WO2005016894A1

WO2005016894A1 - 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders

Info

Publication number: WO2005016894A1
Application number: PCT/EP2004/009099
Authority: WO
Inventors: Carlos Garcia-Echeverria; Takanori Kanazawa; Eiji Kawahara; Keiichi Masuya; Naoko Matsuura; Takahiro Miyake; Osamu Ohmori; Ichiro Umemura; Ruo Steensma; Greg Chopiuk; Jiqing Jiang; Yongqin Wan; Qiang Ding; Qiong Zhang; Nathanael Schiander Gray; Donald Karanewsky
Original assignee: Novartis Ag; Novartis Pharma Gmbh; Irm Llc
Priority date: 2003-08-15
Filing date: 2004-08-13
Publication date: 2005-02-24
Also published as: PL2287156T3; MA27994A1; TWI378923B; CY1117015T1; PT1660458E; MXPA06001759A; EP1660458A1; CY1112571T1; DK2287156T3; TW200526598A; JP4607879B2; US7893074B2; TNSN06052A1; AU2008229685A1; IS8349A; JP2010241830A; KR20060039938A; SI2287156T1; ZA200600464B; CO5680434A2

Abstract

Novel pyrimidine derivatives of formula (I) Wherein R is selected from C16-10 aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl; R0-R6 as described herein; and their use for the manufacture of a medicament for the treatment or prevention of a disease wich responds to inhibition of FAK and/or ALK and/or ZAP-70 and/or IGF-IR.

Description

- 2 -

each of R⁵ and R⁶ independently is hydrogen, C C₈alkyl, d-Csalkoxyd-Csalkyl, haloC C₈alkyl, CrCβalkoxy, halogen, carboxy, Cι-C₈alkoxycarbonyl, unsubstitued or substituted carbamoyl, cyano, or nitro;

R is unsubstituted or substituted by R₇, R₈, R₉, R₁₀, and R'₁₀;

R₇, Rs, R₉, Rio, or R'₁₀ is a substituent independently selected from hydrogen, Cι-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkinyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylCι-C₈alkyl, Cs-doarylC Cβalkyl, hydroxyd-C₈alkyl, CrC₈alkoxyC C₈alkyl, aminod-Csalkyl, haloCrC₈alkyl, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 , 2 or 3 hetero atoms selected from N, O and S, hydroxy, d-C-βalkoxy, hydroxyCτC₈alkoxy, d-Cβalkoxyd-C-salkoxy, halod-C₈alkoxy, unsubstituted or substituted aminoCι-C₈alkoxy, unsubstituted or substituted Cs-doaryld-Csalkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC C₈alkyl, unsubstituted or substituted heterocyclyld-C₈alkoxy, unsubstitued or substituted amino, d- C₈alkylthio, Cι-C₈alkylsulfinyl, d-Csalkylsulfonyl, C₅-C₁₀arylsulfonyl, heterocyclosulfonyl, halogen, carboxy, d-C₈alkylcarbonyl, CrC₈alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano, nitro, -S(O)o-₂NR₁₂Ri3, -S(O)₀-₂Ri₂. -C(0)R_{11 f} -OXRn, -NR₁₂XRιι, -NR₁₂XNR₁₂R₁₃, -OXNR₁₂Rι , -OXOR₁₂ and -XR^; or two adjacent substituents on R may form together with the carbon atoms to which they are attached, a unsubstitued or substituted 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1 , 2 or 3 heteroatoms selected from N, O and S;

X is a bond or d-₆alkylene; and

Rn is independently selected from C₆-ιoaryl, C₅-ι₀heteroaryl, C₃-ι₂cycloalkyl and C₃- _loheterocycloalkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R is optionally substituted by 1 to 3 radicals independently selected from Cι-₆alkyl, C₃-ιoheterocycloalkyl-C₀-₄alkyl optionally substituted with d-ealkyl, - C(0)R₁₂, -C(O)NR₁₂Rι₃. -XNR₁₂Ri3, -NR₁₂XNR₁₂R₁₃ and - NR_t2C(O)R₁₃; wherein X is a bond or C^alkylene; R₁₂ and R₁₃ are independently selected from hydrogen and C^alkyl; and salts thereof in the treatment of of a disease associated to tyrosine kinase activity of anaplastic lymphoma kinase (ALK) or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, as well as use in the treatment of said diseases, to methods of use of such pyrimidine derivatives in the treatment of said diseases, and to pharmaceutical compositions comprising such pyrimidine derivatives for the treatment of said diseases. The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.

The invention relates also to possible tautomers of the compounds of formula I.

C C₈alkyl denotes a an alkyl radical having from 1 up to 8, especially up to 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching; preferably, d-C₈alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl; especially methyl, propyl or tert-butyl.

C₂-C₈alkenyl denotes a an alkenyl radical having from 2 up to 8, especially up to 5 carbon atoms, the radicals in question being either linear or branched with single or multiple branching; preferably, C₂-C₈alkenyl is pentenyl, such as 3-methyl-2-buten-2-yl, butenyl, such as 1- or 2- butenyl or 2-buten-2-yl, propenyl, such as 1-propenyl or allyl, or vinyl.

C₂-C₈alkinyl denotes a an alkinyl radical having from 2 up to 8, especially up to 5 carbon atoms, the radicals in question being either linear or branched; preferably, C₂-C₈alkinyl is propinyl, such as 1 -propinyl or propargyl, or acetylenyl.

C₃-C₈cycloalkyl denotes a cycloalkyl radical having from 3 up to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.

C C₈alkoxy is especially methoxy, ethoxy, isopropyloxy, or tert-butoxy. Hydroxyd-C₈alkyl is especially hydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.

HydroxyC C₈alkoxy is especially 2-hydroxyethoxy or 3-hydroxypropoxy.

d-C₈alkoxyd-C₈alkoxy is especially 2-methoxyethoxy.

CrC₈alkoxyCrC₈alkyl is especially methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.

Halogen is preferably fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.

Halod-C₈alkyl is preferably chloroCι-C₈alkyl or fluorod-Csalkyl, especially trifluoromethyl or pentafluoroethyl.

Halod-C₈alkoxy is preferably chloroC C₈alkoxy or fluoroC C₈alkoxy, especially trifluoromethoxy.

C C₈alkoxycarbonyl is especially tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxy carbonyl.

Unsubstitued or substituted carbamoyl is carbamoyl substituted by one or two substituents selected from hydrogen, d-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkinyl, C₃-C₈cycloalkyl, C₃- C₈cycloalkylCι-C₈alkyl, C₅-C₁₀arylCι-C₈alkyl, hydroxyd-C₈alkyl, Cι-C₈alkoxyd-C₈alkyl, halod- C₈alkyl, unsubstitued or substituted C₅-C ₀aryl, or aminod-C-salkyl, or carbamoyl wherein the substituents and the nitrogen atom of the carbamoyl group represent a 5 or 6 membered heterocyclyl further comprising 0, 1 or 2 hetero atoms selected from N, O and S; and is preferably carbamoyl, methylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl, hydroxyethyl- methyl-carbamoyl, di(hydroxyethyl)carbamoyI, dimethylaminoethylcarbamoyl, or pyrrolidinocarbonyl, piperidinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, especially carbamoyl or dimethylcarbamoyl.

Unsubstitued or substituted sulfamoyl is sulfamoyl substituted by one or two substituents selected from hydrogen, Cι-C₈alkyl. C₂-C₈alkenyl, C₂-C₈alkinyl, C₃-C₈cycloalkyl, C₃- CscycloalkylCrCsalkyl, drdoaryld-Csalkyl, hydroxyCι-C₈alkyl, CrCsalkoxyd-Cβalkyl, halod- - 5 -

C₈alkyl, unsubstitued or substituted C₅-C₁₀aryl, or aminoCι-C₈alkyl, or sulfamoyl wherein the substituents and the nitrogen atom of the sulfamoyl group represent a 5 or 6 membered heterocyclyl further comprising 0, 1 or 2 hetero atoms selected from N, O and S; and is preferably sulfamoyl, methyls ulfamoyl, propylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2- trifluoroethylsulfamoyl, dimethylaminoethylsulfamoyl, dimethylsulfamoyl, hydroxyethyl-methyl- sulfamoyl, di(hydroxyethyl)sulfamoyl, or pyrrolidinosulfonyl, piperidinosulfonyl, N- methylpiperazinosulfonyl or morpholinosulfonyl, especially sulfamoyl or methylsulfamoyl.

Unsubstitued or substituted amino is amino substituted by one or two substituents selected from hydrogen, d-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkinyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylCι-C₈alkyl, C₅- doaryld-Csalkyl, hydroxyd-C₈alkyl, CrC₈alkoxyd-C₈alkyl, halod-C₈alkyl, unsubstitued or substituted C₅-C₁₀aryl, aminoC C₈alkyl, acyl, e.g. formyl, CrC₈alkylcarbonyl, C₅- C₁₀arylcarbonyl, d-C₈alkyisulfonyl or C₅-C ₀arylsulfonyl, and is preferably amino, methylamino, dimethylamino, propylamino, benzylamino, hydroxyethyl-methyl-amino, di(hydroxyethyl)amino, dimethylaminoethylamino, acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, especially amino or dimethylamino.

Aminod-Csalkyl is especially aminoethyl, methylaminoethyl, dimethylaminoethyl or dimethylaminopropyl.

Unsubstitued or substituted C₅-Cι₀aryl is, for example, phenyl, indenyl, indanyl, naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, optionally substituted by d-C₈alkyl, d-Csalkoxyd-Csalkyl, haloCι-C₈alkyl, hydroxy, d-C₈a!koxy, methylenedioxy, amino, substituted amino, halogen, carboxy, d-C₈alkoxycarbonyl, carbamoyl, sulfamoyl, cyano or nitro; preferably phenyl, toiyl, trifluoromethylphenyl, methoxyphenyl, dimethoxyphenyl, methyienedioxyphenyl, chlorophenyl or bromophenyl, whereby the substituents may be in ortho, meta or para position, preferably meta or para.

C₅-C₁₀aryloxy is especially phenoxy or methoxyphenoxy, e.g. p-methoxyphenoxy.

C₅-Cι₀arylCι-C₈alkyl is especially benzyl or 2-phenylethyl.

C₅-C₁₀arylCι-C-₈alkoxy is especially benzyloxy or 2-phenylethoxy. - 6 -

Unsubstitued or substituted 5 or 6 membered heterocyclyl comprising 1 , 2 or 3 hetero atoms selected from N, O and S may be unsaturated, partially unsaturated or saturated, and further condensed to a benzo group or a 5 or 6 membered heterocyclyl group, and may be bound through a hetero 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. Substituents considered are d-C₈alkyl, hydroxyC C₈alkyl, d-Cβalkoxyd-Csalkyl, C C₈alkoxyCι-C₈alkoxy, haloCrC₈alkyl, hydroxy, amino, substituted amino, d-C₈alkoxy, halogen, carboxy, d-C₈alkylcarbonyl, Cι-C₈alkoxycarbonyl, carbamoyl, CrC₈alkylcarbamoyl, cyano, oxo, or unsubstitued or substituted 5 or 6 membered heterocyclyl as defined in this paragraph. 5 or 6 membered heterocyclyl preferably comprises 1 or 2 hetero atoms selected from N, O and S, and is especially indolyl, pyrrolidinyl, pyrrolidonyl, imidazolyl, N-methylimidazolyl, benzimidazolyl, S,S-dioxoisothiazolidinyl, piperidyl, 4-acetylaminopiperidyl, 4-methylcarbamoylpiperidyl, 4- piperidinopiperidyl, 4-cyanopiperidyl, piperazinyl, N-methylpiperazinyl, N-(2- hydroxyethyl)piperazinyl, morpholinyl, 1-aza-2,2-dioxo-2-thiacyclohexyl, or sulfolanyl.

In unsubstituted or substituted heterocyclyloxy, heterocyclyl has the meaning as defined above, and is especially N-methyl-4-piperidyloxy. In unsubstituted or substituted heterocyclyld- C₈alkoxy, heterocyclyl has the meaning as defined above, and is especially 2-pyrrolidinoethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 1-methyl-piperidin-3-ylmethoxy, 3-(N- methylpiperazino)propoxy or 2-(1-imidazolyl)ethoxy.

In a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1 , 2 or 3 heteroatoms selected from N, O and S, and formed by two adjacent substituents together with the benzene ring, the ring may be further substituted, e.g. by d-C₈alkyl, d-C₈alkoxy, halod-C₈alkyl, hydroxy, amino, substituted amino, Cι-C₈alkoxy, halogen, carboxy, Cι-C₈alkoxycarbonyl, carbamoyl, cyano, or oxo. The two adjacent substituents forming such a ring are preferably propylene, butylene, 1-aza-2-propylidene, 3-aza-1-propylidene, 1 ,2-diaza-2-propylidene, 2,3- diaza-1-propylidene, 1-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoromethylene- dioxy, 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 forming a 6 membered ring.

Salts are especially the pharmaceutically acceptable salts of compounds of formula I. - 7 -

Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic 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, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4- aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic 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.

For isolation or purification purposes 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 employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.

In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.

The compounds of formula I have valuable pharmacological properties, as described hereinbefore and hereinafter.

In formula I the following significances are preferred independently, collectively or in any combination or sub-combination. R is C₆-ιoaryl, C₅-ι₀heteroaryl, C₃-₁₂cycloalkyl or C₃- _loheterocycloalkyl, preferably R is

wherein R₇, R₈, R₉, R₁₀, or R'₁₀ are as defined above;

In each of the following significances A, D or E is C or N but A, D and E may not all be N, preferably A, D or E is C:

(a) each of R°or R² independently is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or isopropyl, hydroxyd-C₈aIkyl, e.g. hydroxyethyl or hydroxybutyl, haloC C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloCι-C₈alkoxy, e.g. trifluoromethoxy, C₅-C₁₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3- morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, C C₈alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, piperazino, N-methylpiperazino or l-methyl-4-piperidyloxy, -S(O)₀-₂NR₁₂Ri3. -S(O)₀-₂Ri3. -NR₁₂S(O)o-₂Ri3. -C(0)NR₁₂Rι₃, and -C(0)ORι₃ in particular hydrogen;

(b) R¹ is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or isopropyl, hydroxyC C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, halod-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC C₈alkoxy, e.g. trifluoromethoxy, C₅-Cι₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, d-C₈alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, - 9 -

unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3- morpholinopropoxy or 2-morpholinoethoxy, in particular hydrogen;

(c) R³ is hydrogen, d-C₈alkyl, e.g. methyl or ethyl, hydroxyd-C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, halod-C₈alkyI, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, C C₈alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, C C₈alkylsulfonyl, e.g. methylsulfonyl, propyl-sulfonyl, cyclohexyl-sulfonyl, isopropyl-sulfonyl, C₅- C₁₀arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl, ethyl-amino-carbonyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2- trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl dimethyl-sulfamoyl, ethyl- sulfamoyl, 1-ethyl-propyl-suIfamoyl, cyclopentyl-sulfamoyl, cyclobutyl-sulfamoyl; preferably sulfamoyl, methylsulfamoyl or propylsulfamoyl;

(d) each pair of adjacent substituents R° and R¹, or R¹ and R², or R² and R³ are -CH₂-NH-CO-, -

CH₂-CH₂-NH-CO-, -CH₂-CO-NH-, -CH₂-CH₂-CO-NH-, -CH₂-NH-S0₂-, -CH₂-CH₂-NH-S0₂-, - CH₂-S0₂-NH-, -CH₂-CH₂-S0₂-NH-, -CH₂-CH₂-SO₂-, -CH₂-CH₂-CH₂-S0₂-, -0-CH₂-O-, or -O- CF₂-O-, and such pairs wherein hydrogen in NH is replaced by C C₈alkyl; preferably the pair of adjacent substituents R° and R¹, or R¹ and R² being -O-CH₂-O-, and the pair of adjacent substituents R² and R³ being -CH₂-NH-CO- or -CH₂-NH-S0₂-.

(e) R⁴ is hydrogen or C_rC₈alkyl, e.g. methyl; preferably hydrogen;

(f) R⁵ is hydrogen; d-C₈alkyl, e.g. methyl or ethyl, halogen, e.g. chloro or bromo, halod-

C₈alkyl, e.g. trifluoromethyl, cyano or nitro; preferably hydrogen, methyl, ethyl, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo;

(g) R⁶ is hydrogen;

(h) each of R⁷ and R⁹ independently is hydrogen, C C₈alkyl, e.g. methyl, ethyl or isopropyl, hydroxyd-C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, Cι-C₈alkylcarbonyl, e.g methyl carbonyl, aminoalkoxy, e.g diethylaminoethoxy, halod-C₈alkyl, e.g. trifluoromethyl, - 10 -

unsubstituted or substituted C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, halod-C₈alkoxy, e.g. trifluoromethoxy, C₅-C₁₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3- morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, d-C₈alkylsuϊfonyl, e.g. methylsulfonyl, heterocyclosulfonyl, e.g piperazinylsulfonyl, heterocyclocarbonyl, e.g. methylpirerazinylcarbonyl, cyano, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, methoxyphenyl, piperidino, piperazino, N- methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morphoiinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; 8 is hydrogen, d-C₈aikyl, e.g. methyl, ethyl or isopropyl, hydroxyd-dalkyl, e.g. hydroxyethyl or hydroxybutyl, haloC C₈alkyl, e.g. trifluoromethyl, C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N- methylpiperazino, heterocyclylalkyl, e.g. methylpiperazinoethyl, heterocyclylcarbonyl, e.g. piperazinocarbonyl, heterocyclyl d-C₈alkylamino, e.g. pyridylethyl(methyl)amino, d- C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC C₈alkoxy, e.g. trifluoromethoxy, C₅- doaryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4- piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1- imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, d-Csalkylamino-d-Csalkylamino, e.g. dimethylamino-propylamino, Cι-C₈alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, cyano, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N- methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4- - 11 -

piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;

(j) R¹⁰ is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or butyl, hydroxy, cyano, hydroxyC C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, halod-C₈alkyl, e.g. trifluoromethyl, d-C₈alkoxy, e.g. methoxy or ethoxy, cycloalkylalkoxy, aryloxy, halod-C₈alkoxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro; carboxy, carbamoyl, or unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; and

(k) each pair of adjacent substituents R⁷ and R⁸, or R⁸ and R⁹ or R⁹ and R¹⁰, are -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH₂- 0-, -CH₂C(CH₃)₂O-, -CH=C(CH₃)O-, -OCH₂CH₂O-, -(Morpholinopropyl)N-CH=CH-, - CH=CH-0-, -O-CH₂-O-, or -O-CF₂-0-; preferably the pair of adjacent substituents R⁷ and R⁸ or R⁸ and R⁹ being -O-CH₂-0- or the pair of adjacent substituents R⁹ and R¹⁰ being -NH- CH=CH-, -CH=N-NH-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂- or -O-CF₂-O-.

(I) or R⁷, R⁸, R⁹, R¹⁰ and R'¹⁰are ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl- amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, -XRn, -C(0)Rn and -OXR^; wherein X is a bond, methylene or ethylene; R-π is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1 ,4-dioxa-8-aza- spiro[4.5]dec-8-yl; wherein Rn is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl- propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2- oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.

More preferred are the following meanings, independently, collectively or in any combination or sub-combination:

(a') each of R°or R² independently is hydrogen, C C₈alkyl, e.g. methyl, ethyl or isopropyl, halod-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or - 12 -

isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC C₈alkoxy, e.g. 2-(1-imidazoIyl)ethoxy, 3- morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro; preferably hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyioxy, in particular hydrogen;

(b') R¹ is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or isopropyl, halod-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N- methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro; preferably hydrogen, piperazino, N- methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2- morpholinoethoxy, in particular hydrogen;

(c') R³ is hydrogen, d-C₈alkyl, e.g. methyl or ethyl, halod-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, d-C₈alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, C C₈alkylsulfonyl, e.g. methylsulfonyl, C₅- C ₀arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2- trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl; preferably sulfamoyl, methylsulfamoyl or propylsulfamoyl;

(d') each pair of adjacent substituents R° and R¹, or R¹ and R², or R² and R³ are -CH₂-NH-CO-, - CH₂-NH-S0₂-, -CH₂-CH₂-S0₂-, -0-CH₂-0-, or -0-CF₂-0-, and such pairs wherein hydrogen in NH is replaced by d-C₈alkyl; preferably the pair of adjacent substituents R° and R¹, or R¹ and R² being -O-CH₂-O-, and the pair of adjacent substituents R² and R³ being -CH₂-NH- CO- or -CH₂-NH-S0₂-.

(e') R⁴ is hydrogen; - 13 -

(f) R⁵ is hydrogen, halogen, e.g. chloro or bromo, haloCι-C₈alkyl, e.g. trifluoromethyl, or nitro; preferably hydrogen, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo;

(g¹) R⁶ is hydrogen;

(h') each of R⁷ and R⁹ independently is hydrogen, C C₈alkyl, e.g. methyl, ethyl or isopropyl, haloC_rC₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-Cιoaryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N- methylpiperazino, Cι-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or p-methoxyphenyl, piperidino, piperazino, N- methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morphoiinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;

(P) R⁸ is hydrogen, Cι-C₈alkyl, e.g. methyl, ethyl or isopropyl, halod-C₈alkyI, e.g. trifluoromethyl, C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, halod-C₈alkoxy, e.g. trifluoromethoxy, C₅-C₁₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1- methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)- propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;

(j') R¹⁰ is d-C₈alkyl, e.g. methyl, ethyl or butyl, haloC C₈alkyl, e.g. trifluoromethyl, C C₈alkoxy, e.g. methoxy or ethoxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1- - 14 -

imidazolyl)ethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro; preferably methyl, butyl, methoxy, ethoxy, 2-(1- imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; and (k') each pair of adjacent substituents R⁷ and R⁸, or R⁸ and R⁹ or R⁹ and R¹⁰, are -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -O-CH₂-O-, or -0-CF₂-O-; preferably the pair of adjacent substituents R⁷ and R⁸ or R⁸ and R⁹ being -O- CH₂-O- or the pair of adjacent substituents R⁹ and R¹⁰ being -NH-CH=CH-, -CH=N-NH-, - CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂- or -O-CF₂-O-.

Most preferred as compounds of the formula I are those wherein the substituents have the meaning given in the Examples.

In another embodiment of the invention the invention provides a compound of formula I' with the proviso that this does not include any of the compounds of examples 1 to 52 inclusive.

in which: n' is selected from 1 , 2 and 3;

R' is selected from C₆-₁₀aryl, C₅-₁₀heteroaryl, C₃-₁₂cycloalkyl and C₃- ₁₀heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R is optionally substituted by 1 to 3 radicals independently selected from C^alkyl, C^alkoxy, alkoxy- substituted-C₁.₆alkyl, halo-substituted-d-ealkyl, halo-substituted-d-ealkoxy, -C(0)NR'₅R'₆, - S(O)₀-₂NR'5R'_6> -S(O)o-₂R'₅. -C(0)R'₄, -OXR'₄, -NR'gXNR'sR', -OXNR'₅R'₆, -OXOR'₅ and -XR'₄; wherein X' is a bond or d-ealkylene; R'₅ is selected from hydrogen and Ci-ealkyl; R'β is selected from hydrogen, d-₆alkyl and ds-^cycloalkyl-d^alkyl; and R'₄ is independently selected from C₆-ιoaryl, C₅-₁₀heteroaryl, C₃-ι cycloalkyl and C₃- ₀heterocycloalkyl; - 15 -

and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R'₄ is optionally substituted by 1 to 3 radicals independently selected from C_halky!, C₃-ι₀heterocycloalky1-Co- alkyl optionally substituted with Ci-ealkyl, -C(O)NR'₅R'₆, -XNR'₅R'₆, -NR'sXNR'sR'e and -NR'₅C(O)R'₆; wherein X is a bond or Ci-ealkylene; R'₅ and R'₆ are independently selected from hydrogen and d-₆alkyl;

R'₂ is selected from hydrogen and halo, cyano, Ci-ealkyl, halo-substituted-C - ₆alkyl;

R'₃ is selected from halo, -S(O)₀-₂NR'₅R'6. -S(O)₀-₂R'₆, -NR'₅S(0)o-2R'6, - C(O)NR'₅R'₆, -C(0)R'₆and -C(O)OR'₆; wherein R'₅ is selected from hydrogen and Cι-₆alkyl; and R'e is selected from hydrogen, d-₆alkyl and C₃-ι₂cycloalkyl; and the pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof. Preferably a compound of fomula I' in which: n' is selected from 1 and 2;

R'ι is selected from C₆-ιoaryl and C₅-ι₀heteroaryl; wherein any aryl or heteroaryl of Ri is optionally substituted by 1 to 3 radicals independently selected from d-₆alkyl, Cι-₆alkoxy, - C(O)NR'₅R^,e, -OX'R'₄, -C(O)R'₄, -NR'sX'NR'gR'e, -OX'NR'₅R'e, -OX'OR'₅ and -X'R'₄; wherein X' is a bond or d-₆alkylene; R'₅ is selected from hydrogen and Cι-₆alkyl; R'₆ is selected from hydrogen, Ci-ealkyl and C₃-ι₂cycloalkyl-d-₄alkyl; and R'₄ is C₃-ι₀heterocycloalkyl optionally substituted by 1 to 3 radicals independently selected from Ci-ealkyl, halo-substituted-d-₆alkyl, C₃-ioheterocycloalkyl-C₀-₄alkyl optionally substituted with d-ealkyl, -C(O)NR'₅R'6, -X'NR'₅R'₆, - NR'sX'NR'sR'e and -NR'5C(0)R'₆; wherein X' is a bond or Ci-ealkylene; R'₅ and R'₆ are independently selected from hydrogen and d-ealkyl;

R'₂ is selected from hydrogen and halo;

R'₃ is selected from halo, -S(O)o.₂NR'sR'6. -S(0)o-₂R'e, -NR'₅S(O)o-₂R'₆, ^■ C(O)NR'sR'₆ and -C(O)OR'₆; wherein R'₅ is selected from hydrogen and Ci-ealkyl; and R'₆ is selected from hydrogen, d-₆alkyl and C₃-ι₂cycloalkyl.

more prefably a compound of formula I' in which R'ι is selected from phenyl, pyridinyl, pyrazolyl and pyrimidinyl; wherein any aryl or heteroaryl of R'ι is optionally substituted by 1 to 3 radicals independently selected from ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, - 16 -

cyclobutyloxy, 2,2,2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyioxy, methyl- amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, -X'R' , - C(O)R'₄ and -OX'R'₄; wherein X' is a bond, methylene or ethylene; R'₄ is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1 ,4-dioxa-8-aza-spiro[4.5]dec-8- yl; wherein R'₄ is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl-propylamino, ethyl-methyl- amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.

