12.04

1,1 0,14 1.1 0.14

12.06 12.06

2,6 2.6

13.01 13.01

65 0,81 65 0.81

14.01 14.01

19 0,2 1,47 0,28 19 0.2 1.47 0.28

14.02 14.02

190 2 1,1 1 190 2 1.1 one

14.03 14.03

30 10 1,01 30 10 1.01

14.04 14.04

18 0,54 18 0.54

14.05 14.05

37 > 10 1 37 > 10 one

14.06 14.06

63 10 1,11 63 10 1.11

14.07 14.07

7,5 0,2 1,4 7.5 0.2 1.4

15.01 15.01

15 10 0,47 fifteen 10 0.47

15.02 15.02

21 > 10 0,66 twenty-one > 10 0.66

15.03 15.03

44 2 1,67 44 2 1.67

16.01 16.01

44 > 10 4 44 > 10 4

16.02 16.02

6 > 10 0,6 6 > 10 0.6

16.03 16.03

21 3 > 10 twenty-one 3 > 10

16.04 16.04

9,5 > 10 0,92 9.5 > 10 0.92

16B 16B

11 3 7 eleven 3 7

16C 16C

28 0,9 > 10 28 0.9 > 10

18.01 18.01

19 > 10 1,29 19 > 10 1.29

19.01 19.01

< 1 0,2 0,3 0,29 1,41 <1 0.2 0.3 0.29 1.41

19.02 19.02

1,6 0,13 0,38 0,91 1.6 0.13 0.38 0.91

19.03 19.03

< 1 0,3 0,09 0,64 <1 0.3 0.09 0.64

19.04 19.04

1,6 0,2 0,34 0,14 1.6 0.2 0.34 0.14

19.05 19.05

1,8 0,2 0,67 0,07 0,47 1.8 0.2 0.67 0.07 0.47

19.06 19.06

5 1 0,7 5 one 0.7

19.07 19.07

2,1 0,3 0,11 2.1 0.3 0.11

19.08 19.08

3,2 0,03 0,4 0,29 0,13 3.2 0.03 0.4 0.29 0.13

19.09 19.09

1,3 0,17 0,39 0,3 0,48 1.3 0.17 0.39 0.3 0.48

19.10 19.10

1,3 0,06 0,56 1,02 1.3 0.06 0.56 1.02

19.11 19.11

38 > 10 2 38 > 10 2

19.12 19.12

9 > 10 0,7 0,63 9 > 10 0.7 0.63

19.13 19.13

2,5 0,3 1,1 2.5 0.3 1.1

19.14 19.14

2,6 0,4 1,13 0,44 2.6 0.4 1.13 0.44

19.15 19.15

3,1 0,5 0,36 3.1 0.5 0.36

19.16 19.16

2,3 0,7 1,1 2.3 0.7 1.1

19.17 19.17

1 > 10 0,17 one > 10 0.17

19.18 19.18

7 0,13 0,87 7 0.13 0.87

19.19 19.19

5,7 0,4 5.7 0.4

19.20 19.20

1,6 0,03 0,07 0,23 1.6 0.03 0.07 0.23

19.21 19.21

84 > 10 1,71 84 > 10 1.71

19.22 19.22

3,4 0,12 0,51 3.4 0.12 0.51

19.23 19.23

6,4 0,7 0,71 6.4 0.7 0.71

19.24 19.24

1,8 0,05 0,12 1.8 0.05 0.12

19.25 19.25

7,2 1 0,49 0,24 7.2 one 0.49 0.24

19.26 19.26

6,1 0,1 0,3 6.1 0.1 0.3

19.27 19.27

1,5 0,3 0,4 1.5 0.3 0.4

19.28 19.28

4,8 0,1 0,12 0,3 0,46 4.8 0.1 0.12 0.3 0.46

19.29 19.29

1,9 1.9

19.30 19.30

< 1 0,06 0,1 <1 0.06 0.1

19.31 19.31

1,8 0,4 0,38 1.8 0.4 0.38

19.32 19.32

1,4 0,2 0,31 1.4 0.2 0.31

20.01 20.01

10 0,3 0,18 0,25 0,7 10 0.3 0.18 0.25 0.7

20.02 20.02

9 0,12 0,17 0,75 0,52 9 0.12 0.17 0.75 0.52

20.03 20.03

42 0,4 2,5 2,78 42 0.4 2.5 2.78

20.04 20.04

23 0,58 1,9 2. 3 0.58 1.9

20.05 20.05

6,8 0,87 1,46 6.8 0.87 1.46

20.06 20.06

5 0,36 0,14 49 5 0.36 0.14 49

20.07 20.07

3 0,1 0,05 0,38 3 0.1 0.05 0.38

20.08 20.08

6,8 0,17 0,05 0,29 6.8 0.17 0.05 0.29

20.09 20.09

2 0,3 0,01 2 0.3 0.01

20.10 20.10

2 0,1 0,02 2 0.1 0.02

20.11 20.11

26 2 0,4 26 2 0.4

20.12 20.12

9,5 9.5

20.13 20.13

6,3 0,04 6.3 0.04

20.14 20.14

33 0,32 33 0.32

20.15 20.15

14 0,4 0,97 0,3 14 0.4 0.97 0.3

20.16 20.16

7,5 0,06 7.5 0.06

20.17 20.17

2 0,14 2 0.14

20.18 20.18

15 0,81 fifteen 0.81

20.19 20.19

28 0,21 28 0.21

20.20 20.20

3,12 0,1 3.12 0.1

20.21 20.21

26 3 0,68 26 3 0.68

20.22 20.22

8 > 10 0,19 8 > 10 0.19

20.23 20.23

30 0,49 3 30 0.49 3

20.24 20.24

19 0,48 2 19 0.48 2

20.25 20.25

6,2 0,21 0,06 6.2 0.21 0.06

20.26 20.26

5,3 0,76 0,27 5.3 0.76 0.27

20.27 20.27

12 0,85 0,05 0,29 12 0.85 0.05 0.29

20.28 20.28

9,2 0,17 0,08 0,42 9.2 0.17 0.08 0.42

20.29 20.29

6,1 0,2 0,05 0,31 6.1 0.2 0.05 0.31

20.30 20.30

7,6 0,3 0,08 0,67 7.6 0.3 0.08 0.67

20.31 20.31

39 0,5 39 0.5

20.32 20.32

13 0,11 13 0.11

20.33 20.33

2,5 0,38 2.5 0.38

20.34 20.34

13 1 0,12 13 one 0.12

20.35 20.35

8,7 0,09 0,09 0,15 8.7 0.09 0.09 0.15

21.01 21.01

1 0,07 0,19 0,47 one 0.07 0.19 0.47

21.02 21.02

8,5 0,33 > 10 8.5 0.33 > 10

21.03 21.03

1,7 0,3 0,3 1.7 0.3 0.3

21.04 04.04

1,8 0,05 0,3 1.8 0.05 0.3

22.01 22.01

43 > 10 > 10 43 > 10 > 10

22.02 22.02

26 1 3 26 one 3

22.03 22.03

6,6 0,09 0,15 0,26 6.6 0.09 0.15 0.26

23.01 23.01

3,4 0,6 0,2 0,63 0,53 3.4 0.6 0.2 0.63 0.53

23.02 23.02

1,5 0,2 0,4 0,8 1.5 0.2 0.4 0.8

23.03 23.03

1,7 1 1,12 0,82 1.7 one 1.12 0.82

23.04 23.04

1,2 0,9 1,07 0,6 1.2 0.9 1.07 0.6

23.05 23.05

1,9 > 10 0,59 1.9 > 10 0.59

23.06 23.06

16 1 0,57 16 one 0.57

23.07 23.07

2,1 3 0,84 2.1 3 0.84

23.08 23.08

6,7 0,3 0,49 6.7 0.3 0.49

23.09 23.09

2,1 0,2 0,28 2.1 0.2 0.28

24.01 24.01

3,6 0,11 0,44 0,05 3.6 0.11 0.44 0.05

24.02 24.02

2,1 0,5 0,11 0,39 2.1 0.5 0.11 0.39

24.03 24.03

1 0,3 1,08 one 0.3 1.08

25.01 25.01

8,5 3 1 8.5 3 one

25.02 25.02

3 0,4 0,13 0,64 3 0.4 0.13 0.64

26.01 26.01

4,4 0,05 0,35 0,29 4.4 0.05 0.35 0.29