Even more preferably a compound of of formula I' in which R'₂ is selected from hydrogen and halo; and R'₃ is selected from halo, dimethyl-sulfamoyl, isobutyl-sulfamoyl, methyl-sulfamoyl, ethyl-sulfamoyl, propyl-sulfonyl, ethyl-amino-carbonyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl- sulfamoyl, isopropyl-sulfamoyl, cyclohexyl-sulfonyl, cyclopropyl-methyl-sulfamoyl, cyclobutyl- sulfamoyl, isopropyl-sulfonyl,

Most preferably a compound of example 53

In a yet further embodiment of the invention the present invention also provides a process for the production of a compound of formula I, comprising reacting a compound of formula II

wherein R°, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined above, and Y is a leaving group, preferably halogen such as bromide, iodine, or in particular chloride;

with a compound of formula III - 17 -

wherein R⁷, R⁸, R⁹ and R¹⁰ are as defined above;

and, if desired, converting a compound of formula I, wherein the substituents have the meaning as defined above, into another compound of formula I as defined;

and recovering the resulting compound of formula I in free from or as a salt, and, when required, converting the compound of formula I obtained in free form into the desired salt, or an obtained salt into the free form.

The reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on the reactivity of the leaving group Y and the reactivity of the amino group in the aniline of formula III, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of an acid or a base, with cooling or, preferably, with heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately from 0°C to +100°C, preferably from room temperature (approx. +20 °C) to +80 °C, in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen. Alternatively, the reaction can proceed in the presence of a suitable catalyst (for example, palladium di-benzyl-acetone), in the presence of a base (for example, caesium carbonate) and in the presence of a suitable reaction facilitator (for example, xanthphos).

If one or more other functional groups, for example carboxy, hydroxy or amino, are or need to be protected in a compound of formula II or III, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.

The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as substitution reaction or - 18 -

solvolysis. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove.

Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.

Salts can usually be converted to compounds in free form, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.

Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.

It should be emphasized that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates.

The compounds of formula I, including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).

The compound of formula II used as starting materials may be obtained by reacting a compound of formula IV 19

with a compound of formula V

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above, and Y¹ and Y² are identical or different leaving groups as defined above for Y. The reaction conditions are those mentioned above for the reaction of a compound of formula II with a compound of formula III.

The compounds of formula IV and V are known or may be produced in accordance with known procedures.

The compounds of formula I and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals. In particular, the compounds of the invention are inhibitors of Focal Adhesion Kinase, and are useful as pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with Focal Adhesion Kinase, in particular tumors as described hereinbelow.

Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et al., Prog Biophys Mol Biol 1999, 71, 435-478). Interaction between cells and extracellular matrix (ECM) proteins is transduced as intracellular signals important for growth, survival and migration through cell surface receptors, integrins. FAK plays an essential role in these integrin-mediated outside-in signal cascades. The trigger in the signal transduction cascade is the autophosphorylation of Y397. Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases. The bound c-Src kinase phosphorylates other tyrosine residues in FAK. Among them, phsophorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade. - 20 -

The inhibition of endogenous FAK signalling results in reduced motility and in some cases induces cell death. On the other hand, enhancing FAK signalling by exogenous expression increases cell motility and transmitting a cell survival signal from ECM. In addition FAK is overexpressed in invasive and metastatic epithelial, mesenchymal, thyroid and prostate cancers. Consequently, an inhibitor of FAK is likely to be a drug for anti-tumor growth and metastasis. The compounds of the invention are thus indicated, for example, to prevent and/or treat a vertebrate and more particularly a mammal, affected by a neoplastic disease, in particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of the ovary and prostate, non-small cell lung cancer, small cell lung cancer, cancer of liver, melanoma, bladder tumor and cancer of head and neck.

The relation between FAK inhibition and immuno-system is described e.g. in G.A. van Seventer et al., Eur. J. Immunol. 2001, 31, 1417-1427. Therefore, the compounds of the invention are, for example, useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by immune system disorders, diseases or disorders mediated by T lymphocytes, B lymphocytes, mast cells and/or eosinophils e.g. acute or chronic rejection of organ or tissue allo- or xenografts, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious disease such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock. The agent of the invention are also useful in the treatment and/or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated with therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis. - 21 -

Compounds of the invention are active in a FAK assay system as described in the Examples, and show an inhibition IC₅₀ in the range of 1 nM to 100 nM. Particularly active are the compounds Example No. 3-12 and No. 3-17 described hereinbelow showing IC₅₀ vales in the range of 1 to 5 nM.

Some of the compounds of the invention exhibit also ZAP-70 (zeta chain-associated protein of 70 kD) protein tyrosine kinase inhibiting activity. ZAP-70 protein tyrosine kinase interaction of the agents of the invention may be demonstrated by their ability to prevent phosphorylation of e.g. LAT-11 (linker for activation of T cell) by human ZAP-70 protein tyrosine kinase in aqueous solution, as described in the Examples. The compounds of the invention are thus also indicated for the prevention or treatment of disorders or diseases where ZAP-70 inhibition inhibition play a role.

Compounds of the invention are active in a ZAP-70 assay system as described in the Examples, and show an inhibition IC₅₀ in the range of 1 μM to 10 M, e.g. the compounds Example No. 2 and No. 3-2 described hereinbelow.

Compounds of the present invention are also good inhibitors of the IGF-IR (insulin like growth factor receptor 1) and are therefore useful in the treatment of IGF-1 R mediated diseases for example such diseases include proliferative diseases, such as tumours, like for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastrointestinal tumours 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 Insulin-like growth factor I (IGF-I) induced autophosphorylation of the IGF-IR is determined.

The compounds of formula I and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals. In particular, the compounds of the invention are inhibitors of Anaplastic Lymphoma Kinase (ALK), and are useful as pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with Anaplastic Lymphoma Kinase, in particular tumors as described hereinbelow.

ALK-mediated signaling could play a role in the development and/or progression of a number of common solid tumors (Pulford, K., et al., J. Cell. Physiol. 2004 Jun;199(3):330-58). The - 22 -

compounds of the present invention also exhibit powerful inhibition of the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and its fusion proteins, particularly the fusion protein of NPM-ALK . This protein tyrosine kinase results from a gene fusion of nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK), rendering the protein tyrosine kinase activity of ALK ligand-independent. NPM-ALK plays a key role in signal transmission in a number of hematopoetic and other human cells leading to hematological and neoplastic diseases, for example in anaplastic large-cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK+ NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT) and neuroblastomas. (Duyster J et al. 2001 Oncogene 20, 5623-5637). NPM-ALK has been shown to be a potent oncogene in vitro, being able to transform various cell lines and primary hematopoetic cells. Furthermore, NPM-ALK transduced bone marrow cells are able to induce a lymphoma-like disease after transplantation into irradiated recipient mice. Signaling pathways activated by NPM-ALK include ras, PLC and PI3K pathways and, in addition, STAT5 has been shown to be phosphorylated by NPM-ALK. In addition to NPM-ALK, other gene fusions have been identified in human hematological and neoplastic diseases; mainly TPM3-ALK (a fusion of nonmuscle tropomyosin 3 with ALK). Further, the ALK fusion protein CLTC-ALK, is associated with diseases that include classical T cell or null ALCL, ALK⁺ DLBCL and inflammatory myofibroblastic tumors. CLTCL-ALK is also thought to play a role in the pathogenesis of large B-cell lymphomas.

Further, the ALK fusion protein CLTC-ALK is associated with diseases that include classical T cell or null ALCL, ALK⁺ DLBCL and inflammatory myofibroblastic tumors.

CLTCL-ALK is also thought to play a role in the pathogenesis of large B-cell lymphomas.

Aberrant activity of ALK is involved in the development of brain tumors and overexpression of ALK has been reported in neuroblastomas and several cell lines derived from neural tissue. ALK-mediated signaling could play a role in the development and/or progression of a number of common solid tumors (Pulford, K., et al., J. Cell. Physiol. 2004 Jun;199(3):330-58).

The inhibition of ALK tyrosine kinase activity can be demonstrated using known methods, for example using the recombinant kinase domain of the ALK in analogy to the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000). In vitro enzyme assays using GST-ALK protein tyrosine kinase are performed in 96-well plates as - 23 -

a filter binding assay in 20 mM Tris-HCI, pH = 7.5, 3 mM MgCI₂, 10 mM MnCI₂, 1 mM DTT, 0.1 μCi/assay (=30 μl) [γ-³³P]-ATP, 2 μM ATP, 3 μg/ml poly (Glu, Tyr 4:1) Poly-EY (Sigma P-0275), 1 % DMSO, 25 ng ALK enzyme. Assays are incubated for 10 min at ambient temperature. Reactions are terminated by adding 50 μl of 125 mM EDTA, and the reaction mixture is transferred onto a MAIP Multiscreen plate (Millipore, Bedford, MA, USA), previously wet with methanol, and rehydrated for 5 min with H₂O. Following washing (0.5 % H₃PO ), plates are counted in a liquid scintillation counter. IC₅₀ values are calculated by linear regression analysis of the percentage inhibition. Compared with the control without inhibitor, the compounds of formula I inhibit the enzyme activity by 50 % (IC₅₀), for example in a concentration of from 0.001 to 0.5 μM, especially from 0.01 to 0.1 μM.

The compounds of formula I potently inhibit the growth of human NPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany). The expression of NPM-ALK is achieved by transfecting the BaF3 cell line with an expression vector pClneo™ (Promega Corp., Madison Wl, USA ) coding for NPM-ALK and subsequent selection of G418 resistant cells. Non-transfected BaF3 cells depend on IL-3 for cell survival. In contrast NPM-ALK expressing BaF3 cells (named BaF3-NPM-ALK hereinafter) can proliferate in the absence of IL-3 because they obtain proliferative signal through NPM-ALK kinase. Putative inhibitors of the NPM-ALK kinase therefore abolish the growth signal and result in antiproliferative activity. The antiproliferative activity of putative inhibitors of the NPM-ALK kinase can however be overcome by addition of IL-3 which provides growth signals through an NPM-ALK independent mechanism. [For an analogous cell system using FLT3 kinase 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/microtitre plate well) are transferred to 96-well microtitre plates. The test compounds [dissolved in dimethyl sulfoxide (DMSO)] are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1 % (v/v). After the addition, the plates are incubated for two days during which the control cultures without test compound are able to undergo two cell-division cycles. The growth of the BaF3-NPM-ALK cells is measured by means of Yopro™ staining [T Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995)]: 25 μl of lysis buffer consisting of 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4 % NP40, 20 mM EDTA and 20 mM is added to each well. Cell lysis is completed within 60 min at room temperature and total amount of Yopro bound to DNA is determined by - 24 -

measurement using the Cytofluor II 96-well reader (PerSeptive Biosystems) with the following settings: Excitation (nm) 485/20 and Emission (nm) 530/25.

IC₅₀ values are determined by a computer-aided system using the formula:

IC-so = [(ABStest - ABS_start)/(ABS_cont_raι - ABS_start)] x 100. (ABS = absorption)

The IC5₀ value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor. The compounds of formula I exhibit inhibitory activity with an IC₅₀ in the range from approximately 0.01 to 1 μM.

The antiproliferative action of the compounds of formula I can also be determined in the human KARPAS-299 lymphoma cell line (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. The compounds of formula I exhibit inhibitory activity with an IC₅₀ in the range from approximately 0.01 to 1 μM.

The action of the compounds of formula I on autophosphorylation of the ALK can be determined in the human KARPAS-299 lymphoma cell line by means of an immunoblot as described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002). In that test the compounds of formula I exhibit an IC₅₀ of approximately from 0.001 to 1 μM.

Among the compounds of formula I, 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl- phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide is an especially potent ALK inhibitor, in that this compound inhibits the growth of the BaF3-NPM-ALK cells with an IC₅₀ of 97 nM. Further specifically preferred compounds that inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) are the compounds described hereinafter in the examples 7A and 7B, as well as 7-2, 7-15, 19-5, 21-1 , 26-3 and 28-5, respectively, all of which are having an IC₅₀ within the range from <0.5 to 200 nM.

For the above uses in the treatment of neoplastic diseases and immune system disorders the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be - 25 -

obtained systemically at daily dosages of from about 0.1 to about 100 mg/kg body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.

The compounds of the invention may be administered by any conventional route, in particular parenterally, for example in the form of injectable solutions or suspensions, enterally, preferably orally, for example in the form of tablets or capsules, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. Pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable earner or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance. Topical administration is e.g. to the skin. A further form of topical administration is to the eye.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.

Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80^® (polyoxyethylene(20)sorbitan mono-oleate).

Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. In respect of such, special mention may be made of liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to - 26 -

22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ?-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. As fatty acid esters, therefore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol), "Labrafil M 1944 CS" (unsaturated polygiycolized glycerides prepared by alcoholysis of apricot kernel oil and consisting of glycerides and polyethylene glycol ester), "Labrasol" (saturated polygiycolized glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester; all available from Gattefosse, France), and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C₈ to C_i2 from Hϋls AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.

The manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, by the inclusion of additional excipients, to form tablets or tablet cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners 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. - 27 -

Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions 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 tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol 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 or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity- increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.

Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions. - 28 -

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid. .

The compounds of the invention may be administered as the sole active ingredient or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens. For example, the agents of the invention may be used in accordance with the invention in combination with pharmaceutical compositions effective in various diseases as described above, e.g. with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatory compounds, e.g. CTLA4lg.

In accordance with the foregoing, the present invention also provides:

(1) A compound of the invention for use as a pharmaceutical;

(2) a compound of the invention for use as a 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin- 1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, for example for use in any of the particular indications hereinbefore set forth;

(3) a pharmaceutical composition, e.g. for use in any of the indications herein before set forth, comprising a compound of the invention as active ingredient together with one or more pharmaceutically acceptable diluents or carriers;

(4) a method for the treatment of any particular indication set forth hereinbefore in a subject in need thereof which comprises administering an effective amount of a compound of the invention or a pharmaceutical composition comprising same;

(5) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which FAK and/or ALK and/or ZAP-70 and/or IGF-I activation plays a role or is implicated, preferably ALK; - 29 -

(6) the method as defined above under (4) comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of the invention and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;

(7) a combination comprising a therapeutically effective amount of a compound of the invention and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;

(8) use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease which responds to inhibition of the anaplastic lymphoma kinase;

(9) the use according to (8), wherein the disease to be treated is selected from lymphoma, anaplastic large-cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors and neuroblastomas;

(10) the use according to (8) or (9), wherein the compound is 2-[5-chloro-2-(2-methoxy-4- morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide or 5-Chloro-N*2*-{2- methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)- pheny!]-pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof, or any of the the compounds described hereinafter in the examples or a pharmaceutically acceptable salt of any one of these;

(11 ) a method for the treatment of a disease which responds to inhibition of the anaplastic lymphoma kinase, especially a disease selected from anaplastic large-cell lymphoma, non- Hodgkin's lymphomas, inflammatory myofibroblastic tumors and neuroblastomas, comprising administering an effective amount of a compound of the invention, especially 2-[5-chloro-2-(2- methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide or 5-Chloro- N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof.

Additionally preferred a compound according to the present invention that is useful as herein before described is a compound specifically mentioned in the examples.

Additional specifically preferred compounds according to the present invention that are useful either as FAK inhibitor, as ALK inhibitor or for inhibition of both and which may be prepared essentially according to the methods described hereinbefore are the following:

2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl- benzamide, - 30 -

N²-(4-[1 ,4']Bipiperidinyl-1'-yl-2-methoxy-phenyl)-5-chloro-N⁴-[2-(propane-1-sulfonyl)-phenyl]- pyrimidine-2,4-diamine,

2-{5-Chloro-2-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N- isopropyl-benzenesulfonamide,

2-[5-Bromo-2-(2-methoxy-5-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl- benzenesulfonamide

2-{2-[5-(1-Acetyl-piperidin-4-yloxy)-2-methoxy-phenylamino]-5-bromo-pyrimidin-4-ylamino}-N- methyl-benzenesulfonamide,

N-[5-Bromo-2-(2,5-dimethoxy-phenylamino)-pyrimidin-4-yl]-N-(4-morpholin-4-yl-phenyl)- methanesulfonamide,

5-Bromo-N-4-(4-fluoro-phenyl)-N*2*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4- diamine,

2-[5-Chloro-2-(2-methoxy-4-piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl- benzenesulfonamide,

2-[5-Bromo-2-(5-fluoro-2-methoxy-phenylamino)-pyrimidin-4-ylamino]-N-methyl- benzenesulfonamide,

2-[5-Chloro-2-(5-fluoro-2-methoxy-phenylamino)-pyrimidin-4-ylamino]-N-isobutyl- benzenesulfonamide, and

2-{5-Chloro-2-[2-methoxy-5-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-ylamino}-

N-methyl-benzenesulfonamide,

5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-

(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.

The invention also provides a compound of formula 2-{5-Chloro-2-[4-(3-methylamino-pyrrolidin- 1-yI)-phenylamino]-pyrimidin-4-ylamino}-N-isopropyl-benzenesulfonamide

The invention also provides a compound of formula 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl- piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4- diamine

The following Examples serve to illustrate the invention without limiting the invention in its scope. - 31 -

Examples

Abbreviations

AcOH = acetic acid, ALK = anaplastic lymphoma kinase, ATP = adenosine 5'-triphosphate, brine = saturated sodium chloride solution, BSA = bovine serum albumin, DIAD = diisopropyl azodicarboxylate, DIPCDI = N,N'-diisopropylcarbodiimid, DMAP = 4-dimethyiaminopyridine, DMF = N,N-dimethyIformamide, DTT = 1,4-dithio-D,L-threitol, EDTA = ethylene diamine tetraacetic acid, Et = ethyl, EtOAc = ethyl acetate, EtOH = ethanol, Eu-PT66 = LANCE™ europium-W1024-labelled anti-phosphotyrosine antibody (Perkin Elmer), FAK = Focal Adhesion Kinase, FRET = fluorescence resonance energy transfer, HEPES = N-2-hydroxyethyl- piperazine-N'-2-ethanesulfonic acid, HOAt = 1-hydroxy-7-azabenzotriazole, Me = methyl, RT- PCR = reverse transcription polymerase chain reaction, SA-(SL)APC = Streptavidin conjugated to SuperLight™ allophycocyanin (Perkin Elmer), subst. = substituted, TBTU = 0-(benzotriazol-1- yl)-N,N,N',N'-tetramethylammonium tetrafluoroborate, THF = tetrahydrofuran.

Example 1 : 2-r2-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-ylamino1-N-methyl- benzenesulfonamide

To a solution of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (100 mg, 0.29 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 give the title product in. Rf = o.47 (n-hexane : ethyl acetate = 1:1). ¹H-NMR (400 MHz, CDCI₃), 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, 1H), 7.81 (d, 1H), 8.0-8.2 (m, 1H), 9.13 (s, 1H), 9.41 (br.s, 1H), 11.0 (s, 1H).

Preparation of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide: 2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCI (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. - 32 -

Rf = 0.5 (n-hexane : ethyl acetate = 1:1). ¹H-NMR (400MHz, CDCI₃), δ (ppm): 2.67 (d, 3H), 4.6- 4.7 (m, 2H), 7.41 (dd, 1H), 7.7 (dd, 1H), 8.04 (d, 1 H), 8.15 (d, 1H), 9.21 (s, 1 H), 11.2 (s, 1H).

Example 2: 2-f5-Bromo-2-(2.4-dimethoxy-phenylamino)-pyrimidin-4-ylaminol-N-methyl- benzenesulfonamide

To a solution of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (300 mg, 0.79 mmol), 2,4-dimethoxyaniline (181.5 mg, 1.18 mmol) in ethanol (3 mL), 1 N hydrochloric acid (0.03 mL) is added and stirred under reflux condition for 5 hours. The reaction mixture is cooled to room temperature, poured into water and extracted twice with ethyl acetate. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n- hexane : ethyl acetate = 5:1 to 1 :1) to afford the title compound.

¹H-NMR (CDCIs), δ (ppm): 8.95 (s, 1 H), 8.44 (d, 1 H), 8.20 (s, 1 H), 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 = 1 :1): 0.31.

Preparation of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide A solution 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 at room temperature for 23 hours. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane - ethyl acetate gradient) to afford the title compound as a slightly yellow solid. 1H-NMR (CDCI₃), δ (ppm): 2.67 (d, 3H), 4.79 (q, 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, 1 H). Rf (n-hexane : ethyl acetate = 10:3): 0.33. - 33

Example 3:

The following 2-[5-bromo-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzene- sulfonamides are prepared from 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl- benzenesulfonamide and the corresponding aniline following the procedure of Example 2:

34

CDCI₃: 2.33(s, 3H), 2.63(d, 3H), 3.87(s, 3H), 4.46- -5 0.39 4.44(m, 1H), 6.66(d, 1 H), 6.71 (s, 1 H), 7.48(bs, 1H),

(n-hexane: 7.63-7.59(m, 1H), 7.97(dd, 1 H), 8.05(d, 1 H), 8.23 (s,

AcOEt=1 :1) 1H), 8.44(d, 1H), 8.92(bs, 1H)

CDCI₃: 2.63(d, 3H), 3.90(s, 3H), 4.45-4.40(m, 1 H), -6 )Me 0.27 6.90-6.86(m, 2H), 7.00-6.96(m, 1H), 7.23-7.17 (m, (n-hexane: 3H), 7.45(dd, 1H), 7.50-7.60(m, 2H), 7.97(dd, 1H), AcOEt=3:1) 8.22(d, 1H), 8.26 (s, 1H), 8.43(d, 1H), 8.94(bs, 1H)

CDCI₃: 2.30(s, 3H), 2.63(d, 3H), 4.44-4.43(m, 1 H), -7 0.34 6.68 (bs, 1H), 7.00-6.68(171, 1H), 7.23-7.17(m, 2H), (n-hexane: 7.46-7.43(m, 1H), 7.76(d, 1H), 7.93(dd, 1 H), 8.22 (s, AcOEt=3:1) 1 H), 8.40(d, 1H), 9.01(bs, 1 H)

CDCI₃: 2.62(d, 3H), 2.81 (s, 3H), 4.07-3.98(m, 1H), -8 0.12 4.52-4.45(m, 1H), 6.37(bs, 1H), 6.77-6.73 (m, 2H), (n-hexane: 7.12(dd, 1H), 7.24-7.20(m, 1H), 7.30-7.27(m, 1H),

AcOEt=3:1) 7.35(dd, 1H), 7.88(dd, 1H), 8.18 (s, 1H), 8.41 (d, 1H), 9.19(bs, 1H)

CDCI₃: 2.62(d, 3H), 3.94(s, 3H), 4.49-4.43(m, 1 H),-9 0.28 6.99-6.90 (m, 3H), 7.18-7.23(m, 1H), 7.31-7.24(m,

(n-hexane: 3H), 7.63(bs, 1 H), 7.93-7.86(m, 1 H), 8.28-8.23(m,

AcOEt=3:1) 1H), 8.28 (s, 1H), 8.45(bs, 1H), 8.89(bs, 1H)

CDCI₃: 0.91 (t, 3H), 1.37 (dd, 2H), 1.64-1.55 (m, 2H),-10 0.23 2.64-2.60 (m, 2H), 4.45-4.40 (m, 1H), 6.69 (bs, 1H), (n-hexane: 7.23-7.10(m, 1H), 7.46-7.38 (m, 1H), 7.73 (d 1H), AcOEt=3:1) 7.92 (d, 1H), 8.21 (s, 1H), 8.38-8.46 (m, 1H), 9.09 (bs, 1H)

CDCI₃: 2.63 (d, 3H), 4.15-4.10 (m, 1H), 6.58 (bs, 1H),-11 0.12 7.31-7.10(m, 4H), 7.53-7.49 (m, 1H), 7.71(d 1H), 7.95 (n-hexane: (d, 1H), 8.30-8.23 (m, 1H), 8.26 (s, 1H), 8.45 (d, 1H), AcOEt=3:1)

9.03 (bs, 1H) 35

CDCI₃: 2.09 (dd, 2H), 2.63 (d, 3H), 2.85(t, 2H), 2.96 (t,-12 0.4 2H), 4.46-4.43 (m, 2H), 6.73 (bs, 1 H), 6.99 (d, 1H),

(n-hexane: 7.09 (dd, 1H), 7.25-7.20(m, 1 H), 7.52 (dd, 1 H), 7.74

AcOEt=3:1) (d 1H), 7.92 (dd, 1H), 8.22 (s, 1 H), 8.42 (d, 1H), 9.02 (bs, 1H)

CDCI₃: 2.63 (d, 3H), 4.63-4.64 (m, 1H), 7.11(d, 2H),-13 0.33 7.18(dd, 1H), 7.42-7.34(m, 1H), 7.58-7.55(m, 1H), (AcOEt) 7.96(d, 1H), 8.07(s, 1H), 8.19-8.10(m, 1H), 8.24(s, 1H), 9.15(s, 1H), 11.6-11.4(m, 1H)

CDCI₃: 2.63(d, 3H), 3.88(s, 3H), 3.89(s, 3H), 4.47--14 0.28 4.41 (m, 1H), 6.60(d,1H), 6.92 (dd,1H), 7.64 (dd, (n-hexane: 1H),7.66-7.61(m,1H), 7.89(d, 1H), 7.98(dd, 1H),

AcOEt=3:1) 8.26(s, 1 H), 8.43(d, 1 H), 8.95(s, 1 H)

CDCI₃: 2.63(d, 3H), 3.66(s, 3H), 3.85(s, 3H), 4.45--15 ,OMe 0.30 4.44(m, 1 H), 6.48(dd,1H), 6.79(d,1H), 7.64(dd, 1H), (n-hexane: 7.97(dd, 2H), 8.26(s, 1 H), 8.44(d, 1H), 8.96(s, 1H)

MeO' AcOEt=3:1)

CDCI₃: 2.17(s, 3H), 2.22(s, 3H), 2.64(s, 3H), 2.63(d,-16 0.22 3H), 4.46-4.44(m, 1H), 6.57(bs, 1H), 7.00(s,1H), (n-hexane: 7.17(dd,1H), 7.44-7.40(m,1H), 7.44(s, 1H), 7.93(dd, AcOEt=3:1) 1 H), 8.19(s, 1H), 8.43(d, 1H), 9.06(s, 1 H)

CDCI₃: 2.22(s,3H), 2.63(d, 3H), 3.68(s, 3H), 3.89(s,-17 0.46 3H), 4.52-4.47(m, 1H), 6.51 (s,1H), 6.74(s,1H), (AcOEt) 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)

CDCI₃: 1.16(d, 6H), 2.25 (s, 3H), 2.62(d, 3H), 2.77(t,-18 0.35 1 H), 4.49-4.48(m, 1H), 7.00(s,1H), 7.15(d,1H), 7.41-

(n-hexane: 7.37(m,1H), 7.49(d,2H), 7.54(dd, 1H), 7.92(dd, 1H),

AcOEt=3:1) 8.21 (s, 1 H), 8.32(d, 1 H), 9.02(s, 1H) 36

37

38

DMSO-d₆: 2.43(s, 3H), 2.80-2.82(m, 4H), 3.61-3.64-32 0.3 (m, 4H), 3.75(s,3H), 6.62(dd, 1 H), 6.93(d, 1 H), 7.46(d,

(n-hexane: 1H), 7.54(dd, 1H), 7.77(dd, 2H), 8.14(bs, 1 H), 8.32(s,

AcOEt=1:1) 1 H), 8.38-8.30(m, 1H), 9.14(bs, 1H)

DMSO-d₆: 1.59-1.68(m, 2H), 1.88-1.98(m, 2H), 2.13--33 0.61 2.25(m,2H), 2.19(s, 3H), 2.43(s, 3H), 2.60-2.70(m,

(MeOH: 2H), 3.75(s, 3H), 4.32-4.40(m, 1H), 6.51 (dd, 1 H),

CH2CI2=1: 6.64(d, 1 H), 7.20(dd, 1H), 7.39(d, 1 H), 7.75(dd, 1H),

1 ) 7.70-7.78(s, 1H), 8.22(s, 1 H), 8.26(s, 1H), 8.38- 8.41 (m, 1H), 9.22(s, 1H)

CDCI₃: 2.11(s, 3H), 2.68(d, 3H), 2.76-2.83(m, 2H),-34 0.17 2.89-2.97(m, 2H), 3.47-3.55(m, 2H), 3.58-3.66(m, (AcOEt) 2H), 3.86(s, 3H), 4.70-4.78(m, 1H), 6.53(dd, 1 H),

6.81 (d, 1 H), 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(bs, 1H)

DMSO-d₆: 2.40-2.48(m, 7H), 2.63(t, 2H), 3.50-3.58(m,-35 0.22 4H), 3.77(s, 3H), 3.91 (t, 2H), 6.60(dd, 1H), 6.93(d,

(AcOEt 1H), 7.28(dd, 1 H), 7.56(d, 1H), 7.60(dd, 1H), 7.75- only) 7.80(m, 1 H), 7.80(dd, 1H), 8.10(s, 1H), 8.35(s, 1H), 8.40(d, 1H), 9.21 (s, 1 H) -36 0.4 DMSO-d₆: 2.43(s, 3H), 7.03-7.08(m, 1 H), 7.21- (n-hexane: 7.23(m, 1 H), 7.25-7.36(m, 1H), 7.47-7.57(m, 2H), AcOEt=1 :1) 7.74-7.77(171, 2H), 8.28(s, 1H), 8.35(d, 1H), 9.09(s, 1H), 9.24(s, 1H) -37 0.4 CDCI₃: 2.64(d, 3H), 4.53-4.54(m, 1H), 6.88-6.93(m,

(n-hexane: 1H), 7.14-7.28(m, 3H), 7.54-7.58(m, 1 H), 7.95-

AcOEt=1 :1) 7.98(m, 1H), 8.16-8.21(m, 1H), 8.24(s, 1 H), 8.33- 8.36(m, 1H), 9.05(s, 1H) -38 0.42 CDCI₃: 2.64(d, 3H), 4.46-4.47(m, 1H), 6.63-6.68(m,

(n-hexane: 1H), 7.30-7.32(m, 2H), 7.55(s, 1H), 7.64-7.68(m, 1 H),

AcOEt=1 :1) 7.97-7.99(m, 1H), 8.20-8.39(m, 3H), 9.03(s, 1H) 39

40

41

-42-

43

•44

^■45 H),

-46-

DMSO-d6: 1.41-1.51 (m, 2H), 1.88-1.95 (m, 2H),-79 Ms:563, 2.41-2.45 (m, 3H), 2.54-2.63 (m, 2H), 2.92-3.0 (m, 565 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 (brs, 1H)

DMSO-d6: 2.4-2.46 (m, 3H), 3.79 (s, 3H), 6.72 (ddd,-80 Ms:482, 1H), 6.99 (dd, 1H), 7.21-7.26 (m, 1H), 7.47-7.53 (m, 484 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)

DMSO-d6: 2.41-2.49 (m, 3H), 3.82 (s, 3H), 6.80 (ddd,-81 Ms:482, 1H), 7.01 (dd, 1H), 7.3-7.35 (m, 1H), 7.56-7.63 (m, 484 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 (brs, 1H)

DMSO-d6: 1.73-1.82 (m, 1H), 2.23-2.34 (m, 4H),-82 Ms:563, 2.34-2.42(m, 3H), 2.42-2.46 (m, 3H), 2.59 (dd, 1H), 565 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), 8.37-8.43 (m, 1H), 9.21 (brs, 1H).

2.36 (s, 3H), 2.65 (d, 3H), 3.93 (s, 3H), 4.46-4.51 (m,-83 MS 1H), 6.75-6.80 (m, 2H), 6.97-7.04 (m, 2h), 7.25-7.30 544, 546 (m, 1H), 7.56-7.66 (m, 2H), 7.98 (dd, 1H), 8.29 (s, 1H), 8.36-8.44 (m, 2H), 9.01 (s, 1H).

CDCI3: 2.32 (s, 3H), 2.39-2.47 (m, 4H), 2.64 (d, 3H),-84 MS 2.89-2.97 (m, 4H), 3.85 (s, 3H), 4.54-4.52 (m, 1H), 562, 564 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). .47 .

Example 4: 2-f5-Bromo-2-(subst. phenylamino)-pyrimidin-4-ylamino1-N-propyl-benzene- sulfonamides

These compounds are prepared in analogy to Example 2 using 2-(5-bromo-2-chloro-pyrimidin- 4-ylamino)-N-propyl-benzenesulfonamide and the corresponding aniline to give compounds No. 4-1 to 4-31 having the substituent Rx as listed under Example 3 for compounds No. 3-1 to 3-31. Preparation of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-propyl-benzenesulfonamide To a solution of 5-bromo-2,4-dichloropyrimidine (90 μL, 0.70 mmol) and 2-amino-N-propyl- benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80°C for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane : ethyl acetate = 5 : 1) to afford the title compound as a slightly yellow solid.

¹H-NMR (δ, ppm) : 0.89 (t, 3H), 1.41 (q, 2H), 3.56 (t, 2H), 4.92 (br.s, 2H), 6.71 (dd, 1H), 6.77 (dd, 1H), 7.33 (dd, 1 H), 7.54 (dd, 1 H), 8.79 (s, 1H) Rf (hexane : ethyl acetate = 1 :1): 0.64.

Example 5: 2-r5-Trifluoromethyl-2-(subst. phenylamino)-pyrimidin-4-ylaminol-N-methyl- benzenesulfonamides

These compounds are prepared in analogy to Example 2 using 2-(2-chloro-5-trifluoromethyl- pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and the corresponding aniline to give compounds No. 5-1 to 5-31 having the substituent Rx as listed under Example 3 for compounds

No. 3-1 to 3-31.

Preparation of 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide

To a solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (386 mg, 1.79 mmol) in acetonitrile

(10 mL), 2-amino-N-methyl-benzenesuifonamide (333 mg, 1.79 mmol) and 1 ,8-diaza[5.4.0]- bicyclo-7-undecene (280 μL, 1.88 mmol) are added successively at ambient temperature. After stirring for 15 h at room temperature, dichloromethane (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.

¹H NMR (CDCI₃) δ: 3.73(s, 3H), 6.67-6.69(m, 1 H), 6.72-6.73(m, 1 H), 7.27-7.31 (m, 1 H), 7.78

(dd, 1 H), 8.60(s, 1 H). Rf (hexane : ethyl acetate = 1 :1): 0.28. 48

Example 6: 2-r5-Bromo-2-(2,3-fdifluoromethylenedioxylphenylamino)-pyrimidin-4-ylamino1- benzenesulfonamide

This compound is obtained as a side product formed by N-demethylation on reaction of 2-(5- bromo-2-chloropyrimidin-4-ylamino)-N-methyl-benzenesulfonamide with 2,3-(difiuoromethylene- dioxy)aniline following the procedure of Example 2. It may also be prepared by reaction of 2-(5- bromo-2-chloropyrimidin-4-ylamino)benzenesulfonamide with 2,3-(difluoromethylenedioxy)- aniline.

Rf (n-hexane: ethyl acetate = 1:1): 0.46.

¹H-NMR : (CDCI₃) 4.83 (bs, 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, 1H), 8.02 (dd, 1H), 8.28 (d, 1H), 8.29 (s, 1H), 8.88 (s, 1H).

Preparation of 2-(5-bromo-2-chloropyrimidin-4-ylamino)benzenesulfonamide: To a solution of 5- bromo-2,4-dichloropyrimidine (300 mg, 1.32mmol) 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 at 90°C for 4.5 hours. The mixture is poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate three times. The organic layer 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 afford the title compound. Rf (hexane : ethyl acetate = 1:1): 0.55. ¹H-NMR (400MHz, CDCI3) δ : 4.78 (br.s, 2H), 7.22 (dd, 1H), 7.61 (ddd, 1H), 7.95 (dd, 1H), 8.35 (s, 1H), 8.35 (d, 1H), 9.18 (s, 1H).

Example 7A: 2-r5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino1-N- methyl-benzamide 49 -

To a suspension of 2-(2,5-dichloro-pyrimidin-4-yl-amino)-Λ/-methyl-benzamide (5.05 g, 17.0 mmol) in 90 mL of 2-methoxyethanol are added 2-methoxy-4-morpholinoaniline dihydrochloride (4.56 g, 16.2 mmol) and 17.0 mL of 1 N ethanolic solution of hydrogen chloride (17.0 mmol). After the reaction mixture is stirred at 110°C for 4 hours and cooled to room temperature, the mixture is neutralized with 1 N aqueous NaOH solution and extracted with EtOAc (100 mLX3). The organic layer is washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The resulting black solid is washed with EtOH (90 mL), then purified with silica gel column chromatography (CH₂CI₂ to CH₂CI₂: AcOEt=1:2 ) to give 2-[5-chloro-2-(2-methoxy-4- morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a pale yellow solid. 1H-NMR (400MHz, 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)⁺.

The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-N-methyl- benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and the corresponding aniline following the procedure of Example 7A.

50

DMSO-d6: 1.44-1.33 (m, 2H), 1.64-1.45 (m, 6H),-1 MS: m/z 1.73-1.89 (m, 2H), 2.34-2.44 (m, 1H), 2.43-2.55 (m,

550, 552 4H), 2.65 (t, 2H), 2.80 (d, 3H), 3.75 (s, 3H), 3.72-3.75

(M+1) (m, 2H), 6.48 (dd, 1 H), 6.62 (d, 1 H), 7.06 (dd, 1 H), 7.32 (dd, 1 H), 7.39 (d, 1H), 7.71 (dd, 1H), 8.09(s, 1H), 8.60 (d, 1H), 8.70 (d, 1 H), 11.58 (s, 1H)

CDCI₃: 1.70-1.97(m, 4H) ,2.62-2.79(m, 1H), 3.04(d,-2 0.3 3H), 3.02-3.18(171, 2H), 3.23-3.33( m, 2H), 3.88 (s,

(MeOH: 3H), 5.39-5.47(m, 1 H), 6.15-6.24(m, 1H), 6.55-

AcOEt 6.62(m, 2H), 6.74-6.82(m, 1H), 7.09 (dd, 1 H),7.23-

=5:95) 7.32 (m, 1H), 7.46-7.52(m, 2H), 8.09(s, 1H), 8.15(d, 1H), 8.68(d, 1H) 11.0(bs, 1H)

DMSO-d6: 2.24 (s, 3H), 2.45-2.55 (m, 4H), 2.80 (d,-3 MS (ESI) 3H, J = 4.52 Hz), 3.12-3.17 (m, 4H), 3.76 (s, 3H), 6.48 m/z 482, (dd, 1H, J = 8.56, 2.52 Hz), 6.63 (d, 1H, J = 2.52 Hz), 484 (M+1 )⁺ 7.05-7.10 (m, 1H), 7.27-7.35 (m, 1 H), 7.40 (d, 1 H, J = 8.56 Hz), 7.69-7.72 (m, 1 H), 8.09 (s, 1H), 8.12 (s,

1H), 8.55-8.65 (m, 1 H), 8.67-8.75 (m, 1 H), 11.59 (s, 1H)

DMSO-d6: 2.48-2.55(m, 4H), 2.71 (t, 2H), 2.80(d, 3H),-4 0.46 3.58-3.61 (m, 4H), 3.76(s, 3H), 4.11(t, 2H), 6.52(dd,

(MeOH: 1H), 6.66(d, 1 H), 7.06(dd, 1H), 7.32(dd, 1H), 7.46(d,

CH₂CI₂=1 :4) 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)

DMSO-d6: 1.60-1.70 (m, 2H), 1.90-1.98 (m, 2H),-5 m/z 497, 2.13-2.25 (m, 2H), 2.19 (s, 3H), 2.60-2.67 (m, 2H), 499 (M+1 )⁺ 2.80 (d, 3H, J = 4.52 Hz), 3.75 (s, 3H), 4.30-4.40 (m, 1H), 6.54 (dd, 1H, J = 8.56, 2.0 Hz), 6.65 (d, 1H, J =

2.0 Hz), 7.04-7.09 (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, 1 H), 8.18 (s, 1H) 8.52-8.59 (m, 1 H), 8.68-8.75 (m, 1H), 11.57 (s, 1 H) 51

52

DMSO-d6: 1.78-1.89(m, 1H), 2.13-2.22(m, 1H),-11 0.54 2.22(s, 6H), 2.77-2.87(m, 1H), 2.79(d, 3H), 3.04-

(MeOH: 3.10(m, 1H), 3.23-3.50(m, 3H), 3.75(s, 3H), 6.11(dd,

CH₂CI₂=1:4) 1H), 6.22(d, 1H), 7.05(dd1H), 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)

DMSO-d6: 1.77-1.87(m, 1H), 2.09-2.18(m, 1H),-12 0.27 2.35(s, 3H), 2J9(d, 1H), 3.02-3.07(m, 1H), 3.23-

(MeOH: 3.50(m, 4H), 3.74(s, 3H), 6.09(dd, 1H), 6.20(d, 1H),

CH₂CI₂=1:1) 7.04(dd, H), 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)

CDCI₃: 1.62-1.74(m, 3H), 1.76-1.85(m, 2H), 2.00--13 0.23 2.09(m, 2H), 2.20-2.31 (m, 1H), 2.64-2.69 (m, 2H),

(MeOH: 2.79 (d, 3H), 3.56-4.04(m, 2H), 4.04(s, 3H), 6.49(dd,

AcOEt 1H), 6.63(d, 1H), 6.78(bs, 1H), 7.07 (dd, 1H), 7.28-

=5:95) 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(bs, 1H)

DMSO-d6: 1.61-1.46(m, 2H), 1.92-1.82 (m, 2H), 2.14-14 0.30 (s, 3H), 2.41-2.23 (m, 5H, 2.60-2.45 (m, 4H), 2.67 (t,

(MeOH: 2H), 2.79 (d, 3H), 3.75 (s, 3H), 3.71-3.75 (m, 2H),

CH₂CI₂=4:1) 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 (bs, 1H), 8.65-8.56 (m, 1H), 8.75-8.67 (m, 1H), 11.6 (s, 1H)

53 -

DMSO-d6: 2.19-2.37 (m, 4H), 2.65-2.85 (m, 3H),-15 MS (ESI) 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 (m, 1H), 3.48-3.59 /z 524, (m, 2H), 3.61-3.67 (m, 1 H), 3.72-3.81 (m, 1 H), 3.76

526 (M+1 )⁺ (s, 3H), 6.47 (dd, 1 H, J = 8.6, 2.5 Hz), 6.65 (d, 1 H, 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, 1 H), 8.09 (s, 1H), 8.12

(s, 1 H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1 H)

DMS0-d6: 2.19-2.37 (m, 4H), 2.65-2.85 (m, 3H), 2.80-16 MS (ESI) (d, 3H, J = 4.5 Hz), 3.15-3.21 (m, 1H), 3.48-3.59 (m, m/z 524, 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s,

526 (M+1 )⁺ 3H), 6.47 (dd, 1 H, 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, 1 H), 8.12 (s, 1 H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H)

MS DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84-17 510 (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, 1 H), 6.86(bs, 1H), 7.07(dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1 H), 8.09(s, 1H), 8.15-8.10 (m, 1 H), 8.66- 8.58(m, 1H), 8.77-8.70(m, 1 H), 11.6(s, 1H)

MS DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84-18 510 (m, 3H), 2.68-2.63(171, 1 H), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28(d, 2H), 3.76(s,3H), 6.50 (dd, 1 H), 6.64 (d, 1 H), 6.86(bs, 1H), 7.07(dd, 1 H), 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, 1 H), 8.77-8.70(m, 1H), 11.6(s, 1H)

54

1.40-1.53 (m, 2H), 1.72-1.80 (m, 2H), 2.18 (s, 3H),-19 0.16 2.19-2.44 (m, 5H), 2.80 (d, 3H), 3.46 (m, 2H), 3.74 (s, (CH2C!2:M 3H), 6.65 (dd, 1H), 6.91 (d, 1 H), 7.07-7.10 (m, 1 H), eOH=9:1) 7.36-7.40 (m, 1H), 7.45-7.49 (m, 1H), 7.73 (dd, 1H),

8.12 (s, 1H), 8.18 (s, 1H), 8.61 (d, 1H), 8.72-8.77 (m, 1H), 11.68 (s, 1H)

1.25-1.37 (m, 2H), 1.62-1.79 (m, 3H), 1.81-1.9 (m,-20 Ms : 511 2H), 2.16 (s, 3H), 2.75-2.85 (m, 5H), 3.76 (s, 3H), 3.8- 3.88 (m, 2H), 6.45-6.55 (m, 1H), 6.6-6.67 (m, 1 H), 7.02-7.12 (m, 1 H), 7.25-7.35 (m, 1H), 7.4-7.5 (m, 1H), 7.67-7.78 (m, 1 H), 8.1 (s, 1H), 8.19 (brs, 1H) 8.5-8.62 (m, 1H), 8.66-8.8 (m, 1H), 11.6 (s, 1H)

2.17 (s, 3H), 2.29-2.39 (m, 3H), 2.45-2.56 (m, 4H), 2.7-21 Ms : 526 (t, 2H), 3.76 (s, 3H), 4.09 (t, 2H), 6.52 (dd, 1 H), 6.66 (d, 1H), 7.06 (dd, 1H), 7.31 (dd, 1H), 7.45 (d, 1H), 7.71 (dd, 1H), 8.1 (s, 1H), 8.19 (s, 1H), 8.5-8.6 (m, 1H), 8.67-8.75 (m, 1H), 11.6 (s, 1H)

2.24 (s, 3H), 2.42-2.5 (m, 4H), 2.8 (d, 3H), 2.94-3.0-22 Ms : 482 (m, 4H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.93 (d, 1H), 7.07-7.14 (m, 1H), 7.34-7.4 (m, 1 H), 7.45 (d, 1H), 7.73 (dd, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 8.61 (dd, 1 H), 8.7-8.77 (m, 1 H), 11.7 (s, 1 H)

1.67-1.76 (m, 1H), 2.0-2.1 (m, 1H), 2.25-2.31 (m, 3H),-23 Ms : 482 2.8 (d, 3H), 2.85-2.91 (m, 1H), 3.04-3.12 (m, 1H), 3.14-3.3 (m, 3H), 3.7 (s, 3H), 6.26 (dd, 1H), 6.91 (d, 1 H), 7.01-7.04 (m, 1 H), 7.07 (dd, 1H), 7.32 (dd, 1 H), 7.72 (d, 1H), 8.14 (s, 1H), 8.17 (s, 1 H), 8.63 (d, 1 H),

8.7-8.78 (m, 1H), 11.6 (s, 1H) 55

1.35-1.57 (m, 8H), 1.7-1.78 (m, 2H), 2.81 (d, 3H),-24 Ms : 550 3.46-3.52 (m, 2H), 3.74 (s, 3H), 6.65 (dd, 1 H), 6.91 (d, 1H), 7.05-7.12 (m, 1 H), 7.34-7.42 (m, 1H), 7.46 (d, 1H), 7.73 (dd, 1H), 8.11 (s, 1H), 8.18 (s, 1H), 8.62 (dd, 1H),8.71-8.78 (m, 1H), 11.7 (s, 1 H) -25 DMS0-d6: 1.48-1.58(m, 2H), 1.65-1.72(m, 4H), 1.90-

536 1.97(m, 2H), 2.07-2.14(171, 1H), 2.49-2.55(m, 4H), [M+1]+ 2.70-2.77(m, 2H), 2.79(d, 3H), 3.60-3.65(m, 2H), 3.75(s, 3H), 6.48(dd, 1H), 6.63(d, 1 H), 7.03-7.09(m, 1H), 7.28-7.34(m, 1H), 7.39(d, 1H), 7.71 (dd, 1H), 8.09(s, 1H), 8.11(s, 1H), 8.55-8.65(m, 1H), 8.69- 8.73(m, 1H), 11.59(s, 1H)

-26 DMS0-d6: 2.80(d, 3H), 2.84-2.89(m, 4H), 3.04-

468 3.08(m, 4H), 3.76(s, 3H), 6.47(dd,1H), 6.62(dd, 1H), [M+1]+ 7.04-7.10(m, 1H), 7.28-7.35(m, 1H), 7.40(d, 1 H), 7.69 -7J3(m, 1H), 8.09(s, 1 H), 8.12(s, 1H), 8.55-8.63(m, 1H), 8.68-8.73(m, 1H), 11.59(s, 1H)

N (an aliphatic NH is hidden) H -27 DMS0-d6: 2.80(d, 3H), 6.64-6.67(m, 1H), 7.01-

393 7.08(m, 2H), 7.15(d, 1H), 7.24-7.29(m, 2H), 7.44(d, [M+1]+ 1H), 7.69-7.73(m, 1H), 8.20(s, 1H), 8.65-8.73(m, 2H), 9.15(s, 1H), 11.06(s, 1H), 11.63(s, 1H) -28 DMS0-d6: 2.81 (d, 3H), 3.79(s, 3H), 6.67(d, 1H), 7.05-

407 7.10(m, 1H), 7.12(d, 1H), 7.17(d, 1H), 7.23(d, 1H), [M+1]+ 7.25-7.30(m, 1H), 7.50(d, 1H), 7J0-7.73(m, 1H),

8.20(s, 1H), 8.67(d, 1H), 8.70-8J5(m, 1H), 9.17(s, 1 H), 11.64(s, 1H) 56

The following 2-[5-Bromo-2-(substituted phenylamino)-pyrimidin-4-ylamino]-N-ethyl-benzamide are prepared from 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-ethyl-benzamide and the corresponding aniline following the procedure of Example 7A

57

DMSO-d6: 2.79 (d, 3H, J = 4.04 Hz), 3.10-3.20 (m,

8-2 m/z 513, 4H), 3.77 (s, 3H), 3.70-3.80 (m, 4H), 6.45-6.55 (m, 515 (M+1) 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)

DMSO-d6: 2.80(d, 3H), 3.83(s, 3H), 4.11 (t, 2H),

8-3 0.48 6.82(ddd, 1H), 7.03(dd, 1H), 7.15(dd, 1H), 7.44(dd,

(n-Hexane: 1H), 7.73(d, 1H), 7.93(dd, 1H), 8.13(s, 1H), 8.33 (s, AcOEt=4:1) 1H), 8.50(d, 1H), 8.70-8.77(m, 1H), 11.3(s, 1H).

2.79 (d, 3H), 3.79 (s, 3H), 6.75 (ddd, 1H), 7.0 (dd,

8-4 MS 1H), 7.05-7.12 (m, 1H), 7.3-7.36 (m, 1H), 7.62 (dd, 446, 448 1H), 7.69 (dd, 1H), 8.2 (s, 1H), 8.29 (s, 1H), 8.45 (d,

1H), 8.66-8.73 (m, 1H), 11.4 (brs, 1H).