26.02 26.02

1,9 0,03 0,12 0,09 0,39 1.9 0.03 0.12 0.09 0.39

26.03 26.03

1,4 0,1 0,13 0,23 1.4 0.1 0.13 0.23

26.04 26.04

4,9 0,05 0,43 0,29 1,16 4.9 0.05 0.43 0.29 1.16

26.05 26.05

2,1 0,09 0,23 1,5 2.1 0.09 0.23 1.5

26.06 26.06

4,4 0,1 0,35 4.4 0.1 0.35

26.07 26.07

11 0,5 0,95 eleven 0.5 0.95

26.08 26.08

2,9 0,01 0,18 2.9 0.01 0.18

26.09 26.09

2,3 0,04 0,22 2.3 0.04 0.22

26.10 26.10

2 0,01 0,14 2 0.01 0.14

26.11 26.11

4,4 0,4 0,78 0,5 4.4 0.4 0.78 0.5

26.12 26.12

3,7 0,2 0,19 3.7 0.2 0.19

26.13 26.13

1,6 0,2 0,44 1.6 0.2 0.44

26.14 26.14

5 0,19 5 0.19

26.15 26.15

6,9 1,2 0,08 0,07 6.9 1.2 0.08 0.07

26.16 26.16

9 0,32 2 9 0.32 2

26.17 26.17

17 0,3 0,1 0,26 17 0.3 0.1 0.26

26.18 26.18

1,3 6 1,17 1.3 6 1.17

26.19 26.19

9,2 0,43 0,79 9.2 0.43 0.79

26.20 26.20

10 0,14 0,22 0,6 0,49 10 0.14 0.22 0.6 0.49

26.21 26.21

1,1 0,1 0,49 1.1 0.1 0.49

26.22 26.22

< 1 0,1 0,28 <1 0.1 0.28

26.23 26.23

1,4 0,3 0,09 0,3 0,18 1.4 0.3 0.09 0.3 0.18

26.24 26.24

1 0,5 0,48 0,9 one 0.5 0.48 0.9

26.25 26.25

< 1 0,6 0,73 0,3 <1 0.6 0.73 0.3

26.26 26.26

1,9 0,2 0,07 0,34 1.9 0.2 0.07 0.34

26.27 26.27

4,8 0,6 1,49 4.8 0.6 1.49

26.28 26.28

2,1 0,5 1,52 2.1 0.5 1.52

26.29 26.29

< 1 0,31 0,26 <1 0.31 0.26

26.30 26.30

4,4 1 0,76 4.4 one 0.76

26.31 26.31

2 0,3 0,16 2 0.3 0.16

26.32 26.32

1,6 0,05 0,6 1.6 0.05 0.6

26.33 26.33

4 0,06 0,23 4 0.06 0.23

26.34 26.34

7 0,1 0,25 7 0.1 0.25

26.35 26.35

4,5 0,05 0,3 4,5 0.05 0.3

26.36 26.36

1,9 0,07 0,09 1.9 0.07 0.09

26.37 26.37

< 1 <1

26.38 26.38

< 1 <1

26.39 26.39

3,1 3.1

27.01 27.01

14 0,06 0,47 14 0.06 0.47

27.02 27.02

5,1 0,5 1,1 5.1 0.5 1.1

27.03 27.03

6,3 > 10 0,56 6.3 > 10 0.56

27.04 27.04

11 0,1 0,27 eleven 0.1 0.27

27.05 27.05

8,2 0,04 0,3 8.2 0.04 0.3

27.06 27.06

1 0,08 0,31 one 0.08 0.31

27.07 27.07

5,5 2 0,57 5.5 2 0.57

27.08 27.08

9,3 0,6 0,75 9.3 0.6 0.75

27.09 27.09

4,2 0,5 0,36 4.2 0.5 0.36

28.01 28.01

12 0,3 0,46 0,3 12 0.3 0.46 0.3

28.02 28.02

1,9 0,08 0,44 3,71 1.9 0.08 0.44 3.71

28.03 28.03

7,4 0,07 0,29 7.4 0.07 0.29

28.04 28.04

7,5 0,3 0,3 7.5 0.3 0.3

28.05 28.05

6,7 0,1 0,12 1,39 6.7 0.1 0.12 1.39

28.06 28.06

17 0,6 0,56 17 0.6 0.56