The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-N-ethyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-yIamino)-N-ethyl-benzamide and the corresponding aniline following the procedure of Example 7A

-58-

59 -

Rf DMSO: 1.11 (t, 3H), 1.60-1.69 (m, 1H), 1.88-1.96 (m,

9-6 (AcOEt:Me 2H), 2.19 (s, 3H), 2.55-2.68 (m, 2H), 3.30-3.45 (m,

OH= 4:1) 2H), 3.75 (s, 3H), 4.33-4.43 (m, 1H), 6.54 (dd, 1 H),

0.050 6.65 (d, 1H), 7.07 (dd, 1 H), 7.30 (dd, 1 H), 7.43 (d, 1 H), 7.71 (dd, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.54 (br.d, 1H), 8.75 (dd, 1H), 11.49 (s, 1H).

CDCI3: 1.34 (t, 3H), 1.62-1.68 (m, 2H), 1.93-2.18 (m,

9-7 0.44 8H), 2.37-2.40 (br, 2H), 2.74-2.86 (br, 3H), 3.20-3.23 (CH2CI2:M (m, 2H), 3.34 (br, 2H), 3.53 (q, 2H), 3.85 (s, 3H), 6.47 eOH=8:2) (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, 1 H), 8.22 (d, 1H), 8.42-8.53 (br, 1H), 10.91 (s, 1 H), 11.59- 11.75 (br, 1H)

The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-6,N-dimethyl- benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-6,N-dimethyl-benzamide and the corresponding aniline following the procedure of Example 7A

60

The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-5-fluoro-N-methyl- benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl- benzamide and the corresponding aniline following the procedure of Example 7A

61

12-1 Preparation of 7-l^'5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4- ylaminol-2-methyl-2,3-dihvdro-isoindol-1-one

Synthetic procedure for 7-(2.5-Dichloro-pyrimidin-4-ylamino)-2-methyl-2.3-dihvdro-isoindol-1- one - 62 -

H-Methyl-7-nirto-2,3-dihydroisoindole-1-one. At room temperature, a solution of methyl 2- bromomethyl-6-nitrobenzoate (1.26 g, 4.63 mmol) in THF (13 mL) is treated with 2M soln. of methylamine in THF (14 mL), stirred for 5 h, diluted with EtOAc (100 mL), washed with sat. aqueous solution of NaHC03 (15 mL) and brine (15 mL), dried (MgS04), and evaporated. A flash chromatography (30 g of silica gel; CH2C.2/EtOAc 1:1) gives N-Methyl-7-nirto-2,3- dihydroisoindole-1-one (0.561 g, 2.92 mmol) in 63%. Yellow solid. Rf (C^C^/EtOAc 1:1) 0.46.

¹H-NMR (400 MHz, CDCI₃) 3.21 (s), 4.44 (s), 7.63 - 7.69 (m, 2 H), 7.70 - 7.75 (m, 1 H).

7-Amino-H-methyl-2,3-dihydroisoindole-1-one. At room temperature, a solution of N-Methyl-7- nirto-2,3-dihydroisoindole-1-one (561.0 mg, 2.92 mmol) in EtOAc (8.4 mL) is treated with SnCl2'2H2θ (2.68 g), stirred at 80°C under reflux for 5 h, and treated with 30 mL of 5N NaOH at 0°C. After the both layers are separated, the aqueous layer is extracted with EtOAc (2 x 8 mL), the combined extracts are washed with brine (5 mL), dried (MgSθ4), and evaporated to give 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (455.9 g, 2.81 mmol) in 96%. Yellow solid.

Rf (CH₂CI₂/EtOAc 1:1) 0.53. 1 H-NMR (400 MHz, CDCI3) 3.12 (s), 4.28 (s), 5.20 (br. s), 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-dichloropyrimidin-4-yl)amino-N-methyl-2,3-dihydroisoindole-1-one. At 0°C, 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 with 60% NaH (89.8 mg), stirred at the same temperature for 1.5 h, treated with a solution of 2,4,5-trichlropyrimidine (0.557 g) in DMF (3.5 mL), stirred for 1 h, and warmed to room temperature. After furthermore stirring for 13 h, the mixture is treated with sat. aqueous NH4CI (6 mL), and the resulting brown precipitates are collected by a filtration, followed by washing with H2O, hexane, and CH3CN to give 7-(4-Amino-2,5-dichloropyrimidin-4-yl)amino-N- methyl-2,3-dihydroisoindole-1-one (130.2 g, 0.416 mmol) in 26%. Brown solid. Rf

(CH₂CI₂/EtOAc 1:1) 0.50. ¹H-NMR (400 MHz, CDCI3): 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 (br. s). 63 -

The following 7-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-2-methyl-2,3- dihydro-isoindol-1-one are prepared from 7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methyl-2,3- dihydro-isoindol-1-one and the corresponding aniline following the procedure of Example 7A. 7-r5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino1-2-methyl-2.3- dihvdro-isoindol-1 -one

¹H-NMR (400MHz, DMSO-d6, δ): 3. (s, 3H), 3.13-3.17 (m, 4H), 3.75 (s, 3H), 3.34-3.78 (m, 4H), 4.46 (s, 2H), 6.54 (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)⁺

The following 7-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-2-methyl-2,3- dihydro- isoindol-1-ones are prepared from 7-(2,5-Dichloro-pyrimidin-4-ylamino)- 2-methyl-2,3-dihydro- isoindol-1-one and the corresponding aniline following the procedure of Example 2:

64

65

DMSO-d₆: 2.19-2.42 (m, 4H), 2.65-2.89 (m, 3H), 3.07

12-6 MS (s, 3H), 3.11-3.30 (m, 1H), 3.48-3.61 (m, 2H), 3.62- m/z 3.71 (m, 1H), 3.75 (s, 3H), 3.75-3.83 (m, 2H), 4.47 (s, 536 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

(brs, 1H), 10.57 (s, 1H).

The following 7-(5-Chloro-2-(subst.phenylamino) -pyrimidin-4-ylamino)-2-ethyl-2,3- dihydroisoindol-1-ones are prepared from 7-(2,5-Dichloro-pyrimidin-4-ylarnino)-2- ethyl-2,3- dihydro-isoindol-1-one and the corresponding aniline following the procedure of Example 2:

Example 7B: 2-r5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino1-N- methyl-benzamide (alternative synthesis to Example 7A)

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 are added Et₃N (2.06 mL, 14.8 mmol) and isobutyl chloroformate (1.7 mL, 12.8 mmol) at -5°C. After stirring at the same temperature for 30 min, the reaction mixture is further stirred at room temperature for 1 hour and then H₂0 is added to the reaction mixture. The resulting precipitate is collected by filtration, 66

washed with H₂0, and dried under reduced pressure to give an intermediate (4.80 g) (10.96 mmol, 91%) as yellow solid.

NMR (400MHz, 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 = 9.08 Hz), 8.26 (d, 1H, J = 8.56Hz), 12.60 (s, 1H).

To a 1 M solution of methylamine in THF (560 μl, 0.56 mmol) is added 82 mg of the obtained intermediate (0.187 mmol) followed by 1M solution of NaHMDS in THF (560 μl, 0.56 mmol) dropwise. After the reaction mixture is stirred for 10 minutes, 5 mL of H₂0 is added and extraction is performed with AcOEt. The organic layer is washed with brine, dried over Na₂S0₄, 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. Data are given in Example 7A.

By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained as identified below.

67

68 -

The following 2-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-N-methyl-5- pyrrolidin-1 - yl-benzamides are prepared from 2-(5-Chloro-2-methy!-pyrimidin-4- ylamino)-N-methyl-5- pyrrolidin-1 -yl-benzamide and the corresponding aniline following the procedure of Example 2:

- 69

15-3 DMSO-d6: 1.94-1.99(m, 4H), 2.78(d, 3H), 3.09-

538 3.15(m, 4H), 3.22-3.27(m, 4H), 3.73-3.77(m, 4H), [M+1]⁺ 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)

The following 2-[5-Chloro-2-(4-fluoro-2-methoxy-phenylamino)-pyrimidin-4- ylamino]-5-subst- N-methyl-benzamide are prepared from the corresponding aniline following the procedure of Example 2:

- 70

Example 16B

CDCI₃: 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).

Example 16C

CDCI₃: 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 (brs, 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).

The following 2-(5-Chloro-2-(subst.phenylamino)-pyrimidin-4-ylamino)-5-fluoro-N-methyl- benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl- benzamideand the corresponding aniline following the procedure of Example 2: - 71

The following 2-[5-chloro-2-(subst.phenylamino)-pyrimidin-4-ylamino]-N-isopropyl-benzene- sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-isopropyl- benzenesulfonamide and the corresponding aniline following the procedure of Example 7A

72

73-

74 H),

- 75 -17 0.23 DMSO-d6 : 0.93(d, 6H), 1.24-1.57(m, 4H), 1.69- (n-hexane: 1.78(m, 2H), 1.98-2.04(m, 1H), 2.15-2.33(m, 5H), AcOEt=1 :1) 2.70-2.80(m, 1 H), 3.74(s, 3H), 3.91-3.94(m, 1H), 4.05-4.09(m, 1 H), 6.46-6.49(m, 1H), 6.63(d, 1 H), 7.18-7.22(m, 1H), 7.42-7.46(m, 2H), 7.80(d, 1H),

7.89(d, 1H), 8.17(s, 1H), 8.25(s, 1 H), 8.42 -8.44(m, 1H), 9.31 (s, 1H) -18 0.48 DMSO-d6 : 0.93(d, 6H), 1.03(t, 3H), 1.13(t, 3H), 1.42- (n-hexane: 1.81(m, 4H), 2.57-2.83(m, 4H), 3.17-3.41 (m, 4H), AcOEt=1:1) 3.65-3.75(m, 1H), 3.80(s, 3H), 4.21 (bs, 1H), 6.42- 6.47(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, 1 H), 7.89(d, 1 H), 8.16(s, 1H), 8.47 -8.49(m, 1H), 9.31(s, 1 H)

CDCI3: 1.45-1.62 (m, 2H), 1.72-1.78 (m, 1 H), 1.82--19 0.44 1.90 (m, 1H), 2.40-2.46 (m, 1H), 2.61-2.75 (m, 2H), (CH2CI2:M 3.75-3.70 (m, 2H), 3.76 (s, 3H), 6.45 (dd, 1H), 6.62 (d, eOH=9:1) 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 (br, 1H), 8.16 (s, 2H), 8.43-8.52 (m, 1H), 9.31 (s, 1H)

DMS0-d6 : 0.94 (d, 6H), 1.73-1.82 (m, 1H), 2.23-2.33-20 Ms : 547 (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, 1 H), 7.81 (d, 1H), 7.82-7.94 (m, 1H), 8.16 (s, 1H), 8.22 (brs, 1H), 8.38-8.48 (m, 1H), 9.3 (brs, 1H) -21 DMS0-d6 : 0.92 (d, 6H), 1.61-1.71 (m, 2H), 1.86-1.96

Ms : 579 (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, 1 H), 7.39-7.46 (m, 1 H), 7.81 (dd, 1 H), 7.84-7.92 (m, 1H), 8.21 (s, 1 H), 8.36-8.42 (m, 1 H), 8.62 (s, 1H), 9.28 (s, 1H)

76

-77

78

The following 2-[5-chloro-2-(subst.phenyiamino)-pyrimidin-4-ylamino]-N-methyl-benzene- sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-methyl- benzenesulfonamide and the corresponding aniline following the procedure of Example A

-79

-80

-81 -

-82

83

DMSO-d6: 2.42-2.45 (m, 3H), 3.83 (s, 2H), 6.8 (ddd,-23 Ms:438 1H), 7.02 (dd, 1 H), 7.3-7.36 (m, 1 H), 7.58-7.64 (m, 1H), 7.74-7.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1 H), 8.18 (brs, 1 H), 8.31 (s, 1 H), 8.41 (d, 1H), 9.3 (brs, 1 H)

DMSO-d6: 2.41-2.45 (m, 3H), 3.79 (s, 2H), 6.74 (ddd,-24 Ms:438 1 H), 7.0 (dd, 1 H), 7.22-7.28 (m, 1 H), 7.49-7.55 (m, 1 H), 7.6 (dd, 1H), 7.75-7.8 (m, 2H), 8.21 (s, 1H), 8.37 (brs, 1H), 8.39-8.45 (m, 1H), 9.34 (brs, 1H)

DMS0-d6: 1.24-1.38 (m, 2H), 1.64-1.8 (m, 3H), 1.83--25 Ms:547 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, 1 H), 7.2-7.25 (m, 1H), 7.41 (d, 1 H), 7.43-7.5

(m, 1 H), 7.74-7.8 (m, 2H), 8.16 (s, 1 H), 8.26 (brs, 1 H) 8.44-8.5 (m, 1H), 9.34 (brs, 1 H)

DMS0-d6: 1.18-1.3 (m, 2H), 1.56-1.7 (m, 3H), 1.8--26 Ms:547 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, 1 H), 6.93 (d, 1H), 7.25 (dd, 1 H), 7.51-7.6 (m, 2H), 7.7-7.9 (m, 2H), 8.09 (brs, 1H), 8.28 (s, 1H), 8.45 (d, 1 H), 9.31 (brs, 1 H)

DMS0-d6: 1.62-1.72 (m, 2H), 1.9-1.99 (m, 2H), 2.3--27 Ms:533 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, 1 H), 6.52 (dd, 1H), 6.65 (d, 1H), 7.19-7.25 (m, 1 H), 7.41 (d, 1 H), 7.43-7.49 (m, 1H), 7.74-7.8 (m, 2H), 8.16 (s, 1 H), 8.27 (brs, 1H), 8.42-8.5 (m, 1H), 9.34 (brs, 1H)

DMS0-d6: 0.96-1.2 (m, 2H), 1.75-1.9 (m, 1H), 2.2-2.3-28 Ms:547 (m, 1 H), 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, 1 H), 7.18-7.25 (m, 1H), 7.39-7.52 (m, 2H), 7.73-7.83 (m, 2H), 8.17 (s,

1H), 8.27 (brs, 1 H), 8.44-8.51 (m, 1 H), 9.35 (brs, 1H) - 84 -

DMSO-d6: 1.74-1.83 (m, 1H), 2.23-2.31 (m, 1 H), 2.28-29 Ms:519 (s, 3H), 2.35-2.4 (m, 1 H), 2.41-2.45(m, 3H), 2.58-2.63 (m, 1 H), 2.63-2.7 (m, 1 H), 2.78-2.83 (m, 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.43 (dd, 1 H), 6.58 (d, 1 H),

7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.44-7.51 (m, 1 H), 7.73-7.83 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H), 8.43- 8.52 (m, 1H), 9.34 (brs, 1 H)

DMS0-d6: 1.04 (t, 3H), 1.74-1.82 (m, 1 H), 2.23-2.33-30 Ms : 533 (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, 1 H), 6.44 (dd, 1H), 6.59 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H),

7.44-7.51 (m, 1 H), 7.73-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H), 8.44-8.51 (m, 1H), 9.34 (brs, 1H)

DMS0-d6: 2.23(s, 3H), 2.38-2.47 (m, 7H), 2.87-2.93-31 Ms : 518 (m, 4H), 3.75 (s, 3H), 6.63 (dd, 1H), 6.93 (d, 1 H), 7.22-7.28 (m, 1H), 7.42 (d, 1H), 7.48-7.54 (m, 1H),

7.76-7.84 (m, 1 H), 8.2 (s, 1 H), 8.25(s, 1H), 8.43 (dd, 1H) 9.29 (s, 1 H)

DMSO-d6: 1.35-1.55 (m, 8H), 1.66-1.75 (m, 2H),-32 Ms : 586 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, 1 H),

7.48-7.54 (m, 1H), 7.76-7.87 (m, 1H), 8.16 (s, 1H), 8.25 (s, 1 H), 8.43 (dd, 1H) 9.29 (s, 1H)

DMSO-d6: 1.62-1.71 (m, 1H), 1.95-2.04 (m, 1H),-33 Ms : 518 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, 1 H), 7.07-7.13 (m, 1 H), 7.13-7.2 (m, 1H), 7.4- 7.48 (m, 1H), 7.75 (dd, 1H), 8.06 (brs, 1 H), 8.18 (s, 1 H), 8.4 (d, 1H)

DMSO-d6: 2.02 (m, 1 H), 2.42-2.46 (m, 3H), 2.71-2.91-34 Ms : 546 (m, 4H), 3.44-3.51 (m, 4H), 3.76 (s, 3H), 6.66 (dd, 1 H), 6.94 (d, 1 H), 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 (brs, 1H). - 85 -

The following 2-[5-chloro-2-(sϋbst.phenylamino)-pyrimidin-4-ylamino]-N-sec-butyl-benzene- sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-sec-butyl- benzenesulfonamide and the corresponding aniline following the procedure of Example 7A

- 86 -

The following 2-[5-chloro-2-(subst.phenylamino)-pyrimidin-4-ylamino]-N-/^'so-butyl-benzene- sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-yIamino)-N-sec-butyl- benzenesulfonamide and the corresponding aniline following the procedure of Example 7A

87 -

The following 2-[5-chloro-2-(subst.phenylamino)-pyrimidin-4-ylamino]-N-(1 -ethyl-propyl)- benzenesulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-(1-ethyl- propyl)-benzenesulfonamide and the corresponding aniline following the procedure of Example 7A

88

- 89

The following 2-[5-chloro-2-(subst.phenylamino)-pyrimidin-4-ylamino]-N-/so-butyl-benzene- sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-cyclobutyl- benzenesulfonamide and the corresponding aniline following the procedure of Example 7A

- 90 -

24-1 DMSO-d6 : 1.37-1.48(m. 2H), 1.69-1.91 (m, 4H), 3.09-

0.35 3.12(171, 4H), 3.63-3.74(m, 1H), 3.76(s, 3H), 6.43-

(n-hexane: 6.45(m, 1H), 6.63(d, 1 H), 7.18-7.22(m, 1 H), 7.41-

AcOEt=1:1) 7.47(m, 2H), 7.76-7.78(m, 1H), 8.17-8.24(m, 3H), 8.46(d, 1H), 9.33(s, 1H)

24-2 DMSO-d6: 1.37-1.93(m, 10H), 2.18(s, 3H), 2.59-

0.46 2.62(m, 1H), 3.60-3.74(m, 1H), 3.77(s, 3H), 4.32-

(MeOH: 4.36(m, 1H), 6.46-6.49(m, 1H), 6.62(d, 1H), 7.16-

CH₂CI₂=3:7) 7.20(m, 1H), 7.41-7.44(m, 2H), 7J5-7J7(m, 1H),

8.16(s, 1H), 8.22 (bs, 1H), 8.40-8.42(m, 1H), 9.30(bs, 1 H)

24-3 0.46 CDCI₃: 1.45-1.75(m, 5H), 1.94-2.06(m, 6H), 2.29-

(MeOH: 2.37(m, 1H), 3.21-3.56(m, 4H), 3.72-3.81 (m, 1H),

CH₂CI₂=1 :4) 3.86(s, 3H), 4.55-4.65(m, 1 H), 4.90(d, 1 H), 5J2(d, 1H), 6.07(bs, 1H), 6.15(bs, 1H), 7.18-7.22(m, 2H), 7.52-7.56(m, 1H), 7.89-7.94(m, 2H), 8.08(s, 1H),

8.50(d, 1H), 9.00(s, 1H)

- 91

DMSO-d6 : 1.2-1.38 (m, 4H), 1.42-1.6 (m, 6H), 1.88-

25-2 Ms : 587 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, 1 H), 7.18-7.24 (m, 1 H), 7.38-7.47 (m, 1 H), 7.77-7.82 (m, 1H), 7.88-7.96 (m, 1 H), 8.17 (s,

1 H), 8.22 (s, 1 H), 8.36-8.46 (m, 1H), 9.31 (s, 1H)

The following 5-Chloro-N²-(substituted phenyl)-N⁴-[2-(propane-1-sulfonyl)-phenyl]-pyrimidine- 2,4-diamine are prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-1-sulfonyl)-phenyl]- amine and the corresponding aniline following the procedure of Example 7A

92

93 H)

-94'

-95

96-

97-

-98

- 99

The following 5-Chloro-N²-(substituted phenyl)-N -[2-ethanesuIfonyi-phenyl]-pyrimidine-2,4- diamine are prepared from (2,5-Dichloro-pyrimidin-4-yI)-[2-ethanesulfonyl-phenyl]-amine and the corresponding aniline following the procedure of Example 7A

-100

101 -

Column: YMC CombiScreen ODS-A (5um, 12nm), 50 x 4.6 mm I.D.

Flow rate: 2.0 ml/min

Eluent: A) TFA/water (0.1/100), B) TFA/acetonitrile (0.1/100)

Gradient: 5-100%B (0-5min)

Detection: UV at 215nm

The following 5-Chloro-N -(substituted phenyl)-N -[2-(propane-2-sulfonyl)-phenyl]-pyrimidine- 2,4-diamine are prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]- amine and the corresponding aniline following the procedure of Example 7A

102-

103 1H),

104

-105-

CDCI₃: 1.11 (d, 6H, J=6.55), 1.31 (d, 6H, J=7.05),-14 MS 2.82-2.68(m, 5H), 3.20-3.17(m, 4H), 3.28-3.17(m, 559 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)

CDCI₃: 1.31 (d, 6H, J=7.05), 1.97-1.85(m, 2H), 2.17--15 MS 1.98(m, 2H), 2.35-2.25(m, 1H), 2.75(m, 2H), 559 3.24(sept, 1H), 3.65(d, 2H), 3.88(s, 3H), 5.30 (bs, 1H), 5.48(bs, 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)

CDCl₃: 1.31 (d, 6H, J=7.06), 1.46-1.43(m, 1H), 1.79--16 MS 1.68(m, 2H), 2.08-1.99(m, 2H),2.99-2.88(m, 2H), 532 3.24(sept, 1H), 3.51-3.45(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) -17 CDCI₃: 1.31 (d, 6H, J=6.96), 2.18-2.12(m, 2H),

MS 3.24(sept, 1H),3.37-3.32(m, 2H), 3.39(s, 3H), 3.43(d, 532 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(bs, 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) -106

107

108

109-

110-

111 -

112

113

114

Ex MS NMR (400MHz), CDCI₃, δ ppm

No

1.05 (t, 3H), 1.69-1.78 (m, 2H), 2.86-2.95 (m, 1H), 4-7 MS 3.16-3.25 (m, 1H), 6.57-6.68 (m, 2H), 7.17 (dd, 1H), 435, 436 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)

0.94 (t, 3H), 1.69-1.80 (m, 2H), 2.38 (s, 3H), 2.55-2.64 4-8 MS (m, 4H), 3.02-3.08 (m, 2H), 3.22-3.29 (m, 4H), 3.88 (s, 549, 551 3H), 6.55 (ddd, 1H), 6.60-6.66 (m, 1H), 7.13-7.18 (m, 1H), 7.34 (br.s, 1H), 7.44 (d, 1H), 8.10 (s, 1H), 8.10- 8.23 (m,2H), 8.88 (s,1H).

115

Example 36 (Intermediates for Left anilines)

36-1 Preparation of 2-amino-Λ/-methyl-benzamide

To a suspension of 16.3 g (100 mmol) of isatoic anhydride in 100mL of H₂0 is added portionwise 100mL of 2N methylamine - tetrahydrofuran solution (200 mmol) at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic layer is washed with H₂0 and brine, dried over Na₂S0₄, and concentrated under 116

reduced pressure to give 13.79 g of desired product, 2-amino- v^*-methyl-benzarnide (92 mmol, 92%) as colorless solid.

NMR (400MHz, CDCI3, δ): 2.97 (d, 3H, J = 4.52 Hz), 5.49 (bs, 1H), 6.07 (bs, 1 H), 6.64 (ddd, 1 H, J = 8.04, 7.56, 1.0 Hz), 6.68 (dd, 1 H, J = 8.32, 1.0 Hz), 7.20 (ddd, 1 H, J = 8.32, 7.56, 1.52 Hz), 7.29 (dd, 1 H, J = 8.04, 1.52 Hz).

36-2

2-(2.5-Dichloro-pyrimidin-4-ylamino)-A/-methyl-benzamide

To a solution of 15.0 g (99.8 mmol) of 2-amino-Λ/-methyl-benzamide in DMF (300mL) are added 2, 4, 5-trichloropyrimidine (23.8 g, 130 mmol) and potassium carbonate (17.9 g, 130 mmol). The reaction mixture is stirred at 75°C for 5 hours, cooled to room temperature, and then poured into H 0 (600mL). The resulting precipitate is collected by a filtration followed by washing with 50% aqueous CH₃CN (200mL) and dried under reduced pressure (40°C, 10 hours) to give desired 2- (2,5-dichloro-pyrimidin-4-yl-amino)-Λ/-methyl-benzamide as ivory solid (26.4 g, 88.9 mmol, 89%).

NMR (400MHz, DMSO-d6, δ): 2.81 (d, 3H, J = 4.52 Hz), 7.22 (dd, 1 H, J = 8.56, 8.04 Hz), 7.60 (ddd, 1 H, J = 8.56, 8.56, 1.0 Hz), 7.81 (dd, 1H, J = 8.04, 1.0 Hz), 8.48 (s, 1 H), 8.52 (d, 1H, J = 8.56 Hz) 8.80-8.90 (m, 1 H), 12.18 (s, 1H).

According the manner described above, the following compounds are prepared.

36-3 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide

- 117 -

NMR (400MHz, DMSO-d₆, δ): 2.81 (d, 3H), 7.23(ddd, 1 H, J=7.54, 7.54, 1.0Hz), 7.59(ddd, 1H, J=7.93, 8.06, 1.52Hz),7.79(dd, 1 H, J=7.8, 1.52Hz), 8.47(dd, 1 H J=8.06, 1.0Hz), 8.55(s, 1 H), 8.81-8.87(m, 1H), 12.0(brs, 1 H). Rf: 0.46 (n-Hexane: AcOEt=7:3).

36-4 2-(2.5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide

NMR (400MHz, CDCI₃, δ): 1.28 (t, d=7.04, 3H), 3.48-3.57 (m, 2H), 6.22 (br. s, 1H), 7.11-7.17 (m, 1H), 7.51 (dd, J=1.0, 8.04, 1 H), 7.53-7.61 (m, 1H), 8.22 (s, 1H), 8.69-8.74 (m, 1 H), 11.66 (br. s, 1 H). Rf : 0.60 (Hexane :AcOEt=1 :1).

36-5

Preparation of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide

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 at room temperature for 23 hours. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane - ethyl acetate gradient) to afford the title compound as a slightly yellow solid. 1H-NMR (CDCIs), δ (ppm): 2.67 (d, 3H), 4.79 (q, 1H), 7.26 (s, 1H), 7.29 (ddd, 1 H), 7.66 (ddd, 1 H), 7.95 (dd, 1 H), 8.37 (s, 1 H), 8.48 (d, 1H), 9.52 (s, 1 H). Rf (n-hexane : ethyl acetate = 10:3): 0.33.

According to the manner described above, the following compound is prepared. - 118 -

36-6 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide

¹H-NMR (400MHz, CDCI_3> δ);2.67(d, 3H),4.97-5.04(m, 1 H), 7.29(ddd, 1H, J=7.54, 7.54, 1.0Hz), 7.66(ddd, 1H, =7.93, 8.08, 1.48Hz),7.94(dd, 1H, =8.04, 1.52Hz), 8.24(s, 1 H), 8.51 (dd, 1H J=8.06, 1.0Hz), 9.64(brs, 1 H). Rf: 0.45 (n-Hexane: AcOEt=4:1).

36-7 2-(2.5-Dichloro-pyrimidin-4-ylamino)-N-isopropyl-benzenesulfonamide

To a solution of 2-amino-N-isopropyl-benzenesulfonamide (16.1g, 75.1mmol) in DMI (150mL) is added sodium hydride (6.6g, 165.3mmol) portionwise at 0°C. After the mixture is stirred at room temperature for one hour, 2, 4, 5-trichloropyrimidine (20.7g, 112.7mmol) is added at 0°C. After further stirring at room temperature for 5 hrs, water is added and the mixture is extracted with AcOEt three times. Organic layer 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 afford the title compound as pale brown solid (10.2g, 38%).

¹H-NMR (400MHz, CDCI₃, δ);1.06(d, 6H), 3.43-3.53(m, 1 H), 4.38(d,1 H), 7.29(dd, 1H), 7.66(dd, 1H), 7.98(d, 1H), 8.29(s, 1 H), 8.51 (d, 1 H), 9.51 (brs, 1 H). Rf: 0.45 (n-Hexane:AcOEt=4:1)

The following compounds are prepared in the same manner described above. - 119

36-10

Preparation of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide:

2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCI₃ (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-hexane : ethyl acetate = 1 :1). ¹H-NMR (400MHz, CDCI₃), δ (ppm): 2.67 (d, 3H), 4.6- 4.7 (m, 2H), 7.41 (t, 1H), 7.7 (t, 1H), 8.04 (d, 1 H), 8.15 (d, 1 H), 9.21 (s, 1 H), 11.2 (s, 1 H).

36-11

Preparation of (2.5-Dichloro-pyrimidin-4-yl)-r2-(propane-1 -sulfonvP-phenvπ-amine 120 -

To a solution of 2-(Propane-1-sulfonyl)-phenylamine (3.69g, 18.5 mmol) of N,N- dimethylformamide (40mL), sodium hydride (1.48g, 37 mmol) is added portionwise at 0°C. After stirring, 2,4,5-trichloropyrimidine (2.1mL, 18.5 mmol) is added. The mixture is stirred at 0°C for 30 minutes and is further stirred at room temperature for 7hrs. After adding saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane - ethyl acetate gradient) to afford the title compound as colorless solids.

¹H-NMR (CDCIs), δ (ppm): 0.99 (t, 3H), 1.77 (d, 2H), 3.07-3.11 (m, 2H), 7.26 (s, 1 H), 7.32 (ddd, 1 H), 7.73 (ddd, 1 H), 7.95 (dd, 1 H), 8.31 (s, 1 H), 8.61 (dd, 1H), 9.94 (bs, 1 H). Rf (n-hexane : ethyl acetate = 3:1): 0.63

According to the manner described above, the following compounds are prepared.

121 -

Example 36-16

Synthesis of substituted amines which are commercially not available:

Preparation of 3-amino-4'-methoxy-4-methylbiphenyl

To a solution of 4-methoxyphenyl-boronic acid (500 mg, 3.29 mmol) in toluene (5.2 mL) and ethanol (1.3 mL), 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) are added and stirred at 100 C for 7 hours. The mixture is poured into water and extracted with ethyl acetate two times. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane : ethyl acetate = 5 : 1 ) to afford the 4^*-methoxy-4-methyl-3-nitro- biphenyl as a yellow solid.

¹H-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 charcoal (63 mg, 0.059 mmol) in methanol (6 mL) is stirred under hydrogen atmosphere for

12 hours. Palladium catalyst is removed by filtration and the resulting solution is evaporated in vacuo to afford the title compound.

¹H-NMR (δ, ppm) : 2.20 (s, 3H), 3.84 (s, 3H), 6.87 (d, 1H), 6.89 (dd, 1 H), 6.95 (d, 2H), 7.09 (d,

1H), 7.48 (d, 2H). Rf (n-hexane : ethyl acetate = 1 :1): 0.50.

Preparation of 4-(3-amino-4-methylbenzoyl^')-piperazine-1 -carboxylic acid tert-butyl ester - 122 -

To a solution of 4-methyl-3-nitro-benzoic acid (300 mg, 2.76 mmol), N-butoxycarbonyl- piperazine (340 mg, 1.83 mmol) in DMF (3.0 mL), triethylamine (300 μ L, 3.59 mmol), TBTU (800 mg, 2.49 mmol) and HOAt (270.5 mg,1.99 mmol) are added and stirred at room temperature for 24 hours. The mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n- hexane : ethyl acetate = 5 : 1) to afford 4-(4-methyl-3-nitrobenzoyl)-piperazine-1 -carboxylic acid tert-butyl ester as a colorless solid.

¹H-NMR (δ, ppm) : 1.47 (s, 9H), 2.64 (s, 3H), 3.28-3.88 (m, 8H), 7.42 (d, 1 H), 7.56 (dd, 1H), 8.03 (d, 1 H). Rf (hexane : ethyl acetate = 10:1): 0.13.

The title compound is obtained by reduction with hydrogen over 10% palladium on charcoal in methanol solution.

Preparation of 4-(3-amino-4-methylphenyl)-morpholine

To a solution of 4-bromo-1-methyl-2-nitrobenzene (225 mg, 1.04 mmol), morpholine (125 μ L,

1.25 mmol), and cesium carbonate (474.4 mg, 1.46 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 at 100°C for 5 hours. After cooling, the mixture is filtered to remove insoluble material.

The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane : ethyl acetate = 5 : 1) to afford 4-(4-methyl-3-nitrophenyl)-morpholine as a yellow solid.

¹H-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, 1 H). Rf (hexane : ethyl acetate = 5:1): 0.20.

Example 37: Synthesis of substituted amines which are commercially not available:

37-1

Preparation of 1-(3-Methoxy-4-nitro-phenyl)-piperdin-4-ol 123

To a suspension of piperidin-4-ol (2.79g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) in N,N-dimethylformamide (40 mL), 4-Fluoro-2-methoxy-1-nitro-benzene (4.0g, 23 mmol) is added and stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is collected by a filtration. The resulting solid is dried in vacuo at 50°C to afford 1-(3- methoxy-4-nitro-phenyl)-piperidin-4-ol (5.23g) as yellow solids in 89% yield. 1H-NMR (400MHz, CDCI₃, 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).

By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained.

124

-125

-126

127 -16 ⁿH-NMR (400MHz, CDCI₃): 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, 1 H), 6.33(d, 1H), 6.43(dd, 1 H) 8.00(d, 1 H). Rf 0.10 (AcOEt)

¹ H-NMR (400MHz, CDCI₃): 2.18-2.07 (m, 1H), 2.30-2.22 (m,-17 1 H), 3.38(s, 3H), 3.56-3.44(m, 4H),3.95 (s, 3H), 4.13 (ddd,1H), 5.96(d, 1 H), 6.12(dd, 1H) 8.03(d, 1 H). Rf 0.30 (AcOEt)

-18 'H-NMR (400MHz, CDCI₃): 1.46(s, 9H),1.81-1.68(m, 4H), 2.73(bs, 3H),3.07-2.97(m, 2H), 3.95(s,3H), 4.03-3.94 (m, 2H), 6.32(d, 1 H), 6.43(dd, 1 H) 8.00(d, 1H). Rf 0.55 (Hexane:AcOEt)

-19 ¹H-NMR (400MHz, CDCI₃): 3.60-3.57(m, 2H),3.68-3.65(m, 2H), 3.97(s, 3H),4.07(s, 2H), 6.17(bs, 1H), 6.26(d, 1H), 6.39(dd, 1H) 8.04(d, 1 H). Rf 0.85 (AcOEt)

128 -20 'H-NMR (400MHz, CDCI₃): 3.08(s, 3H), 3.54(dd, 2H),3.67(dd, 2H), 3.96 (s, 3H), 4.05(s, 2H), 6.25(d, 1 H), 6.38(dd, 1H) 8.03(d, 1 H) . Rf 0.30 (AcOEt)

-21 'H-NMR (400MHz, CDCI₃): 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, 1 H) . Rf 0.10 (AcOEt:MeOH=4:1)

-22 ¹ H-NMR (400MHz, CDCI₃): 3.90(s, 3H), 3.98(s, 3H), 3.98 (s, 3H), 6.56(s, 1H), 7.59(s, 1H) . Rf 0.605 (AcOEt)

-23 'H-NMR (400MHz, CDCI₃): 3.25-3.22 (m, 4H), 3.90-3.87 (m, 4H), 3.95(s, 3H), 6.48(s, 1H), 7.57(s, 1 H) . Rf 0.060 (Hexane:AcOEt=5:1)

129 -24 'H-NMR (400MHz, CDCI₃): 2.37 (s, 3H), 2.61 (bs, 4H),3.27 (bs, 4H), 3.88 (s, 3H), 3.95(s, 3H), 6.48(s, 1H), 7.56(s, 1H) Rf 0.10 (AcOEt:MeOH=5:1)

-25 'H-NMR (400MHz, CDCI₃): 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)

-26 'H-NMR (400MHz, CDCI₃): 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(d, 1H), 6.43(dd, 1H), 8.02(d, 1 H) . Rf 0.10 (AcOEt)

-27 'H-NMR (400MHz, CDCI₃): 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, 1 H), 6.43(dd, 1 H), 8.00(d, 1H) . Rf 0.070(AcOEt)

-28 'H-NMR (400MHz, CDCI₃): 1.16(d, 3H), 2.57(dd, 1 H), 3.00- 2.89 (m, 4H), 3.18-3.11 (m, 1 H), 3.75-3.68 (m, 2H),3.96 (s, 3H), 6.31 (d, 1H), 6.43(dd, 1H), 8.01 (d, 1 H) . Rf 0.070 (AcOEt)

130 -29 'H-NMR (400MHz, CDCI₃): 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)

-30 'H-NMR (400MHz, CDCI₃): 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)

-31 'H-NMR (400MHz, CDCI₃): 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)

-32 'H-NMR (400MHz, CDCI₃): 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)

- 131 -33 'H-NMR (400MHz, CDCI₃): 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, 1 H), 6.26(dd, 1H), 8.05(d, 1 H) . Rf 0.030 (AcOEt)

-34 'H-NMR (400MHz, CDCI₃): 2.54-2.23 (m, 4H), 2.67 (t, 2H), 3.29-3.23(m, 2H), 3.74(t, 4H), 3.94(s, 3H), 6.07(d, 1 H), 6.16 (dd, 1 H), 8.00(d, 1 H) . Rf 0.15 (AcOEt)

-35 Η-NMR (400MHz, CDCI₃): 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, 1 H), 6.55(d, 1H), 7.99(d, 1H) . Rf 0.10 (AcOEt)

-36 'H-NMR (400MHz, CDCI₃): 2.14(s, 3H), 3.87-3.34(m, 8H), 3.99 (s, 3H), 7.01(dd, 1 H), 7.16(d, 1 H), 7.88(d, 1H) . Rf 0.25 (AcOEt)

132 -37 'H-NMR (400MHz, CDCI₃): 3.49-3.37(m, 2H), 3.88-3.55(m, 6H), 3.99 (s, 3H), 7.00(dd, 1H), 7.16(d, 1 H), 7.87(d, 1 H) . Rf 0.50 (AcOEt)

-38 'H-NMR (400MHz, CDCI₃): 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, 1 H), 6.34 (d, 1 H), 6.44(dd, 1H), 6.90-6J9(m, 1H), 8.00(d 1H) . Rf 0.20 (AcOEt)

-39 'H-NMR (400MHz, CDCI₃): 1.44-1.34 (m, 2H),1.84-1.77 (m, 1 H), 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, 1 H), 6.42(dd, 1H), 8.00(d, 1H) . Rf 0.30 (AcOEt)

-40 Η-NMR (400MHZ, CDCI₃): 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, 1 H) . Rf 0.45 (AcOEt)

133-

134-

135

136

38

Preparation of 1 -r4-(4-Methoxy-3-nitro-phenv0-piperazin-1 -yll-ethanone

To a solution of 5-bromo-1-methoxy-2-nitrobenzene (300 mg, 1.29 mmol) in dioxane, 1 -acetyl piperazine (400mg, 3.12 mmol), cesium carbonate (1.0g, 3.07 mmol), palladium diacetate (29.0 mg, 0.129 mmol) and 2-(di-t-butylphosphino)biphenyl (77 mg, 0.258 mmol) are added and stirred at 100°C for 8 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane : ethyl acetate gradient) to afford 1-[4-(4-Methoxy- 3-nitro-phenyl)-piperazin-1-yl]-ethanone (319mg, 44%) as yellow solids. 1H-NMR (400MHz, CDCI₃, 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

Preparation of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one

To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065mol) in DMF (80 mL) are added 4-Fluoro-2-methoxy-1-nitro-benzene (10.0 g, 0.058 mol) and potassium carbonate - 137 -

(20.2 g), and the mixture is stirred at 70°C for 20 h. After a filtration, the filtrate is poured into H2O (ca. 300 mL), and the resulting precipitates are collected by a filtration followed by washing with H2O for several times to give title compound (8.98 g) in 61% yield. Orange solid. ¹ H-NMR (400 MHz, CDCI3, δ): 2.65-2.62 (4H, m), 3.81-3.78 (4H, m), 3.98 (3H, s), 6.34 (1H, of), 6.45 (1H, dd), 8.05 (1 H, GQ-

Preparation of 1 -H -(3-Methoxy-4-nitro-phenvπ-piperidin-4-yl1-4-methyl-piperazine

To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one (4.96g, 0.020mol) in dichloroethane (50 ml) is added N-methylpiperazine (2.7ml, 0.024 mol) at 0°C and the mixture is stirred at room temperature. After 4 h, sodium triacetoxy-borohydride (5.04g, 0.024mol) is added and the mixture is further stirred at room temperature for 24 h. After addition of 1N sodium hydroxide at 0 °C, the mixture is poured into water and extracted three times with dichloromethane. The organic layer is combined and extracted three times with 1N hydrochloride. The water layer is basified with 2N sodium hydroxide and extracted three times with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound as yellow solids (6.04g) in 91% yield.

¹ H-NMR (400 MHz, CDCI3. 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, ), 3.95 (3H, s), 6.31 (1H, d,), 6.42 (1H, dd), 8.00 (1 H, d).

_____

Preparation of 4'-Methoxy-4-methyl-3-nitro-biphenyl - 138 -

To a solution of 4-methoxyphenyl-boronic acid (500 mg, 3.29 mmol) in toluene (5.2 mL) and ethanol (1.3 mL), 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) are added and stirred at 100^°C for 7 hours. The mixture is poured into water and extracted with ethyl acetate two times. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane : ethyl acetate = 5 : 1) to afford the 4^*-methoxy-4-methyl-3-nitro- biphenyl (630mg, 79%) as a yellow solid.

'H-NMR (400MHz, CDCI₃, 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.

42

Preparation of 4-(2-Ethoxy-ethoxy)-1 -(3-methoxy-4-nitro-phenyl)-piperidine

To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-oI (300mg, 1.2 mmol) in N,N- dimethylformamide (3.0 mL), sodium hydride (1.52g, 3.8 mmol) is added. After stirring, 2- bromoethyl methyl ether (150μl, 1.6 mmol) is added and the mixture is further stirred at 70°C for 15 hours. After addition of saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane - ethyl acetate gradient) to afford 4-(2-Methoxy-ethoxy)-1-(3- methoxy-4-nitro-phenyl)-piperidine (111mg, 29%) as a yellow oil.

'H-NMR (400MHz, CDCI₃, 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 (n-hexane: AcOEt=1 :1).

According the procedure described above using appropriate alkyl halides, the following compounds are prepared.

139 -1 'H-NMR (400MHz, CDCI₃, δ, ppm) : 2.04-2.21 (m, 1 H), 2.63(t, 2H), 2.68(t, 2H), 3.42(t, 4H), 3.87(t, 4H), 3.96(s, 3H), 6.33(d, 1 H), 6.44(dd, 1 H), 8.02(d, 1 H). Rf 0.09 (AcOEt).

-2 'H-NMR (400MHz, CDCI₃, 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, 1 H), 8.00(d, 1 H). Rf 0.35 (n-hexane: AcOEt=1:1 )

Example : 43

2-Methoxy-4-(1 -methyl-piperidin-4-yloxy)-phenylamine 4-(3-Methoxy-4-nitro-phenoxy)-1 -methyl- piperidine

To a solution of 4-Fluoro-2-methoxy-1-nitro-benzene (10.3g, 60 mmol) in toluene (50 mL) and 25% KOH aq.(50mL), 4-hydroxy-1-methylpiperidine (13.8g, 120 mmol) and tetra-n-butyl ammonium bromide (3.87g, 12mmol) 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 layer is successively washed with dil.HCI and brine, dried over sodium sulfate, and evaporated in vacuo to afford the crude compound in quantitative yield (13.4g). - 140 -

Rf = 0.22 (methanol : dichloromethane = 1:4). Η-NMR (400 MHz, CDCI₃, 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, 1 H), 6.49 (dd, 1 H), 6.99 (d, 1H), 6.54 (d, 1 H), 7.99 (d, 1H).

Example : 44

2-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine

3-Methoxy-4-nitro-phenol

To a solution of 3-Fluoro-4-nitro-phenol (15.7g, 100 mmol) in THF (300 mL) , 30% KOMe in Methanol(49mL, 210mmol) is added at 0°C. The mixture is heated to gentle reflux for 18 hours.

4-f2-(3-Methoxy-4-nitro-phenoxy)-ethyl1-morpholine

To a solution of 3-Methoxy-4-nitro-phenol (1.69g, 10 mmol) in DMF (25 mL) , 4-(2- Chloroethyl)morpholine hydrochloride(2.05g, 11 mmol), K2C03(1.52g, 11 mmol), Kl(332mg, 2mmol) are added at room temperature. The mixture is heated to 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 then the organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in 90% yield (2.55g).

Rf = 0.11 (AcOEt only). ¹H-NMR (400 MHz, CDCI₃), δ (ppm): 2.56-2.61(m, 4H), 2.83(t, The reaction mixture is cooled to room temperature and quenched slowly with 1 NHCI aq at 0°C. The resulting mixture is extracted twice with ethyl acetate and then the organic layer is successively washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in 94% yield(15.9g).

Rf = 0.22 (methanol : dichloromethane = 1:4). ¹H-NMR (400 MHz, CDCI₃), δ (ppm): 3.95(s, 3H), 5.49(s, 1 H), 6.44 (dd, 1 H, =8.8, 2.52Hz), 6.54 (d, 1 H, J=2.52Hz), 7.96 (d, 1H J=8.6Hz). 141 -

3.72-3.76(m, 4H), 3.94(s, 3H), 4.18(t, 2H), 6.51 (dd, 1 H, J=9.08, 2.52Hz), 6.56 (d, 1H,

J=2.48Hz), 8.00 (d, 1 H =9.08Hz).

2H),

Example : 45

2-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine Acetic acid 4-methoxy-3-nitro-phenyl ester

To a solution of 4-Methoxyphenol (12.4g, 100 mmol) in AcOH (50 mL), Ac₂0 (50mL) is added at room temperature. The mixture is heated to gentle reflux for 1.5 hour. The reaction mixture is cooled to room temperature and c.HN0₃ (d=1.38, 10mL) is added slowly at 0 °C. The mixture is heated to 55°C for 1.5h. The reaction mixture is cooled to room temperature and quenched with water at OoC. The resulting solid is filtered on Buchner funnel to afford the crude compound in 76% yield (16.0g).

Rf = 0.59 (AcOEt : n-Hexane = 3:7). ¹ H-NMR (400 MHz, CDCI₃), δ (ppm): 2.31 (s, 3H), 3.96(s, 3H), 7.08 (d, 1H, J=9.04Hz), 7.31 (dd, 1H, J=9.04, 3.04Hz), 7.96 (d, 1 H J=3.04 Hz).

4-Methoxy-3-nitro-phenol

To a solution of Acetic acid 4-methoxy-3-nitro-phenyl ester (1.06g, 5 mmol) in EtOH (20 mL) , 1N NaOH aq (5.5mL) is added at 0°C. The mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with AcOH and extracted twice with ethyl acetate. The organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in quantitative yield (840mg). Rf = 0.59 (AcOEt : n-Hexane = 3:7). ¹H-NMR (400 MHz, CDCI₃), δ (ppm): 3.91 (s, 3H), 6.99 (d, 1 H, J=9.04Hz), 7.17 (dd, 1 H, J=9.04, 3.00Hz), 7.38 (d, 1 H J=3.04 Hz). - 142 -

4-r2-(4-Methoχy-3-nitro-phenoxy)-ethvn-morpholine

To a solution of 4-Methoxy-3-nitro-phenol (1.01g, 6 mmol) in DMF (15 mL) , 4-(2-

Chloroethyl)morpholine hydrochloride (1.34g, 7.2mmol), K2C03 (2.49g, 18mmol), Kl(2.99g,

18mmol) are added at room temperature. The mixture is heated to 80°C for 4 hours. The reaction mixture is cooled to room temperature and quenched with saturated NH4CI solution in water. The resulting mixture is extracted twice with ethyl acetate and then the organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in quantitative yield (1.70g). Rf = 0.14 (AcOEt only). ¹H-

NMR (400MHz, DMSO, 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).

Preparation of 2-Methoxy-4-(1 -methyl-piperidin-4-yloxy)-phenylamine:

To a solution of 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine (3.0g, 11.3 mmol) in ethanol (50 mL), 5% palladium on carbon(300mg) is added under a nitrogen atmosphere. The reaction vessel is fitted with a balloon adapter and 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 a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo to afford 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)- phenylamine in quantitative yield (2.7g).

Rf = 0.41 (methanol : dichloromethane = 1 :1). Η-NMR (400 MHz, CDCI₃), 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(brs, 2H), 3.82(s, 3H), 4.1-4.2(171, 1 H), 6.37(dd, 1H), 6.46 (d, 1H), 6.61 (d, 1 H). 143 -

1H).

Rf

144

145 1H,

146

147-

148

149

-150 (d,

151

152

153

154-

155

- 156 -

To a solution of 4-methy!-3-nitro-benzoic acid (300 mg, 2.76 mmol), N-butoxycarbonyl- piperazine (340 mg, 1.83 mmol) in DMF (3.0 mL), triethylamine (300 μ L, 3.59 mmol), TBTU (800 mg, 2.49 mmol) and HOAt (270.5 mg,1.99 mmol) are added and stirred at room temperature for 24 hours. The mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n- hexane : ethyl acetate = 5 : 1) to afford 4-(4-methyl-3- nitrobenzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless solid.

¹H-NMR (δ, ppm) : 1.47 (s,9H), 2.64 (s, 3H), 3.88-3.28 (m, 8H), 7.42 (d, 1H), 7.56 (dd, 1 H), 8.03 (d, 1 H). Rf (hexane : ethyl acetate = 10:1): 0.13.

To a suspension of 4-bromo-1-methyl-2-nitrobenzene (225 mg, 1.04 mmol), morpholine (125 μ L, 1.25 mmol), and cesium carbonate (474.4 mg, 1.46 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 at 100°C for 5 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in - 157 -

vacuo. The residue is purified with silica gel column chromatography (n-hexane : ethyl acetate

5 : 1) to afford 4-(4-methyl-3-nitrophenyI)-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, 1 H), 7.21 (d,

1 H), 7.47 (d, 1H). Rf (hexane : ethyl acetate = 5:1): 0.20.

49

Preparation of 2-r5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]- benzoic acid

To a solution of 1.0 g (3.37 mmol) of 2-(2,5-dichloro-pyrimidin-4-ylamino)-Λ/-methyl-benzamide in 15 mL of acetic acid are added 2-methoxy-4-morphoIinoaniline dihydrochloride (1.9 g, 6.73 mmol) and 6.0 mL of 1 N ethanolic solution of hydrogen chloride (6.0 mmol). After the reaction mixture is stirred at 120°C for 16 hours and cooled to room temperature, aqueous NaHC0₃ solution is added to adjust the acidity between pH 5 and pH 6. The resulting precipitate is collected by a filtration and dried under reduced pressure to give 2-[5-chloro-2-(2-methoxy-4- morpholin-4-yl-phenyl-amino)-pyrimidin-4-ylamino]-benzoic acid (970 mg, 2.12 mmol, 63%) as ivory solid.

NMR (400MHz, DMSO-d6, δ): 3.10-3.20 (m, 4H), 3.78 (s, 3H), 3.70-3.80 (m, 4H), 6.52 (dd, 1 H, J = 8.56, 2.52 Hz), 6.67 (d, 1H, J = 2.52 Hz), 7.08 (dd, 1 H, J = 8.04, 8.04 Hz), 7.39 (d, 1 H, J = 8.56 Hz), 7.35-7.45 (m, 1 H), 7.99 (dd, 1 H, J = 8.04, 1.52Hz), 8.14 (s, 1H), 8.28 (s, 1 H) 8.70- 8.80 (m, 1H).