28.07 28.07

47 3 > 10 47 3 > 10

28.08 28.08

4,6 0,4 0,37 4.6 0.4 0.37

28.09 28.09

3,1 0,5 0,36 3.1 0.5 0.36

28.10 28.10

20 3 1,85 twenty 3 1.85

28.11 28.11

4,2 0,5 0,63 4.2 0.5 0.63

28.12 28.12

3,2 0,3 0,43 0,1 3.2 0.3 0.43 0.1

28.13 28.13

7,8 0,1 0,55 0,29 7.8 0.1 0.55 0.29

28.14 28.14

3 0,1 1,44 3 0.1 1.44

28.15 28.15

10 0,5 0,69 10 0.5 0.69

28.16 28.16

11 0,11 1 0,6 eleven 0.11 one 0.6

28.17 28.17

15 0,16 1,9 fifteen 0.16 1.9

28.18 28.18

9,1 > 10 2,03 9.1 > 10 2.03

28.19 28.19

3,7 0,5 0,14 3.7 0.5 0.14

28.20 28.20

4,4 2 0,4 4.4 2 0.4

28.21 28.21

1,3 0,1 0,23 1.3 0.1 0.23

28.22 28.22

1,3 0,1 0,3 1.3 0.1 0.3

28.23 28.23

5,9 0,5 0,28 5.9 0.5 0.28

28.24 28.24

2,9 0,2 0,09 2,57 2.9 0.2 0.09 2.57

28.25 28.25

3,9 0,04 0,13 3.9 0.04 0.13

28.26 28.26

6,6 0,2 0,57 6.6 0.2 0.57

28.27 28.27

2,4 0,3 0,42 0,5 2.4 0.3 0.42 0.5

28.28 28.28

5,2 0,4 0,52 1 5.2 0.4 0.52 one

28.29 28.29

11 0,4 0,36 eleven 0.4 0.36

28.30 28.30

2,3 0,9 0,11 2.3 0.9 0.11

28.31 28.31

7,4 0,06 1,06 7.4 0.06 1.06

29.01 29.01

13 0,7 2,2 0,09 13 0.7 2.2 0.09

29.02 29.02

3,3 0,7 1,1 3.3 0.7 1.1

29.03 29.03

5,6 0,1 0,99 5.6 0.1 0.99

30.01 30.01

22 0,2 0,89 22 0.2 0.89

30.02 30.02

12 0,2 0,47 12 0.2 0.47

30.03 30.03

19 0,5 0,68 19 0.5 0.68

30.04 30.04

25 0,3 0,99 25 0.3 0.99

30.05 30.05

8,5 2 0,29 8.5 2 0.29

30.06 30.06

15 1 1,03 fifteen one 1.03

30.07 30.07

8,8 0,6 0,47 8.8 0.6 0.47

31.01 31.01

30 > 10 1,6 30 > 10 1.6

31.02 31.02

31 0,28 0,29 0,42 31 0.28 0.29 0.42

32.01 32.01

4,1 0,1 0,29 4.1 0.1 0.29

32.02 32.02

5,9 0,05 0,37 0,12 5.9 0.05 0.37 0.12

33.01 33.01

2,5 0,08 0,25 2.5 0.08 0.25

33.02 33.02

5,2 0,06 0,25 0,1 5.2 0.06 0.25 0.1

34.01 34.01

8 0,1 0,37 0,28 8 0.1 0.37 0.28

34.02 34.02

11 0,08 1,17 eleven 0.08 1.17

34.03 34.03

33 0,19 2,25 33 0.19 2.25

34.04 34.04

13 > 10 1,22 13 > 10 1.22

34.05 34.05

51 0,36 5,1 51 0.36 5.1

34.06 34.06

14 > 10 3 14 > 10 3

34.07 34.07

27 > 10 2,7 27 > 10 2.7

34.08 34.08

8,7 > 10 1,9 8.7 > 10 1.9

35.01 35.01

6,8 > 10 1,43 6.8 > 10 1.43

35.02 35.02

6,1 0,7 0,23 6.1 0.7 0.23

51.00 51.00

8,1 0,013 0,19 0,2 8.1 0.013 0.19 0.2

52.00 52.00

13 0,2 0,41 < 0,08 13 0.2 0.41 <0.08

Claims (6)