Example 50: Sulfonamide moieties are prepared as follows: - 158 -

Preparation of 2-amino-4-chloro-5-rnethyl-benzenesulfonyl chloride

To a solution of 2-amino-5-chloro-4-methyl-benzenesulfonic acid (3.0 g, 1.35 mmol) in dichloroethane (10 mL) is added sulfuryl chloride (4.4 mL, 3.83 mmol) and stirred at 60°C. After one hour, thionyl chloride (1.3 mL) is added and the mixture is further stirred at 100°C for 7.0 hours. The mixture is poured into iced water and extracted with ether three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo.

Η-NMR (δ, ppm) : 2.35 (s, 3H), 6.68 (s, 1 H), 7.75 (s, 1 H).

This substituted sulfonyl chloride is reacted with a suitable amine. On reaction e.g. with methylamine, 2-amino-5-chloro-4,N-dimethylbenzenesulfonamide is formed.

Example 51

Preparation of 2-f5-bromo-2-f2-methoxy-4-morpholin-4-yl-phenylamino^')-pyrimidin-4-ylamino1-

N. N-dimethyl-benznensulfonamide

To a solution of 2-[5-Bromo-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]- N-methyl-benzenesulfonamide (Ex3-19) (1.0g, 1.82mmol) in DMF (10mL), potassium carbonate (300mg, 2.17mmol) and iodomethane (116μl, 1.86mmol) are added. The resulting suspension is stirred at 50°C for 1h. To the reaction mixture, water is added and extracted with ethyl acetate three times. The organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by aluminum oxide column chromatography (AcOEt) to afford the title compound (728mg, 71 % yield).

NMR (400MHz, CDCI₃, δ): 2.74 ((s, 6H), 3.05-3.18 (m, 4H), 3.84-3.93 (m, 4H), 3.88 (s, 3H), 6.43 (dd, 1 H), 6.53 (d, 1 H), 7.24 (m, 1H), 7.31 (s, 1 H), 7.56 (m, 1 H), 7.87 (dd, 1 H), 8.05 (d, 1H), 8.21 (s, 1 H), 8.49 (d, 1H), 8.49 (d, 1H), 9.27 (s, 1H). Rf: 0.23 (AcOEt:Hexane=1 :1).

Example 52

Preparation of 2-F5-Bromo-2-(2-methoxy-4-morpholin-4-yl-phenylamino^')-pyrimidin-4-ylamino1-5- fluoro-N-methyl-benzenesulfonamide - 159 -

Preparation of 7-Fluoro-1 ,1-dioxo-1 ,4-dihvdro-2H-1 λ -benzofl ,2.41thiadiazin-3-one

To a solution of chlorosulfonylisocyanate (1.2mL, 13.5mmol) in nitroethane (10mL), 4- fluoroaniline (1.0g, 8.97mmol) is added dropwise at 0°C and the reaction mixture is stirred for

30min. To the solution, aluminum chloride (1.3g, 9.87mmol) is added at 0°C and the mixture is stirred at 100°C for 1 hour. After cooling to room temperature, water is added and the mixture is extracted with ethyl acetate twice. The organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting solids are collected by a filtration and wahed with ether to give slightly gray solids (803.9mg, 41%).

NMR (400MHz, DMSO-d6, δ): 7.22-7.28 (m, 1H), 7.45-7.57 (m, 1 H), 7.60 (m, 1H), 11.15-11.30

(m, 1H). Rf: 0.43 (MeOH:AcOEt=1 :5).

Preparation of 7-Fluoro-2-methyl-1 ,1-dioxo-1 ,4-dihvdro-2H-1 λ ⁶-benzo[1 ,2,41thiadiazin-3-one

To a solution of 7-Fluoro-1 ,1-dioxo-1 ,4-dihydro-2H-1- l ⁶-benzo[1 ,2,4]thiadiazin-3-one (5.19g,

24.0mmol) in DMF (50mL), sodium hydride (1.04g, 26.0mmol) and iodomethane (1.5mL,

24.0mmol) are added successively and the mixture is stirred for 1 hour at 70°C. After cooling to room temperature, the mixture is poured into water and the precipitate is collected by a filtration and washed with water and hexane, successively, to give slightly gray solids (5.38g, 94%).

NMR (400MHz, DMSO-d6, δ): 3.32 (s, 3H), 7.44 (dd, 1H), 7.75 (ddd, 1 H), 7.94 (dd, 1 H).

Rf (MeOH:AcOEt = 1:5): 0.21. Rf: 0.39 (Hexane:AcOEt=1 :1).

Preparation of 2-Amino-5-fluoro-N-methyl-benzenesulfonamide

6.79g of 7-Fluoro-2-methyl-1 ,1 -dioxo-1 ,4-dihydro-2H-1 λ ⁶-benzo[1 ,2,4]thiadiazin-3-one

(29.5mmol) is dissolved in 20% aq. sodium hydroxide and the resulting solution is stirred at

100°C for 13.5 hours. The mixture is cooled to room temperature and poured into water. 78mL of 5M HCl aq. is added and the precipitate is collected by a filtration and washed with water to afford slightly purple solids (3.96g, 65%).

NMR (400MHz, CDCI₃, δ): 2.60 (d, 3H), 4.55-4.82 (m, 3H), 6.74 (dd, 1 H), 7.05-7.12 (m, 1 H),

7.45 (dd, 1 H). Rf: 0.41 (Hexane:AcOEt=1 :1).

2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzenesulfonamide 160

The reaction of pyrimidine with 2-Amino-5-fluoro-N-methyl-benzenesulfonamide is performed in the same manner described in example B.

NMR (400MHz, CDCI₃, δ): 2.67 (d, 3H), 4.56 (m, 1 H), 7.36-7.45 (m, 1 H), 7.68 (dd, 1H), 8.39 (s, 1 H), 8.42 (dd, 1 H), 9.26 (s, 1H). Rf 0.59 (Hexane.AcOEt = 1 :1).

2-r5-Bromo-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino1-5-fluoro-N- methyl-benzenesulfonamide

The introduction of substituted aniline is performed according to the manner described in

Example A.

NMR (400MHz, CDCI₃, δ): 2.65 (d, 3H), 3.09-3.16 (m, 4H), 3.87 (s, 3H), 4.50 (q, 1H), 6.41 (dd,

1 H), 6.52 (d, 1 H), 7.25-7.33 (m, 2H), 7.69 (dd, 1 H), 7.95 (d, 1 H), 8.20 (s, 1H), 8.37 (dd, 1H),

8.70 (s, 1 H). Rf 0.30 (Hexane.AcOEt = 1 :1)

Example 53: Compoun Structure Physical Data d ¹H NMR 400 MHz (DMSO-d₆) and/or MS Number (m/z)

5 ¹H NMR 400 MHz (CDCI₃) δ 12.5 (s, br, 1H), 10.3 (s, 1 H), 8.39 (d, 1H, J = 8.38 Hz), 7.97 (s, 1H), 7.87 (dd, 1H, J = 1.63, 7.55 Hz), 7.49 (d, 1H, J = 8.69 Hz), 6.54 (d, 1H, J = 2.49 Hz), 6.43 (dd, 1H, J =

2.51 , 873 Hz), 4.70 (s, 1H), 4.04 (q, 2H, J = 6.98 Hz), 3.51 (m, 2H), 3.29 (d, 1H, J = 19.2 Hz), 3.18 (m, 2H), 2.89 (d, 3H, J = 3.26 Hz), 2.77 (s, 6H), 2.39 (m, 2H), 2.22 (m, 2H), 1.40 (t, 3H, J = 6.97 Hz). MS m/z 561.4 (M + 1)

- 161 -

MS m/z 633.4/635.4 (M + 1).

MS m/z 591.3/593.3 (M + 1).

1H NMR 400 MHz (acetone-d₆) δ 9.45 (br, 1H), 8.88 (br, 1H), 8.23 (m, 1 H), 8.07 (s, 1H), 7.83 (m, 1H), 7.72 (dd, 1H, J = 1.25, 7.96 Hz), 7.45 (m, 1H), 7.14 (m, 2H), 6.86

(m, 1H), 6.79 (br, 1H), 6.62 (m, 1H), 6.13 (m, 1H), 3.97 (t, 2H, J = 6.98 Hz), 3.63 (m, 2H), 3.21 (m, 2H), 2.44 (m, 1H), 2.34 (s,

3H), 1.99 (m, 4H), 1.17 (t, 3H, J = 6.98 Hz). MS m/z 560.4 (M + 1).

MS /z 591.3/593.3 (M + 1 ).

-162-

MS m/z 547.4 (M + 1).

MS m/z 605.3/607.3 (M + 1 ).

163

MS m/z 532.4 (M + 1).

164 -

¹H NMR 600 MHz (acetone-c.₆) δ 11.20 (br, 1H), 9.75 (d, J = 15.25 Hz, 1H), 8.46 (m, 2H), 8.04 (dd, J = 1.12, 7.93 Hz, 1H), 7.71 (m, 1H), 7.69 (m, 1H), 7.47 (t, J = 7.63 Hz, 1H), 7.06 (m, 1H), 7.02 (m, 1H), 4.07 (m, 2H), 3.99 (s, 3H), 377 (m, 2H), 3.67 (m, 1H), 3.27 (m, 2H), 3.13 (t, J =

12.2 Hz, 2H), 2.85 (m, 2H), 2.46 (m, 2H), 2.26 (m, 3H), 2.08 (m, 3H), 1.95 (m, 1H), 1.75 (m, 1H), 1.66 (m, 1H), 0.89 (d, J = 6.65 Hz, 6H). MS m/z 672.4/674.4 (M +

1 ).

165

MS m/z 630.3/632.3 (M + 1).

MS m/z 633.4/635.3 (M + 1).

166

¹H NMR 600 MHz (acetone-c.₆) £ 8.47(d, J = 7.13, 1H), 8.43 (s, 1H), 8.09 (d, J = 7.85 Hz, 1H), 7.83 (m, 1H), 7.73 (t, J = 7.67 Hz, 1H), 7.50 (m, 1H), 6.87 (m, 1H), 6.71 (m, 1H), 5.46 (d, J = 31.2 Hz, 1H), 4.22 (m,

3H), 3.55 (m, 5H), 2.51 (m, 1H), 2.49 (m, 1H), 2.21 (m, 1H), 1.50 (m, 6H), 1.10 (d, J = 6.56 Hz, 6H) .MS m/z 575.4 (M + 1). -167-

-168-

- 169 - 35 00 64 (s, m-

m,

2H), 3.80 (t, J = 8.45 Hz, 1H), 3.58 (q, J = 8.38 Hz, 1 H), 3.36 (m, 1H), 3.17 (s, 1 H), 2.78 (m, 1H), 2.66 (m, 1H), 2.15 (m, 2H), 1.73 (d, J = 12.9 Hz, 2H), 1.59 (d, J = 12.9 Hz, 1H), 1.55 (m, 2H), 1.43 (m, 3H), 1.35 (m, 2H), 1.25 (m, 1H). MS m/z 599.4 (M + 1).

-170-

MS m/z 644.4/646.4 (M+1).

- 171 -

59 HN J MS m/z 560.4 (M + 1).

60 J MS m/z 586.4 (M + 1 ).

HN-

RI MS m/z 586.4 (M + 1).

62 MS m/z 574.4 (M + 1).

^OΛ '

172

MS m/z 590.4/592.4 (M + 1).

HN J

1H), 2.26 (m, 1H), 1.39 (t, J = 7.28 Hz, 3H), 1.34 (t, J = 6.96 Hz, 3H). MS m/z 524.4 (M + 1). 173 -

¹H NMR 600 MHz (CD₃OD) δ 8.23 (s, 1H), 8.18 (d, J = 8.16 Hz, 1H), 7.98 (d, J = 8.44 Hz, 2H), 7.68 (m, 1H), 7.43 (m, 1H), 7.22 (d, J = 2.29 Hz, 1H), 6.97 (dd, J = 2.30, 8.81 Hz, 1H), 4.20 (q, J = 6.99 Hz, 2H), 3.77 (m, 2H), 3.58 (m, 2H), 2.75 (d, J =

7.03 Hz, 2H), 2.72 (m, 1H), 2.18 (m, 4H), 1.47 (t, J = 6.97 Hz, 3H), 075 (m, 1H), 0.30 (m, 2H), 0.00 (m, 2H). MS m/z 600.4 (M + 1).

-174

72 MS m/z 604.3/606.3 (M + 1).

- 175

78 MS m/z 511.4 (M + 1).

79 MS m/z 525.5 (M + 1).

176

177-

178

3.23 (br, 2H), 3.00 (t, J = 12.19 Hz, 2H), 2.73 (s, 6H), 2.33 (d, J = 12.14 Hz, 2H), 1.97 (m, 2H), 1.30 (d, J = 6.04 Hz, 6H). MS m/z 630.5 (M + 1).

179

¹H NMR 600 MHz (DMSO-d₆) tf 11.7 (bs, 1H), 11.14 (bs, 1H), 9.50 (b, 2H), 7.89 (d, 1H, J = 9.1 Hz), 7.72 (m, 2H), 7.55 (m, 2H), 7.18 (m, 1 H), 6.62 (s, 1H), 6.46 (m,

1H), 4.06 (q, 2H, J = 6.6 Hz), 3.73 (t, 4H, J = 4 .8 Hz), 3.11 (m, 4H), 2.40 (m, 3H), 1.24 (m, 3H); MS m/z 485.1 (M + 1).

¹H NMR 600 MHz (DMSO-d₆) δ 9.97 (bs, 1H), 9.34 (s, 1H), 8.48 (bs, 1H), 8.34 (bs, 1H), 8.28 (s, 1 H), 7.80 (q, 1H, J = 4.8 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.48 (m, 1H), 7.39 (d, 1H, J = 8.4 Hz,), 7.25 (t, 1H, J =

98 7.2 Hz), 6.71 (s, 1H), 6.49 (d, 1H, J = 8.4 Hz), 3.93 (t, 2H, J = 6.0 Hz), 3.85 (d, 2H, J

= 12 Hz), 3.54 (d, 2H, J = 12 Hz), 3.18 (q, 2H, J = 9.0 Hz), 2.94 (t, 2H, J = 11 Hz), 2.88 (s, 3H), 2.42 (d, 3H, J = 4.8 Hz), 1.64 (m, 2H), 0.85 (t, 3H, J = 7.2 Hz); MS m/z 590.1 (M + 1).

O 2005/016

180

¹H NMR 600 MHz (DMSO-c^* _β) δ 10.0 (bs, 1H), 9.34 (s, 1 H), 8.47 (bs, 1H), 8.33 (bs, 1H), 8.30 (s, 1H), 7.79 (s, 1H), 778 (d, 1H, J = 7.2 Hz), 7.50 (m, 2H), 7.27 (t, 1H, J = 7.8 Hz,), 6.75 (s, 1H), 6.53 (d, 1H, J = 7.8

101 Hz), 4.12 (t, 2H, J = 4.8 Hz), 3.84 (d, 2H, J = 12 Hz), 3.59 (t, 2H. J = 4.8 Hz), 3.53 (d,

2H, J = 12 Hz), 3.23 (s, 3H), 3.17 (q, 2H, J = 9.0 Hz), 2.94 (t, 2H, J = 11 Hz), 2.88 (s, 3H), 2.43 (d, 3H, J = 4.8 Hz); MS m/z 606.1 (M + 1).

103 MS m/z 547.1 (M + 1).

¹H NMR 400 MHz (DMSO-d₆) δ 9.35 (s, 1H), 9.02 (s, 1H), 8.52 (s, 1H), 8.17 (bs, 1H), 7.80 (m, 2H), 7.45 (bs, 1H), 7.29 (m, 2H), 6.66 (s, 1H), 6.47 (d, 1H, J = 8.0 Hz), 4.02 (q, 2H, J = 7.2 Hz), 376 (t, 4H, J =

4.8 Hz), 3.14 (t, 4H, J = 4.8 Hz), 2.41 (d, 3H, J = 4.0 Hz), 1.23 (t, 3H, J = 7.2 Hz); MS m/z 510.4 (M + 1).

P

107 Γ W βNH(Λ ^'NHMe MS m/z 524.5 (M + 1). A N,s J

'CN 181

¹H NMR 600 MHz (DMSO-cfe) δ 9.61 (s, 1H), 9.10 (bs, 1H), 8.35 (bs, 1H), 8.18 (s, 1H), 7.77 (m, 2H), 7.41 (bs, 1H), 7.26 (t, 1H, J = 7.2 Hz), 7.15 (d, 1H, j = 7.8 Hz), 6.89 (s, 1H), 6.85 (d, 1H, j = 9.6 Hz), 3.77

(t, 4H, J = 4.8 Hz), 3.15 (t, 4H, j = 4.8 Hz), 2.52 (q, 2H, J = 7.2 Hz), 2.41 (d, 3H, J = 4.8 Hz), 1.06 (t, 3H, J = 7.2 Hz); MS m/z 503.2 (M + 1).

109 MS m/z 547.2 (M + 1).

- 182 - H NMR 400 MHz (DMSO-d_s) δ 9.91 (bs, 1 H), 9.50 (s, 1H), 8.94 (s, 1H), 8.49 (bs, 1H), 8.17 (s, 1H), 7.74 (d, 1H, J = 7.6 Hz), 7.41 (bs, 1H), 7.23 (t, 1H, J = 7.2 Hz), 7.18

(d, 1H, J = 8.0 Hz), 6.89 (m, 2H), 3.84 (d, 2H, J = 11.4 Hz), 3.54 (d, 2H, J = 11.4

Hz), 3.18 (q, 2H, J = 8.0 Hz), 2.95 (t, 2H, J = 11.4 Hz), 2.88 (s, 3H), 2.64 (s, 6H), 2.53 (m, 2H), 1.06 (t, 3H, J = 8.0 Hz); MS m/z 530.2 (M + 1).

¹H NMR 400 MHz (DMSO-c.₆) δ 10.24 (bs, 1H), 9.54 (s, 1H), 8.50 (bs, 1H), 8.41 (d, 1H, J = 7.2 Hz), 8.21 (s, 1H), 7.80 (m, 2H), 7.50 (t, 1H, J = 7.2 Hz), 7.32 (d, 1H, J = 8-^{4 Hz)}" ^{7-28 (t}' ^1H' ^{J = 8-}° ^Hz)' ^{6*32 (d}' 1H, J = 2.4 Hz), 6.17 (dd, 1H, J₁ = 2.4 Hz, J₂ = 8.4 Hz), 4.61 (m, 2H), 4.01 (m, 1H),

3.60 (m, 1H), 3.48 (m, 2H), 3.25 (q, 1H, J = 8.8 Hz), 2.88 (s, 6H), 2.42 (d, 3H, J = 4.8 Hz), 2.19 (m, 1H), 1.20 (d, 6H, J = 4.8 Hz); MS m/z 560.2 (M + 1).

-183-

127 MS /z573.2(M + 1).

129 MS m/z 576.2 (M + 1).

184

¹H NMR 600 MHz (DMSO-cf₆) δ 10.35 (bs, 1H), 9.45 (s, 1H), 8.47 (d, 1H, J = 7.2 Hz), 8.33 (s, 1H), 8.23 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7.57 (t, 1H, J = 7.2 Hz), 7.52 (d, 1H, J = 9.6 Hz), 7.23 (t, 1H, J = 7.2 Hz), 6.68 (s, 0.4H), 6.64 (s, 0.6H), 6.50 (s,

139 0.6H), 6.49 (s, 0.4H), 5.19 (s, 0.6H), 5.15 (s, 0.4H), 4.58 (m, 1H), 3.99 (m, 0.4H),

3.73 (m, 1.6H), 3.36 (m, 0.6H), 3.26 (m, 0.8H), 3.15 (m, 0.6H), 2.96 (s, 1.2H), 2.89 (s, 1.8H), 2.64 (s, 6H), 2.60 (m, 1H), 2.24 (m, 0.6H), 2.07 (m, 0.4H), 1.20 (d, 6H, J = 6.0 Hz); MS m/z 561.2 (M + 1).

- 185 -

¹H NMR 600 MHz (DMSO-d₆) δ 9.81 (bs, 0.4H), 9.74 (bs, 0.6H), 9.59 (bs, 1H), 8.48 (bs, 1H), 8.34 (s, 0.4H), 8.33 (s, 0.6H), 8.232 (s, 0.6H), 8.228 (s, 0.4H), 7.82 (d, 1H, J = 7.8 Hz), 7.59 (m, 1H), 7.49 (d, 0.6H, J = 8.4 Hz), 7.47 (d, 0.4H, J = 8.4 Hz), 7.34 (q, 1H, J = 7.2 Hz), 675 (s, 1H), 6.68 (s, 1H), 6.57 (dd, 0.6H, J, = 2.4 Hz, J₂ 8.4 Hz), 6.54 (dd, 0.4H, J, = 2.4 Hz, J₂

¹⁴⁷ = 8.4 Hz), 4.73 (m, 0.6H), 4.58 (m, 1H),

4.52 (m, 0.4H), 3.52 (m, 1 H), 3.43 (m, 1 H), 3.35 (m, 0.4H), 3.33 (m, 0.6H), 3.21 (m, 1H), 3.11 (m, 1H), 2.85 (d, 1.8H, J = 4.8 Hz), 2.82 (d, 1.2H, J = 3.0 Hz), 2.25 (m, 1H), 2.07 (m, 0.4H), 2.05 (m, 0.6H), 1.98 (m, 1H), 1.76 (m, 1H), 1.20 (d, 3.6H, J = 6.0 Hz), 1.18 (d, 2.4H, J = 6.0 Hz), 1.15 (d, 6H, J = 7.2 Hz); MS m/z 574.2 (M + 1). - 186

¹H NMR 400 MHz (DMSO-cfe) δ 10.07 (bs, 1H), 9.44 (s, 1H), 8.54 (s, 1H), 8.52 (bs, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.79 (d, 1 H, J = 8.0 Hz), 7.61 (t, 1 H, J = 7.6 Hz), 7.32

153 (t, 1H, J = 7.6 Hz), 7.22 (d, 1H, j = 8.8

Hz), 7.14 (d, 1H, J = 8.8 Hz), 4.10 (m, 2H), 3.86 (s, 3H), 3.46 (m, 2H), 3.22 (m, 2H), 3.08 (m, 2H), 2.83 (s, 3H), 2.66 (s, 6H); MS m/z 560.1 (M + 1).

187

¹H NMR 400 MHz (DMSO- /_e) δ 10.05 (bs, 1H), 9.42 (s, 1H), 8.43 (d, 1H, J = 7.6 Hz), 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.79 (dd, 1H, J, = 1.6 Hz, J₂ = 8.0 Hz),

157 7.58 (t, 1H, J = 8.0 Hz), 7.32 (t, 1H, J = 8.4 Hz), 7.15 (m, 2H), 4.70 (m, 1H), 4.07 (m,

2H), 3.45 (m, 2H), 3.21 (m, 2H), 3.06 (m, 2H), 2.83 (s, 3H), 2.65 (s, 6H), 1.27 (d, 6H, J = 6.0 Hz); MS m/z 588.2 (M + 1).

¹H NMR 600 MHz (DMSO-c/₆) δ 9.45 (s, 1 H), 8.44 (d, 1H, J = 7.8 Hz), 8.38 (s, 1 H), 8.27 (s, 1H), 7.81 (d, 1H, J = 7.8 Hz), 7.66 Hz), 7.64 (t, 1H, J = 7.2

160 J = 7.2 Hz), 6.97 (s, 1H), 8.4 Hz), 4.06 (q, 2H, J = 7.2 Hz), 3.59 (m, 6H), 3.29 (m, 4H), 2.92 (m, 2H), 2.86 (s, 3H), 2.64 (s, 6H), 1.31 (t, 3H, J = 6.6 Hz); MS m/z 574.2 (M + 1).

188 -

¹H NMR 600 MHz (DMSO- /₆) δ 9.66 (s, 1H), 8.48 (bs, 1H), 8.40 (d, 1H, J = 8.8 Hz), 8.30 (s, 1H), 7.66 (dd, 1H, J = 1.6 Hz, j₂ = 7.6 Hz), 7.71 (t, 1H, J = 8.4 Hz), 7.46 (s, 1H), 7.41 (t, 1H, J = 8.0 Hz), 7.17 (bs,

171 1H), 6.96 (s, 1H), 6.93 (bs, 1H), 4.67 (m, 1H), 4.02 (q, 1H, J = 7.2 Hz), 3.65 (m, 2H),

3.46 (m, 1H), 3.34 (m, 1H), 2.54 (m, 1H), 1.94 (m, 4H), 1.26 (d, 6H, j = 6.0 Hz), 1.15 (d, 6H, J = 6.0 Hz); MS m/z 587.2 (M + 1). 189

¹H NMR 600 MHz (DMS0-c/₆) £ 9.63 (bs, 1 H), 8.50 (bs, 1H), 8.46 (bs, 1H), 8.29 (s, 1 H), 7.82 (d, 1H, J = 7.2 Hz), 7.61 (t, 1H, J = 7.2 Hz), 7.43 (d, 1H, J = 8.4 Hz), 7.34 (t, 1H, J = 7.2 Hz), 6.75 (s, 1H), 6.58 (d, 1 H, J = 6.6 Hz), 4.04 (q, 2H, J = 7.2 Hz), 3.82

(m, 2H), 3.76 (m, 5H), 3.44 (m, 1 H), 3.22 (m, 4H), 2.85 (s, 3H), 2.82 (m, 2H), 2.09 (m, 2H), 1.71 (m, 2H), 1.25 (t, 3H, J = 7.2 Hz), 1.16 (d, 6H, J = 7.2 Hz); MS m/z 628.2 (M + 1).

¹H NMR 600 MHz (DMS0-α^* ₆) δ 9.43 (s, 1H), 8.45 (bs, 1 H), 8.38 (bs, 1H), 8.24 (s, 1H), 7.91 (d, 1H, J = 8.4 Hz), 7.84 (d, 1H, J = 8.4 Hz), 7.51 (t, 1H, J = 7.2 Hz), 7.48 (d, 1H, J = 8.4 Hz), 7.26 (t, 1H, J = 7.2 Hz), 6.76 (s, 1H), 6.55 (d, 1H, J = 7.2 Hz),

4.05 (q, 2H, J = 6.6 Hz), 3.82 (m, 2H), 3.59 (m, 5H), 3.30 (m, 1H), 3.25 (m, 4H), 2.85 (s, 3H), 2.82 (m, 2H), 2.09 (m, 2H), 1.71 (m, 2H), 1.26 (t, 3H, J = 6.6 Hz), 0.92 (d, 6H, J = 7.2 Hz); MS m/z 643.2 (M + 1).

.-cA rι- MS m/z 643.3 (M + 1).

190

H NMR 400 MHz (DMSO-d₆) δ 9.94 (bs, 1H), 9.53 (s, 1H), 8.49 (m, 2H), 8.23 (s, 1 H), 7.79 (dd, 1H, J, = 2.0 Hz, J₂ = 8.0 Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.38 (d, 1H, J = 9.2 Hz), 7.32 (t, 1H, J = 8.0 Hz), 6.68 (d, 1H, J = 2.0 Hz), 6.51 (dd, 1H, J, = 2.0 Hz,

184 J₂ = 8.4 Hz), 4.21 (m, 2H), 4.04 (q, 2H, J

= 6.8 Hz), 3.86 (d, 2H, J = 12 Hz), 3.68 (t, 2H, J = 12 Hz), 3.51 (d, 2H, J = 11.2 Hz), 3.38 (t, 1H, J = 12 Hz), 3.13 (m, 2H), 2.73 (t, 2H, J = 11.2 Hz); 2.64 (s, 6H), 2.16 (d, 2H, J = 11.2 Hz), 1.73 (m, 2H), 1.24 (t, 3H, J = 7.2 Hz); MS m/z 616.3 (M + 1).

191 -

¹H NMR 400 MHz (DMSO-cfe) <5 9.86 (bs, 1H), 9.56 (s, 1H), 8.59 (bs, 1H), 8.47 (bs, 1H), 8.24 (s, 1H), 7.79 (dd, 1H, J, = 1.6 Hz, J₂ = 8.0 Hz), 7.58 (t, 1H, J = 8.0 Hz), 7.38 (d, 1H, J = 8.4 Hz), 7.33 (t, 1H, J = 7.2Hz), 6.70 (d, 1H, J = 2.4 Hz), 6.51 (dd, 1H, J., = 2.4 Hz, J₂ = 8.4 Hz), 4.03 (q, 2H,

J = 6.8 Hz), 3.81 (d, 2H, J = 12.4 Hz), 3.58 (m, 2H), 3.28 (m, 1H), 3.11 (m, 2H), 2.74 (t, 2H, J = 12 Hz), 2.64 (s, 6H), 2.15 (d, 2H, J = 11.6 Hz), 2.03 (m, 2H), 1.86 (m, 2H), 173 (m, 2H), 1.24 (t, 3H, J = 6.8 Hz); MS m/z 600.2 (M + 1).

- 192

¹H NMR 400 MHz (CD₃OD) δ 8.29 (s, br, 1H), 8.07 (s, br, 1H), 7.96 (d, 1 H, J=7.8 Hz), 7.60 (m, 1 H), 7.39 (t, 1H, J=7.2 Hz), 7.22(s, br, 1H), 6.31 (s, 1H), 6.22 (s, br, 1 H), 4.08(q, 1H, J=6.6 Hz), 3.95 (p, 1H, J=6.0 Hz), 3.61 (m, 2H), 3.53 (dd, 1 H, J=4.2, 11.4 Hz), 3.36 (m, 2H), 2.78 (s,

3H), 2.52 (m, 1H), 2.22 (m, 1H), 1.31(t, 3H, J=6.6 Hz), 0.98 (d, 6H, J=6.6Hz); MS m/z 560.40 (M + 1).

¹H NMR 400 MHz (CD₃OD) δ 8.30 (s, br, 1H), 8.05 (s, br, 1H), 7.87 (d, 1 H, J=7.8 Hz), 7.60 (m, 1H), 7.42 (m, 1H), 7.17 (s, br, 1H), 6.28 (s, 1H), 6.19 (s, br, 1 H), 4.04 (q, 2H, J=6.6 Hz), 3.91 (p, 1H, J=5.4 Hz), 3.60 (m, 2H), 3.50(dd, 1H, J=3.6, 10.8Hz),

3.33 (m, 1H), 2.75 (s, 3H), 2.66 (s, 6H), 2.48 (m, 1H), 2.20 (m, 1H), 1.27 (t, 3H, J=6.6 Hz); MS m/z 546.40 (M + 1).

193 -

¹H NMR 400 MHz (CD₃OD) δ 8.37 (s, br 1H), 8.11(8, br, 1H), 8.00 (d, 1H, J=7.8 Hz,), 7.65 (s, br, 1H), 7.43 (t, 1 H, J=7.2 Hz), 7.25 (s, br, 1H), 6.34 (s, 1H), 6.25 (s, 1H), 4.11(q, 2H, J=7.2 Hz), 3.99 (m, 1H),

199 3.65 (m, 2H), 3.57 (dd, 1H, J=3.6, 10.8 Hz), 3.41 (m, 2H), 2.82 (s, 3H), 2.56 (m,

1 H), 2.28 (m, 1H), 1.35 (t, 3H, J=6.6 Hz), 1.01 (d, 6H, J=6.6 Hz); MS m/z 560.40 (M + 1).

¹H NMR 400 MHz (CD₃OD) δ 8.30 (s, br, 1H), 8.10 (s, br, 1H), 7.91 (d, 1 H, J=7.8 Hz), 7.57 (s, br, 1H), 7.38 (t, 1H, J=7.2 Hz), 7.21 (s, 1H), 6.30 (s, 1H), 6.21 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 3.95 (m, 1H), 3.68 (m, 1H), 3.62 (m, 2H), 3.53 (dd, 1H, J=4.2, 10.8 Hz), 3.36 (m, 1H), 2.78 (s,

3H), 2.50 (m, 1H), 2.25 (m, 1H), 1.94 (m, 2H), 1.75 (m, 2H), 1.50 (m, 2H), 1.31 (t, 3H, J=7.2 Hz); MS m/z 572.40 (M + 1).

194

¹H NMR 400 MHz (CD₃OD) δ 8.27 (s, br, 1H), 8.07 (m,1H), 7.94 (d, 1H, J=7.8 Hz), 7.61 (s, br, 1H), 7.40(t, 1H, J=7.2Hz), 7.20 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 3.95 (m, 1H), 3.60 (m, 2H), 3.53 (dd, 1H, J=4.2, 10.8 Hz), 3.35 (m, 1H), 2.78 (s, 3H), 2.73 (d, 1H, J=6.6 Hz),

2.51 (m, 1H), 2.23 (m, 1H), 1.31 (t, 3H, J=7.2 Hz), 0.742 (s, br 1H), 0.32 (s, 2H), 0.00(s,2H); MS m/z 572.40 (M + 1). 1H NMR 400 MHz (CD₃OD) δ 8.24 (s, br, 1H), 8.07 (s, br, 1H), 7.93 (d, 1H, J=8.4 Hz), 7.57 (s, 1H), 7.38 (t, 1H, J=7.2 Hz), 7.20 (s, 1H), 6.29 (s, 1H), 6.19 (s, br, 1H), 4.06 (q, 2H, J=7.2 Hz), 3.93 (m, 1 H), 3.60

206 (m, 2H), 3.50 (dd, 1H, J=6.0, 10.8 Hz), 3.35 (m, 1H), 2.76 (s, 3H), 2.72 (d, 1H,

J=6.6 Hz), 2.50 (m, 1H), 2.22 (m, 1H), 1.30 (t, 3H, J=7.2 Hz), 0.73 (m, 1H), 0.31 (m, 2H), 0.01 (m, 2H); MS m/z 572.40 (M + 1).

195-

- 196 -

¹H NMR 400 MHz (CD₃OD) δ 8.30 (d, 1H, J=7.8Hz), 8.11 (s, 1 H), 7.91 (d, 1H, J=7.8Hz), 7.58 )t, 1H, J=7.8 Hz), 7.55 (d, 1H, J=8.4 Hz), 7.36 (t, 1H, J=7.8 Hz), 6.65

(s, 1H), 6.47 (d, 1H, J=8.4 Hz), 5.20 (s, 1H), 4.07 (q, 2H, J=7.2 Hz), 3.87 (m, 1 H), 3.38 (m, 1H), 3.23 (m, 1H), 3.00 (m, 2H), 2.64 (m, 1H), 2.50 (s, 3H), 2.38 (m, 1H),

1.35 (t, 3H, J=7.2Hz); MS m/z 533.30 (M + 1).

-197-

198

199

200

201

, 1H, 1H, 7.36 Hz), 4.10 2.82 1.78 0.23

- 202 -

1H NMR 400 MHz (CD₃OD) δ 8.26 (s, 1H), 8.10 (d, 1H, J=8.0 Hz), 7.90 (dd, 1H,

J=1.2, 8.0Hz), 7.80 (d, 1H, J=8.4Hz), 7.62 (m, 1H), 7.38 (t, 1H, J=8.0Hz), 7.05 (d, 1H, J=1.6Hz), 6.83 (dd, 1H, J=1.6, 8.4Hz), 3.86 (s, 3H), 3.43 (m, 4H), 3.00(m, 4H), 2.10 (m, 2H), 1.95 (m,2H), 1.72 (m, 6H),

1.45 (m, 2H); MS m/z 658.4 (M + 1). 203-

-204-

205

-206-

-207-

-208

209

210

¹H NMR 400 MHz (CD₃OD) δ 8.17 9s, 1H0, 8.15 (d, 1H, J=8.0Hz), 7.89 9dd, 1H, J=1.2, 8.0 Hz), 7.86 (d, 1H, J=8.4hz), 7.61 (m, 1H), 7.36 (m, 1H), 7.01 (d, 1H, J=1.6Hz), 6.81 (dd, 1H, J=1.6, 8.0Hz), 4.10 (q, 2H, J=7.2Hz), 3.45 (m, 3H), 2.94 9m, 4H), 2.44 (s, 3H), 2.08 ( m, 2H), 1.94 (m, 2H), 1.75 (m, 6H), 1.49 (m, 1H), 1.37 (t, 3H, J=6.8Hz); MS m/z.628.5 (M + 1)

¹H NMR 400 MHz (CD₃OD) δ 8.17 (d, 1H, J=8.0 Hz), 7.93 (s, 1H), 7.74 (dd, 1H, J=1.6, 8.0Hz), 7.47 (t, 1H, J=8.0 Hz), 7.25 (m, 1H), 7.13 (d, 1H, 8.8Hz), 6.48 (d, 1 H, J=2.4 Hz), 6.37 (dd, 1H, J=2.4, 8.8Hz), 3.66 (m, 4H), 3.34 (m, 2H), 3.14 (m, 4H), 2.81 (m, 2H), 2.65 (m, 2H), 2.98 (d, 2H, J=12Hz), 1.68 (m, 7H), 1.30 (m, 1H), 1.02 (d, 6H, J=6.8 Hz), 0.99 (m, 1H), 0.32 (m,

2H), 0.04 (m,2H); MS m/z.639.5 (M + 1 )

211

- 212 -

NMR 400 MHz (CD₃OD) δ 8.30 (d, 1H, J=8.0Hz), 8.21 (s, 1 H), 8.00 (d, 1H, J=8.4 Hz), 7.91 (dd, 1H, J=1.63, 8.0 Hz), 7.71 (m, 1 H), 7.42 (m, 1H), 7.08 (d, 1H, J=2.0 Hz), 6.91 (dd, 1H, J=1.6, 8.4 Hz), 4.30 (m, 2H), 4.13(q, 2H, J=7.2 Hz), 3.60 (m, 4H), 3.16 (m, 2H),1.41 (t, 3H, J=7.2 Hz), 1.90 9d,

6H, J=6.8 Hz); MS m/z.573.40 (M + 1) 213

, , , , , , , ,

214

215

NMR 400 MHz (CD₃OD) δ 8.31 (d, 1H, J=8.4 Hz), 8.14 (s, 1H), 7.90 (dd, 1H, J=1.2, 7.8 Hz), 7.59 (m, 1H), 7.53 (d, 1H, J=3.0 Hz), 7.33 (t, 1 H, J=7.8 Hz), 6.96 (d, 1 H, J=9.0 Hz), 6.76 (dd, 1 H, J=3.0, 8.4 Hz), 4.18 (t, 2H, J=4.2 Hz), 3.80 (s, 3H), 3.55 (m, 2H), 3.46 (t, 2H, J=4.8 Hz), 3.00 (t, 2H, J=12.0 Hz), 2.50 (s, 3H), 1.89 (m,

2H), 177 (m, 3H), 1.52 (m, 1H); MS m/z.547.4 (M + 1)

216-

217

218-

219

220

NMR 400 MHz (CD₃OD) δ 8.17 (d, 1H, J=8.0 Hz), 7.88 (m, 2H), 7.56 (t, 1H, J=8.0 Hz), 7.37 (m, 1H), 7.17 (d, 1H, J=8.8 Hz), 6.61 (d, 1H, J=2.4 Hz), 6.47 9dd, 1H, J=2.4, 8.4 Hz), 375(m, 7H), 3.12 (m, 4H), 2.42 (s, 3H); MS m/z.489.1 (M + 1)

221

-222-

-223-

224-

225

8 (d, 1H, Hz), 7.86 1H), 7.46 2H), 3.75 3H); MS

226

227

228

MS m/z 635.20 / 637.20 (M + 1 )

MSm/z456.10/458.10(M + 1)

MS m/z 472.10/ 474.10 (M + 1)

MS m/z 585.20 / 587.20 (M + 1 )

MS m/z 571.20 / 573.10 (M + 1 )

MS m/z 448.10/ 450.10 (M + 1)

229

MS m/z 464.10 / 466.10 (M + 1 )

¹H NMR 400 MHz (DMSO-d₆) δ 9.54 (s, br,

1H), 8.76 (s, br, 1H), 8.31 (s, 1), 8.28 (d, J

= 8.14Hz, 1H), 7.95 (t, J = 5.64 Hz, 7.85

(dd, J = 7.95, 1.48 Hz, 1 H), 7.51 (t, J =

7.53 Hz, 1H), 7.33 (m, 2H), 673 (s, 1H),

4.05 (q, J = 6.92, 2H), 3.98 (m, 4H), 3.71

(m. 2H). 3.12 (m. 4H). 2.82 (D, J = 5.77 MS m/z 563.20 / 565.20 (M + 1)

MS m/z 412.10 / 414.10 (M + 1)

MS m/z 428.10 / 430.10 (M + 1 )

MS m/z 541.20 / 543.20 (M + 1 )

230

MS m/z 527.20 / 529.20 (M + 1)

MS m/z 492.10 / 494.10 (M + 1 )

MS m/z 508.00 / 510.05 (M + 1)

MS m/z 607.10 / 609.10 (M + 1)

MS m/z 563.10 / 565.10 (M + 1)

MS m/z 487.10 / 489.10 (M + 1 )

231

MS m/z 649.20 / 651.20 (M + 1 )

MS m/z 591.20 / 593.20 (M + 1 )

MS m/z 605.20 / 607.20 (M + 1)

MS m/z 448.10 / 450.10 (M + 1)

¹H NMR 600 MHz (DMSO--/₆) δ 9.46 (s,

1H), 8.46 (s, 1H), 8.37 (d, J = 8.12 Hz,

1H), 8.25 s, (1H), 7.75 (dd, 7.87, 1.40 Hz,

1H), 7.55 (t, J = 7.50 Hz, 1H), 7.37 (s, 1H),

7.30 (dt, J = 8.05, 0.8 Hz, 1 H), 6.91 (d, J =

8.92 Hz, 1H), 6.58 (dd, J = 8.88, 3.04 Hz,

1H). 3.70 (s. 3H). 3.55 (s. 3H). 2.58 (s. MS m/z 577.20 / 579.20 (M + 1)

- 232

MS m/z 563.20 / 565.20 (M + 1 )

MS m/z 519.20 / 521.20 (M + 1 )

MS m/z 533.20 / 535.20 (M + 1)

MS m/z 476.20 / 478.20 (M + 1 )

¹H NMR 600 MHz (DMSO-c/₆) δ 9.39 (s,

1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.25 (s,

1H), 7.88 (t, J = 6.02 Hz, 1H), 7.76 (dd, J =

7.94, 1.35 Hz, 1H), 7.50 (dt, J = 8.24, 1.89

Hz, 1H), 7.40 (s, 1H), 7.25 (t, J = 7.39 Hz,

1H), 6.90 (d, J = 8.92 Hz, 1H) 5.65 (dd, J =

8.87. 3.03 Hz, 1 H).. 3.70 (s. 3H). 3.54 (s. MS m/z 605.30 / 607.20 (M + 1)

233 -

MS m/z 591.20 / 593.20 (M + 1 )

MS m/z 547.20 / 549.20 (M + 1)

MS m/z 561.20 / 563.20 (M + 1)

MS m/z 548.20 / 550.20 / 552.20 (M + 1 )

548.20 / 550.20 / 552.20 (M + 1 )

m/z 563.30 / 565.30 (M + 1 )

- 234 -

384 MS m/z 577.30 / 579.30 (M + 1)

385 MS m/z 591.40 / 593.30 (M + 1 )

386 MS m/z 605.40 / 607.40 (M + 1)

387 MS m/z 617.40 / 619.40 (M + 1)

388 MS m/z 619.40 / 621.40 (M + 1 )

389 MS m/z 576.30 / 578.30 (M + 1 )

235

390 MS m/z 563.30 / 565.30 (M + 1)

391 MS m/z 560.40 / 562.40 (M + 1)

392 MS m/z 574.40 / 576.50 (M + 1)

393 Η NMR 400 MHz (DMSO-c.₆) δ 9.47 (s, 1H), 8.45 (d, J = 7.37 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.83 (d, J = 7.93 Hz,

1H), 7.59 (t, J = 8.07 Hz, 1H), 7.47 (d, J = 8.69 Hz, 1H), 7.32 (t, J = 7.54 Hz, 1H),

6.63 (dd, J = 12.67, 2.42 Hz, 1H), 6.49 (m,

1H). 5.16 (m. 1H), 4.01-3.68 m. 3H). 3.48-

394 MS m/z 587.40 / 589.40 (M + 1)

395 MS m/z 573.40 / 575.40 (M + 1)

236

396 MS m/z 587.40 / 589.40 (M + 1 )

397 MS m/z 586.40 / 588.40 (M + 1)

398 MS m/z 586.40 / 588.40 (M + 1 )

399 MS m/z 560.40 / 562.40 (M + 1)

400 ¹H NMR 400 MHz (DMSO-cfe) δ 10.30 (s, br, 1H), 9.53 (s, 1H), 8.53 (s, 1H), 8.41 (d,

J = 7.90 Hz, 1H), 8.26 (s, 1H), 7.90 (dd, J

= 7.91,1.25 Hz, 1H), 7.64 (t, J = 7.93 Hz,

1H), 7.46 (d, J = 8.70 Hz, 1H), 7.38 (t, J =

7.48 Hz, 1H), 6.67 (dd, J = 13.68, 2.49 Hz,

1H), 6.46 (m. 1H). 5.19 (m. 1H). 4.04 (m,

401 MS m/z 573.20 / 575.20 (M + 1 )

- 237 -

402 MS m/z 573.20 / 575.20 (M + 1 )

403 MS m/z 587.40 / 589.40 (M + 1 )

404 MS m/z 573.40 / 575.40 (M + 1 )

405 MS m/z 587.40 / 589.40 (M + 1)

406 MS m/z 586.40 / 588.40 (M + 1)

407 MS m/z 586.40 / 588.40 (M + 1 )

- 238

408 ¹H NMR 600 MHz (CD₃OD) δ 8.18 (d, J =

7.80 Hz, 1 H), 8.03 (s, 1H), 7.87 (dd, J =

7.96, 1.21 Hz, 1H), 7.47 (m, 2H), 7.25 (t, J

= 7.82 Hz, 1H), 6.59 (s, 1H), 6.40 (d, J =

8.56 Hz, 1 H), 5.13 (s, 1H), 3.78 (m, 4H),

3.30 (m, 2H), 3.28 (s, 3H), 2.92 ( , 2H),

2.56 (m, 1H). 2.30 (m, 2H). 0.89 (d, J =

409 MS m/z 547.40 / 549.40 (M + 1)

410 MS m/z 547.40 / 549.40 (M + 1 )

411 MS m/z 587.50 / 589.40 (M + 1 )

412 MS m/z 588.50 / 590.40 (M + 1)

413 MS m/z 637.50 / 639.50 (M + 1)

- 239

414 MS m/z 638.50 / 640.50 (M + 1 )

415 MS m/z 602.50 / 604.50 (M + 1 )

416 MS m/z 583.40 / 585.40 (M + 1)

417 MS m/z 584.40 / 586.40 (M + 1 )

418 MS m/z 548.40 / 550.40 (M + 1 )

419 MS m/z 540.40 / 542.40 (M + 1 )

240 -

420 MS m/z 541.40 / 543.40 (M + 1 )

421 MS m/z 505.40 / 507.40 (M + 1)

422 MS m/z 667.30 / 669.30 (M + 1 )

423 MS m/z 632.30 / 634.30 (M + 1 )

MS m/z 573.40 / 575.40 (M + 1 )

241 -

242-

-243

432 MS m/z 562.10 (M + 1).

244-

436 MS m/z 480.10 (M + 1).

-245-

246

-247-

444 MS m/z 588.30 (M + 1)

248

249

250

251

457 MS m/z 531.20 (M + 1)

-252-

253

- 254 -

Example 54: Cell-free ZAP-70 Kinase assay

The ZAP-70 kinase assay is based on time-resolved fluorescence resonance energy transfer (FRET). 80 nM ZAP-70 are incubated with 80 nM Lck (lymphoid T-cell protein tyrosine kinase) and 4 μM ATP in ZAP-70 kinase buffer (20 mM Tris, pH 7.5, 10 μM Na₃V0₄, 1 mM DTT, 1 mM MnCI₂, 0.01 % BSA, 0.05 % Tween-20) for 1 hour at room temperature in a siliconized polypropylene tube. Then, the selective Lck inhibitor PP2 (1-tert-butyl-3-(4-chloro-phenyl)-1 H- pyrazolo[3,4-d]pyrimidin-4-ylamine; Alexis Biochemicals) is added (final concentration 1.2 μM) and incubated for further 10 min. 10 μL of this solution is mixed with the 10 μL biotinylated peptide LAT-11 (1 μM) as 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 % BSA, 0.05 % Tween-20). 50 μL europium-labelled anti-phosphotyrosine antibody (Eu-PT66; final concentration 0.125 nM); and 50 μL streptavidin-allophycocyanine (SA-APC; final concentration 40 nM) in detection buffer are added. After 1 hour incubation at room temperature fluorescence is measured on the Victor2 Multilabel Counter (Wallac) at 665 nm. Background values (low control) are obtained in the absence of test samples and ATP and are subtracted from all values. Signals obtained in the absence of test samples are taken as 100% (high control). The inhibition obtained in the presence of test compounds is calculated as percent inhibition of the high control. The concentration of test compounds resulting in 50% inhibition (IC₅₀) is determined from the dose- response curves. In this assay, the agents of the invention have IC₅₀ values in the range of 10 nM to 2 μM, preferably from 10 nM to 100 nM. - 255 -

Recombinant ZAP-70 kinase is obtained as follows: A nucleic acid encoding full-length human ZAP-70 (GenBank #L05148) is amplified from a Jurkat cDNA library by RT-PCR and cloned into the pBluescript KS vector (Stratagene, California, USA). The authenticity of the ZAP-70 cDNA insert is validated by complete sequence analysis. This donor plasmid is then used to construct a recombinant baculovirus transfer vector based on the plasmid pVL1392 (Pharmingen, California, USA) featuring in addition an N-terminal hexahistidine tag. Following co-transfection with AcNPV viral DNA, 10 independent viral isolates are derived via plaque-purification, amplified on small scale and subsequently analyzed for recombinant ZAP-70 expression by Western Blot using a commercially available anti-ZAP-70 antibody (Clone 2F3.1 , Upstate Biotechnology, Lake Placid, NY, USA). Upon further amplification of one positive recombinant plaque, titrated virus stocks are prepared and used for infection of Sf9 cells grown in serum-free SF900 II medium (Life Technologies, Basel, Switzerland) under defined, optimized conditions. ZAP-70 protein is isolated from the lysate of infected Sf9 cells by affinity chromatography on a Ni-NTAcolumn (Qiagen, Basel, Switzerland).

Recombinant His-tagged ZAP-70 is also available from PanVera LLC, Madison, Wisconsin, USA.