REIVINDICACIONES 1. Compuesto de fórmula I 1. Compound of formula I imagen1image 1 5 en la que R0 o R2 son en cada caso independientemente hidrógeno, piperazino, N-metilpiperazino o 1-metil-4-piperidiloxi; R1 es hidrógeno, piperazino, N-metilpiperazino, morfolino, 1-metil-4-piperidiniloxi, 3-morfolinopropoxi o 2morfolinoetoxi; R3 es sulfamoílo, metilsulfamoílo o propilsulfamoílo; o 5 in which R0 or R2 are independently hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy in each case; R1 is hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2morpholinoethoxy; R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; or 10 la pareja de sustituyentes adyacentes R0 y R1 o R1 y R2 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R2 y R3 es -CH2-NH-CO-o -CH2-NH-SO2-; R4 es hidrógeno; R5 es hidrógeno, cloro, bromo, trifluorometilo o nitro; R6 es hidrógeno; 10 the pair of adjacent substituents R0 and R1 or R1 and R2 is -O-CH2-O-, or the pair of adjacent substituents R2 and R3 is -CH2-NH-CO-or -CH2-NH-SO2-; R4 is hydrogen; R5 is hydrogen, chlorine, bromine, trifluoromethyl or nitro; R6 is hydrogen; 15 R7 y R9 son en cada caso independientemente hidrógeno, metilo, isopropilo, trifluorometilo, fenilo, o-, m-o pmetoxifenilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, isopropoxi, fenoxi, 3morfolinopropoxi, 2-morfolinoetoxi, 2-(1-imidazolil)etoxi, dimetilamino, fluoro, morfolinocarbonilo, piperidinocarbonilo, piperazinocarbonilo o ciclohexilcarbamoílo; R8 es hidrógeno, metilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, trifluoro-metoxi, fenoxi, 1In each case, R7 and R9 are independently hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, mo pmethoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3morpholinopropoxy, 2-morpholinoe - (1-imidazolyl) ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoro-methoxy, phenoxy, 1 20 metil-4-piperidiloxi, 3-morfolino-propoxi, 2-morfolinoetoxi, 3-(N-metilpiperazino)-propoxi, metilamino, fluoro, cloro, sulfamoílo o nitro; y R10 es metilo, butilo, metoxi, etoxi, 2-(1-imidazolil)-etoxi, metilamino, dimetilamino o fluoro; o la pareja de sustituyentes adyacentes R7 y R8 o R8 y R9 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R9 y R10 es -NH-CH=CH-, CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-o -O-CF2-O-; y 20-methyl-4-piperidyloxy, 3-morpholino-propoxy, 2-morpholinoethoxy, 3- (N-methylpiperazino) -propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; and R 10 is methyl, butyl, methoxy, ethoxy, 2- (1-imidazolyl) -ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O-, or the pair of adjacent substituents R9 and R10 is -NH-CH = CH-, CH = N-NH-, -CH2- CH2-CH2-, -CH2-CH2-CH2-CH2-or -O-CF2-O-; Y 25 A es C. 25 A is C. 2. Compuesto de fórmula I de acuerdo con la reivindicación 1, en el que R0, R1 o R2 son respectivamente hidrógeno; R3 es sulfamoílo, metilsulfamoílo o propilsulfamoílo; 2. Compound of formula I according to claim 1, wherein R0, R1 or R2 are respectively hydrogen; R3 is sulfamoyl, methylsulfamoyl or propylsulfamoyl; 30 R4 es hidrógeno; R5 es cloro o bromo; R6 es hidrógeno; R7 y R9 son en cada caso independientemente hidrógeno, metilo, isopropilo, trifluorometilo, fenilo, o-, m-o pmetoxifenilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, isopropoxi, fenoxi, 3R4 is hydrogen; R5 is chlorine or bromine; R6 is hydrogen; R7 and R9 are independently hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or pmethoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3 35 morfolinopropoxi, 2-morfolinoetoxi, 2-(1-imidazolil)etoxi, dimetilamino, fluoro, morfolinocarbonilo, piperidino-carbonilo, piperazinocarbonilo o ciclohexilcarbamoílo; R8 es hidrógeno, metilo, piperidino, piperazino, N-metilpiperazino, morfolino, metoxi, etoxi, trifluoro-metoxi, fenoxi, 1metil-4-piperidiloxi, 3-morfolino-propoxi, 2-morfolinoetoxi, 3-(N-metilpiperazino)-propoxi, metilamino, fluoro, cloro, sulfamoílo o nitro; y Morpholinopropoxy, 2-morpholinoethoxy, 2- (1-imidazolyl) ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; R8 is hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoro-methoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholino-propoxy, 2-morpholinoethoxy, 3- (N-methylpiperazino) - propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro; Y 40 R10 es metilo, butilo, metoxi, etoxi, 2-(1-imidazolil)-etoxi, metilamino, dimetilamino o fluoro; o la pareja de sustituyentes adyacentes R7 y R8 o R8 y R9 es -O-CH2-O-, o la pareja de sustituyentes adyacentes R9 y R10 es -NH-CH=CH-, CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-o -O-CF2-O-; y A es C. R10 is methyl, butyl, methoxy, ethoxy, 2- (1-imidazolyl) -ethoxy, methylamino, dimethylamino or fluoro; or the pair of adjacent substituents R7 and R8 or R8 and R9 is -O-CH2-O-, or the pair of adjacent substituents R9 and R10 is -NH-CH = CH-, CH = N-NH-, -CH2- CH2-CH2-, -CH2-CH2-CH2-CH2-or -O-CF2-O-; and A is C.

45 3. El compuesto de fórmula I de acuerdo con la reivindicación 1, en el que R0, R1 o R2 son respectivamente hidrógeno, R3 es metilsulfamoílo, R4 es hidrógeno, R5 es bromo, R6 es hidrógeno, R7 y R8 son respectivamente metoxi, R9 es hidrógeno y R10 es metilo y A es C. 3. The compound of formula I according to claim 1, wherein R0, R1 or R2 are respectively hydrogen, R3 is methylsulfamoyl, R4 is hydrogen, R5 is bromine, R6 is hydrogen, R7 and R8 are respectively methoxy, R9 is hydrogen and R10 is methyl and A is C.

4. El compuesto de fórmula I de acuerdo con la reivindicación 1, en el que R10, R1 o R2 son respectivamente hidrógeno, R3 es metilsulfamoílo, R4 es hidrógeno, R5 es bromo, R6 es hidrógeno, R7 y R8 son respectivamente hidrógeno y la pareja de sustituyentes adyacentes R9 y R10 es –CH2-CH2-CH2-y A es C. 4. The compound of formula I according to claim 1, wherein R10, R1 or R2 are respectively hydrogen, R3 is methylsulfamoyl, R4 is hydrogen, R5 is bromine, R6 is hydrogen, R7 and R8 are respectively hydrogen and pair of adjacent substituents R9 and R10 is –CH2-CH2-CH2- and A is C.

5 5. Un compuesto seleccionado del grupo de compuestos formado por los que presentan los nombres o fórmulas siguientes: 2-[2-(2,5-dimetoxi-fenilamino)-5-nitro-pirimidin-4-il-amino]-N-metil-bencenosulfonamida; 2-[5-bromo-2-(2,4-dimetoxi-fenilamino)-pirimidin-4-il-amino]-N-metil-bencenosulfonamida; un compuesto de fórmula 5. A compound selected from the group of compounds formed by those having the following names or formulas: 2- [2- (2,5-dimethoxy-phenylamino) -5-nitro-pyrimidin-4-yl-amino] -N -methylbenzenesulfonamide; 2- [5-Bromo-2- (2,4-dimethoxy-phenylamino) -pyrimidin-4-yl-amino] -N-methyl-benzenesulfonamide; a compound of formula

10 10 imagen1image 1 en la que Rx posee uno de los significados indicados en la tabla siguiente: in which Rx has one of the meanings indicated in the following table: imagen1image 1 (continuación) (continuación) (continuación) (continuación) (continued) (continued) (continued) (continued) imagen1image 1 imagen1image 1 imagen1image 1 imagen1image 1 y 2-[5-bromo-2-(2,3-[difluorometilendioxi]fenilamino)-pirimidin-4-ilamino]-bencenosulfonamida; o una sal del mismo. and 2- [5-Bromo-2- (2,3- [difluoromethylenedioxy] phenylamino) -pyrimidin-4-ylamino] -benzenesulfonamide; or a salt thereof. 6. Composición farmacéutica que comprende un compuesto de acuerdo con una cualquiera de las 6. Pharmaceutical composition comprising a compound according to any one of the reivindicaciones 1 a 6 como ingrediente activo junto con uno o más diluyentes o vehículos farmacéuticamente 5 aceptables. claims 1 to 6 as active ingredient together with one or more pharmaceutically acceptable diluents or carriers. 7. Uso de un compuesto de acuerdo con una cualquiera de las reivindicaciones 1 a 5 para la preparación de un medicamento para el tratamiento o la prevención de enfermedades neoplásicas y trastornos del sistema inmune. 7. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of neoplastic diseases and immune system disorders. 10 10 8. Combinación que comprende una cantidad terapéuticamente eficaz de un compuesto de acuerdo con una cualquiera de las reivindicaciones 1 a 5 y una o más sustancias farmacéuticas adicionales, siendo dicha sustancia farmacéutica adicional útil en el tratamiento de enfermedades neoplásicas o de trastornos del sistema inmune. 8. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5 and one or more additional pharmaceutical substances, said additional pharmaceutical substance being useful in the treatment of neoplastic diseases or immune system disorders.