LAT-11 (linker for activation of T cell): The biotinylated peptide LAT-11 (Biotin- EEGAPDYENLQELN) used as a substrate in the ZAP-70 kinase assay is prepared in analogy to known methods of peptide synthesis. The N-α Fmoc group of Fmoc-Asn(Trt)-oxymethyl-4- phenoxymethyl-co(polystyrene-1 %-divinyl-benzene), content of Asn approx. 0.5 mmol/g, is cleaved using piperidine, 20% in DMF. Four equivalents per amino-group of Fmoc-amino acid protected in their side chains [Asp(OtBu), Glu(OtBu), Asn(Trt), Gln(Trt) and Tyr(tBu)] are coupled using DIPCDI and HOBt in DMF. After complete assembly of the peptide chain the terminal Fmoc-protecting group is removed with piperidine in DMF as before. L(+)-biotinyl- aminohexanoic acid is then coupled to the terminal amino group using DIPCDI and HOBt in DMF using four equivalents of the reagents for four days at RT. The peptide is cleaved from the resin support and all side-chain protecting groups are simultaneously removed by using a reagent consisting of 5% dodecylmethylsulfide and 5% water in TFA for two hours at RT. Resin particles are filtered off, washed with TFA and the product is precipitated from the combined filtrates by the addition of 10 to 20 volumes of diethyl ether, washed with ether and dried. The product is purified by chromatography on a C-18 wide-pore silica column using a gradient of acetonitrile in 2% aqueous phosphoric acid. Fractions containing the pure compound are - 256 -

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

Example 56: Anchorage-independent tumor cell growth assay

Mouse mammary carcinoma 4T1 cells (5 x 10³) are plated in 96-well Ultra low Attachment plates (#3474, Corning Inc.) in 100 μL of Dulbecco's modified eagle medium containing 10% FBS. Cells are cultured for 2 h and inhibitors are added at various concentrations in a final concentration of 0.1% DMSO. After 48 h, cell growth is assayed with the cell counting kit-8 (Wako Pure Chemical), which uses a water soluble tetrazolium salt WST8. Twenty μL of the reagent is added into each well and cells are further cultured for 2 h. The optical density is measured at 450 nm. The concentration of compound causing 50 % inhibition of growth is determined.

Example 59 In vivo activity in the nude mouse xenograft model: female or male BALB/c nude mice (5-8 weeks old, Charles River Japan, Inc., Yokohama, Japan) are kept under sterile conditions with water and feed ad libitum. Tumours are induced by subcutaneous injection of tumour cells (human epithelial cell line MIA PaCa-2; European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, Catalogue Number 85062806; cell line from a 65 year old Caucasian male; undifferentiated human pancreatic carcinoma cell line) into left or right flank of mice under Forene^® anaesthesia (Abbott Japan Co., Ltd., Tokyo, Japan). Treatment with the test compound is started when the mean tumor volumes reached approximately 100 mm³. Tumour growth is measured two times per week and 1 day after the last treatment by determining the length of two perpendicular axis. The tumour volumes are calculated in accordance with published methods (see Evans et al., Brit. J. Cancer 45, 466-8, 1982). The anti-tumour efficacy is determined as the mean increase in tumour volume of the treated animals divided by the mean increase in tumour volume of the untreated animals (controls) and, after multiplication by 100, is expressed as delta T/C [%]. Tumour regression is reported as the mean changes of tumor volume of the treated animals divided by the mean tumor volume at start of treatment and, after multiplication by 100, is expressed as regression [%]. The test compound is orally administered daily with or without drug holidays. - 257 -

As an alternative to cell line MIA PaCa-2, another cell line may also be used in the same manner, for example:

- the 4T1 breast carcinoma cell line (ATCC Number CRL-2539; see also Cancer. 88(12 Supple), 2979-2988, 2000) with female BALB/c mice (injection into mammary fat pad).

On the basis of these studies, a compound of formula I according to the invention shows therapeutic efficacy especially against proliferative diseases responsive to an inhibition of a tyrosine kinase.

Example 60: Tablets

Tablets comprising 50 mg of active ingredient, for example one of the compounds of formula I described in Examples 1 to 131 , and having the following composition are prepared in customary manner:

Composition: active ingredient 50 mg wheat starch 150 mg lactose 125 mg colloidal silicic acid 12.5 mg talc 22.5 mg magnesium stearate 2.5 mg

Total: 362.5 mg

Preparation: The active ingredient is mixed with a portion of the wheat starch, with the lactose and the colloidal silicic acid and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste, on a water bath, with five times the amount of water and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained.

The plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are again forced through a sieve. Then the remainder of the wheat starch, the talc and the magnesium stearate are mixed in and the mixture is compressed to form tablets weighing 145 mg and having a breaking notch. - 258 -

Example 61: Soft Capsules

5000 soft gelatin capsules comprising each 50 mg of active ingredient, for example one of the compounds of formula I described in Examples 1 to 131, are prepared in customary manner:

Composition: active ingredient 250 g

Lauroglykol 2 litres

Preparation: The pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to a particle size of approx. 1 to 3 μm. 0.419 g portions of the mixture are then dispensed into soft gelatin capsules using a capsule-filling machine.

259

Biological results:

Exam pi FA Pho Growt Cell IGF- K IC50 (nM) S IC50 (μM) h IC50 (μM) Migration IR IC50 (μM) IC50 (μM)

1.00 140 0.7 >10 2.00 13 1.2 3.01 44 0.34 >10 3.02 36 0.85 4 3.03 9.1 0.14 0.8 3.04 32 0.53 2 3.05 21 0.17 2 >10 3.06 13 0.11 2 3.07 16 0.45 2 3.08 74 0.3 6 3.09 48 0.5 07 3.10 52 0.95 >10 3.11 9 0.04 0.3 0.2 3.12 5.4 0.01 1 3.13 58 1.7 0.6 0J4 3.14 54 0.4 5 3.15 7 0.02 0.8 0.94 3.16 48 1.1 3 <0.0

3.17 2.8 0.03 0.2

3.18 130 1.5 9 3.19 6.8 0.35 0.8 0.1 3.20 16 0.22 0.3 3.22 120 0.9 2 3.23 38 0.39 0.5 3.24 64 3.5 5 3.25 22 0.3 0.3 0.81 3.26 50 079 2 3.28 43 071 0.7 3.29 89 0.6 >10 3.30 69 0.6 3 3.31 13 1.1 5

0.2

3.32 14 0.18 0.49 0.12

0.0 3.33 2.9 0.03 0.05 0.13

0.1 <0.0

3.34 0.1 0.24

3.35 13 0.02 0.17 0.8 3.55

3.36 43 1.8 2.8

3.37 39 1.1 2.6

3.38 64 1.7 3.8

3.39 2 0.02 0.03 0.09

3.40 9 >10 0.9

3.41 22 >10 0.43

3.42 29 0.35 0.3

3.43 5.6 0.2 0.11 0.27

3.44 11 0.05 0.09 0.09

3.45 0.9 0.02 0.02

3.46 4 0.1 0.18 0.3 en to w co 00 σ> - h- in N- CM

C\| r o D CD h- CD d o^" v d d d d odd d d d

CD co

o

CD CM ■ o c o^*- - o. C T-I ( ^" i ^ -ςf f o- p in co o o o co oo oo oo M in v- co o o o CM CM C . o o wSoonf CMϋSinoi oo m T- o co M CD T-; o co oq σ> oq co σ> d^{"" 0} d d d Λ o d d d ^τ~ o o o d <ό ό ό o o Λ Λ d d d d ό d d d d d d

O) no O) oocoτ-ιnocMcoι*- in in in CM in m o _ιn CM - CO o o - in en CM CM -- r-; CM co in σ>

CO CM CM CO -- d CO CM CM CM C3> Cn t- CO CM in oo T- co in oo^* CM v- N- T- CD T- ^lo v- CM - CM T- in ^■^j- - CM in (6 rf oo 00 D M -t-^"

90

*0 f- 00 CO O t- CM CO m cD h~ oo c33 θ τ- cM co r in co f- oo σ> θτ-Nf * ιo ω s oo o) θ -M -* o o t- CM co -«t in co - oo en o -- CM

^■<t ^■* ^■* in in in in m -n in in in in cD CD CD cq CD CD co cq CD cq s s Ks N s s N o oq o c ∞ o o o o o o o_ p q T- T- t- co cό co^" co co oo co^" co^" co co co co co co co co co co co co co co co co cό co co^' co co co^' co co co^' co^' co co co co cd ^ ! r~: t^^{" *} -^* r-^{* "} r-^* N^" s^{" "} r»^*

O o o

261

7.13 5.5 0.8 1.22

7.14 7.6 0.3 0.36 0.33

7.15 4.5 0.06 0.19 0.26

7.16 6.4 0.2 0.42

7.17 4.3 0.7 0.69

7.18 6.2 0.5 0.7

7.19 13 0.33

7.20 2.5 >10 0.11

7.21 3.3 >10 0.46

7.22 25 0.48

7.23 1.4 0.25

7.24 5.1 0.09

7.25 13 0.2 0.73

7.25 2 >10 0.57

7.26 4.1 0.15

7.27 21 0.5 0.22

7.28 34 1 0.15

7.29 57 2 0.48

7.30 2.1 0.3

8.01 6.6 0.6 0.33

8.02 2.4 0.5 0.99

8.03 13 0.22 1 >10

8.04 8 >10 1.1

9.01 22 0.36 1 0.6

9.02 15 0.5 0.81

9.03 18 0.1 0.37

9.04 13 0.2 0J3

9.05 22 0.36 1.6 0.6

9.06 23 3 0.4 0.3

9.07 17 >10 0.26

10.01 39 1 0.44

10.02 26 0.9 1.06

10.03 23 0.9 2.4

11.01 9 0.7 0.85

11.02 4.1 0.8 0.69

11.03 26 0.41 0.1

11.04 4.3 >10 3.2

12.01 0.2

2.5 0.09 0.4

12.02 1.6 0.05

12.03 2.3 0.25

12.04 1.1 0.14

12.06 2.6

13.01 65 0.81

14.01 0.2

19 0.2 1.47

14.02 190 2 1.1

14.03 30 10 1.01

14.04 18 0.54

14.05 37 >10 1

14.06 63 10 1.11

14.07 7.5 0.2 1.4

15.01 15 10 0.47

15.02 21 >10 0.66

15.03 44 2 1.67

16.01 44 >10 4 262

16.02 6 >10 0.6 16.03 21 3 >10 16.04 9.5 >10 0.92 16B 11 3 7 16.C 28 0.9 >10 18.01 19 >10 1.29

0.2

19.01 <1 0.2 0.3 1.41

19.02 1.6 0.13 0.38 0.91 19.03 <1 0.3 0.09 0.64 19.04 1.6 0.2 0.34 0.14

0.0

19.05 1.8 0.2 0.67 0.47

19.06 5 1 0.7 19.07 2.1 0.3 0.11

0.2

19.08 3.2 0.03 0.4 0.13

19.09 1.3 0.17 0.39 0.3 0.48 19.10 1.3 0.06 0.56 1.02 19.11 38 >10 2 19.12 9 >10 0.7 0.63 19.13 2.5 0.3 1.1 19.14 2.6 0.4 1.13 0.44 19.15 3.1 0.5 0.36 19.16 2.3 0.7 1.1 19.17 1 >10 0.17 19.18 7 0.13 0.87 19.19 57 0.4 19.20 1.6 0.03 0.07 0.23 19.21 84 >10 1.71 19.22 3.4 0.12 0.51 19.23 6.4 0.7 0.71 19.24 1.8 0.05 0.12 19.25 7.2 1 0.49 0.24 19.26 6.1 0.1 0.3 19.27 1.5 0.3 0.4 19.28 4.8 0.1 0.12 0.3 0.46 19.29 1.9 19.30 <1 0.06 0.1 19.31 1.8 0.4 0.38 19.32 1.4 0.2 0.31

0.2

20.01 10 0.3 0.18 0.7

5 0.7

20.02 0.12 0.17 0.52 5

20.03 42 0.4 2.5 2.78 20.04 23 0.58 1.9 20.05 6.8 0.87 1.46 20.06 5 0.36 0.14 49 20.07 3 0.1 0.05 0.38 0.2

20.08 6.8 0.17 0.05

20.09 2 0.3 0.01 20.10 2 0.1 0.02 20.11 26 2 0.4 20.12 9.5 20.13 6.3 0.04 263

20.14 33 0.32

20.15 14 0.4 0.97 0.3

20.16 7.5 0.06

20.17 2 0.14

20.18 15 0.81

20.19 28 0.21

3.1

20.20 0.1 2

20.21 26 3 0.68

20.22 8 >10 0.19

20.23 30 0.49 3

20.24 19 0.48 2

20.25 6.2 0.21 0.06

20.26 5.3 0.76 0.27

20.27 12 0.85 0.05 0.29

20.28 9.2 0.17 0.08 0.42

20.29 6.1 0.2 0.05 0.31

20.30 7.6 0.3 0.08 0.67

20.31 39 0.5

20.32 13 0.11

20.33 2.5 0.38

20.34 13 1 0.12

20.35 87 0.09 0.09 0.15

21.01 1 0.07 0.19 0.47

21.02 8.5 0.33 >10

21.03 1.7 0.3 0.3

21.04 1.8 0.05 0.3

22.01 43 >10 >10

22.02 26 1 3

22.03 6.6 0.09 0.15 0.26

0.6

23.01 3.4 0.6 0.2 0.53

23.02 1.5 0.2 0.4 0.8

23.03 1.7 1 1.12 0.82

23.04 1.2 0.9 1.07 0.6

23.05 1.9 >10 0.59

23.06 16 1 0.57

23.07 2.1 3 0.84

23.08 6.7 0.3 0.49

23.09 2.1 0.2 0.28

24.01 3.6 0.11 0.44 0.05

24.02 2.1 0.5 0.11 0.39

24.03 1 0.3 1.08

25.01 8.5 3 1

25.02 3 0.4 0.13 0.64

26.01 4.4 0.05 0.35 0.29

0.0

26.02 1.9 0.03 0.12 0.39

26.03 1.4 0.1 0.13 0.23

0.2

26.04 4.9 0.05 0.43 1.16

26.05 2.1 0.09 0.23 1.5

26.06 4.4 0.1 0.35

26.07 11 0.5 0.95

26.08 2.9 0.01 0.18

26.09 2.3 0.04 0.22

26.10 2 0.01 0.14 264

26.11 4.4 0.4 0J8 0.5

26.12 3.7 0.2 0.19

26.13 1.6 0.2 0.44

26.14 5 0.19

26.15 6.9 1.2 0.08 0.07

26.16 9 0.32 2

0.2

26.17 17 0.3 0.1 6

26.18 1.3 6 1.17

26.19 9.2 0.43 0.79

26.20 10 0.14 0.22 0.6 0.49

26.21 1.1 0.1 0.49

26.22 <1 0.1 0.28

26.23 1.4 0.3 0.09 0.3 0.18

26.24 1 0.5 0.48 0.9

26.25 <1 0.6 0.73 0.3

26.26 1.9 0.2 0.07 0.34

26.27 4.8 0.6 1.49

26.28 2.1 0.5 1.52

26.29 <1 0.31 0.26

26.30 4.4 1 076

26.31 2 0.3 0.16

26.32 1.6 0.05 0.6

0.2

26.33 4 0.06 3

0.2

26.34 7 0.1 5

26.35 4.5 0.05 0.3

0.0

26.36 1.9 0.07 n

26.37 <1

26.38 <1

26.39 3.1

27.01 14 0.06 0.47

27.02 5.1 0.5 1.1

27.03 6.3 >10 0.56

27.04 11 0.1 0.27

27.05 8.2 0.04 0.3

27.06 1 0.08 0.31

27.07 5.5 2 0.57

27.08 9.3 0.6 0.75

27.09 4.2 0.5 0.36

28.01 12 0.3 0.46 0.3

28.02 1.9 0.08 0.44 371

28.03 7.4 0.07 0.29

28.04 7.5 0.3 0.3

28.05 6.7 0.1 0.12 1.39

28.06 17 0.6 0.56

28.07 47 ^' 3 >10

28.08 4.6 0.4 0.37

28.09 3.1 0.5 0.36

28.10 20 3 1.85

28.11 4.2 0.5 0.63

28.12 3.2 0.3 0.43 0.1

0.2

28.13 7.8 0.1 0.55

28.14 3 0.1 1.44 265 -

28.15 10 0.5 0.69

28.16 11 0.11 1 ^' 0.6

28.17 15 0.16 1.9

28.18 9.1 >10 2.03

28.19 3.7 0.5 0.14

28.20 4.4 2 0.4

28.21 1.3 0.1 0.23

28.22 1.3 0.1 0.3

28.23 5.9 0.5 0.28

28.24 2.9 0.2 0.09 2.57

28.25 3.9 0.04 0.13

28.26 6.6 0.2 0.57

28.27 2.4 0.3 0.42 0.5

28.28 5.2 0.4 0.52 1

28.29 11 0.4 0.36

28.30 2.3 0.9 0.11

28.31 7.4 0.06 1.06

29.01 13 0.7 2.2 0.09

29.02 3.3 0.7 1.1

29.03 5.6 0.1 0.99

30.01 22 0.2 0.89

30.02 12 0.2 0.47

30.03 19 0.5 0.68

30.04 25 0.3 0.99

30.05 8.5 2 0.29

30.06 15 1 1.03

30.07 8.8 0.6 0.47

31.01 30 >10 1.6

31.02 31 0.28 0.29 0.42

32.01 4.1 0.1 0.29

32.02 5.9 0.05 0.37 0.12

33.01 2.5 0.08 0.25

33.02 5.2 0.06 0.25 0.1

34.01 8 0.1 0.37 0.28

34.02 11 0.08 1.17

34.03 33 0.19 2.25

34.04 13 >10 1.22

34.05 51 0.36 5.1

34.06 14 >10 3

34.07 27 >10 2.7

34.08 8.7 >10 1.9

35.01 6.8 >10 1.43

35.02 6.1 0.7 0.23

<0.0

52.00 13 0.2 0.41

Claims

266 -Claims

1. A compound of formula I

wherein

R is selected from C₆-ιoaryI, C₅-₁₀heteroaryl, C₃-₁₂cycloalkyl and C₃-₁₀heterocycloalkyl; each of R°, R¹, R²,and R³ independently is hydrogen, CrCβalkyl, C₂-C₈alkenyl, C₂-C₈alkinyl, C₃- C₈cycloalkyl, C-s-CβcycloalkylCrC-salkyl, C₅-C₁₀aryICι-C₈alkyI, hydroxyCrC₈alkyl, C C₈alkoxyCι-C₈alkyl, aminoC C₈alkyl, haloC C₈alkyl, unsubstituted or substituted C₅- C₁₀aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 , 2 or 3 hetero atoms selected from N, O and S, hydroxy, C-_t-C₈alkoxy, hydroxyC C₈alkoxy, C CsalkoxyC Cβalkoxy, haloC C₈alkoxy, unsubstituted or substituted C5-C₁₀arylC C₈alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC C₈alkoxy, unsubstitued or substituted amino, C-rC₈alkylthio, C-i-C-salkylsulfinyl, d- C₈alkylsulfonyl, C₅-C₁₀arylsulfonyl, halogen, carboxy, Cι-C₈alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano, nitro, -S(O)o-₂NRι₂Ri3, -S(O)₀-₂Ri3, -NR₁₂S(0)o-₂Ri3, -C(O)NR₁₂Ri3, -C(0)R₁₃and -C(O)OR₁₃; wherein R₁₂ is selected from hydrogen and C^alkyl; and R₁₃ is selected from hydrogen, C^alkyl and C₃. 1₂cycloalkyl; or R° and R¹, R¹ and R², and/or R² and R³ form, together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1 , 2 or 3 heteroatoms selected from N, O and S;

R⁴ is hydrogen or C-ι-C₈alkyl; each of R⁵ and R⁶ independently is hydrogen, C-ι-C₈alkyl, CrC₈alkoxyCrC₈alkyl, haloCrC₈alkyl, C_rC₈alkoxy, halogen, carboxy, C-i-Cβalkoxycarbonyl, unsubstitued or substituted carbamoyl, cyano, or nitro;

R is unsubstituted or substituted by R₇, R₈, R₉, R₁₀, and R'₁₀; - 267 -

R₇, R₈, R₉, R₁₀, or R'₁₀ is a substituent independently selected from hydrogen, d-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkinyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylCrC₈aIkyl, C-s-doaryld-Csalkyl, hydroxyC C₈alkyl, d-C-salkoxyd-C-salkyl, aminoC C₈alkyl, haloC C₈alkyl, unsubstituted or substituted C₅-C₁₀aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 , 2 or 3 hetero atoms selected from N, O and S, hydroxy, d-C₈alkoxy, hydroxyd-C₈alkoxy, C C₈alkoxyCι-C₈alkoxy, haloC C₈alkoxy, unsubstituted or substituted aminod-C₈alkoxy, unsubstituted or substituted C₅-C₁₀arylCι-C₈alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocycIyld-C₈alkyl, unsubstituted or substituted heterocyclylC C₈alkoxy, unsubstitued or substituted amino, d- C₈alkylthio, C C₈alkylsulfinyl, C-i-C₈alkylsulfonyI, C₅-C₁₀arylsulfonyl, heterocyclosulfonyl, halogen, carboxy, C-rC₈alkylcarbonyl, CrC₈alkoxycarbonyl, unsubstitued or substituted carbamoyl, unsubstitued or substituted sulfamoyl, cyano, nitro, -S(O)o-₂NR₁₂Rι₃, -S(O)₀-₂Ri2. -C(0)Rn, -OXRn, -NR₁₂XRn, -NR₁₂XNR₁₂Ri3, -OXNR₁₂Rι₃, -OXOR₁₂ and -XRn; or two adjacent substituents on R may form together with the carbon atoms to which they are attached, a unsubstitued or substituted 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1 , 2 or 3 heteroatoms selected from N, O and S;

X is a bond or Cι-₆alkylene; and

Rn is independently selected from C₆-ιoaryl, Cs-ioheteroaryl, C₃-₁₂cycloalkyl and C₃- _loheterocycloalkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of Rn is optionally substituted by 1 to 3 radicals independently selected from Ci-ealkyl, C₃-₁₀heterocycloalkyl-C₀-₄alkyl optionally substituted with C_halky!, - C(0)R₁₂, -C(0)NR₁₂Rι₃, -XNR₁₂R₁₃, -NR₁₂XNR₁₂R₁₃ and - NR₁₂C(0)R₁₃; wherein X is a bond or d-₆alkylene; R₁₂ and R₁₃ are independently selected from hydrogen and d-₆alkyl; and salts thereof for the treatement of a disease associated to tyrosine kinase activity of anaplastic lymphoma kinase (ALK).

2. use of a compound of formula I according to claim 1 wherein

R°or R² independently is hydrogen, Cι-C₈alkyl, e.g. methyl, ethyl or isopropyl, hydroxyd-

C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC C₈alkoxy, e.g. trifluoromethoxy, C₅-C₁₀aryloxy, e.g. phenoxy, - 268 -

unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, C C₈alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy, -S(O)₀-₂NR₁₂R₁₃, - S(0)o-₂Ri₃, -NR₁₂S(O)₀-₂Ri3, -C(O)NR₁₂R₁₃, and -C(O)OR₁₃ in particular hydrogen; R¹ is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or isopropyl, hydroxyd-C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, halod- C₈alkoxy, e.g. trifluoromethoxy, C₅-C₁₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld- C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, d- C₈alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyi or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, piperazino, N- methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2- morpholinoethoxy, in particular hydrogen;

R³ is hydrogen, Cι-C₈alkyl, e.g. methyl or ethyl, hydroxyd-Csalkyl, e.g. hydroxyethyl or hydroxybutyl, halod-C₈aIkyI, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, d-C₈alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, C C₈alkylsulfonyl, e.g. methylsulfonyl, propyl-sulfonyl, cyclohexyl-sulfonyl, isopropyl-sulfonyl, C₅- C₁₀arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl, ethyl-amino-carbonyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, - 269 -

propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2- trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl dimethyl-sulfamoyl, ethyl- sulfamoyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl-sulfamoyl, cyclobutyl-sulfamoyl; preferably sulfamoyl, methylsulfamoyl or propylsulfamoyl;

each pair of adjacent substituents R° and R¹, or R¹ and R², or R² and R³ are -CH₂-NH-CO-, - CH₂-CH₂-NH-CO-, -CH₂-CO-NH-, -CH₂-CH₂-CO-NH-, -CH₂-NH-SO₂-, -CH₂-CH₂-NH-SO₂-, - CH₂-S0₂-NH-, -CH₂-CH₂-SO₂-NH-, -CH₂-CH₂-SO₂-, -CH₂-CH₂-CH₂-SO₂-, -0-CH₂-O-, or -O- CF₂-O-, and such pairs wherein hydrogen in NH is replaced by d-C₈alkyl; preferably the pair of adjacent substituents R° and R¹, or R¹ and R² being -0-CH₂-O-, and the pair of adjacent substituents R² and R³ being -CH₂-NH-CO- or -CH₂-NH-S0₂-.

R⁴ is hydrogen or d-C₈alkyl, e.g. methyl; preferably hydrogen;

R⁵ is hydrogen; d-C₈alkyl, e.g. methyl or ethyl, halogen, e.g. chloro or bromo, halod-C₈alkyl, e.g. trifluoromethyl, cyano or nitro; preferably hydrogen, methyl, ethyl, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo;

R⁶ is hydrogen; each of R⁷ and R⁹ independently is hydrogen, C C₈alkyI, e.g. methyl, ethyl or isopropyl, hydroxyd-C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, Cι-C₈alkylcarbonyl, e.g methyl carbonyl, aminoalkoxy, e.g diethylaminoethoxy, haloCι-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-C_1oaryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC C₈alkoxy, e.g. trifluoromethoxy, C₅-C₁₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3- morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, d-C₈alkylsulfonyl, e.g. methylsulfonyl, heterocyclosulfonyl, e.g piperazinylsulfonyl, heterocyclocarbonyl, e.g. methylpirerazinylcarbonyl, cyano, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, methoxyphenyl, piperidino, piperazino, N- methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3- - 270 -

morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morphoiinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;

R⁸ is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or isopropyl, hydroxyd-C₈alkyI, e.g. hydroxyethyl or hydroxybutyl, halod-C₈alkyl, e.g. trifluoromethyl, C₅-Cι₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N- methylpiperazino, heterocyclylalkyl, e.g. methylpiperazinoethyl, heterocyclylcarbonyl, e.g. piperazinocarbonyl, heterocyclyl d-C₈alkylamino, e.g. pyridyIethyl(methyl)amino, d- C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, halod-C₈alkoxy, e.g. trifluoromethoxy, C₅- C₁₀aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4- piperidyloxy, unsubstituted or substituted heterocyclylC C₈alkoxy, e.g. 2-(1- imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, C-ι-C₈alkylamino-C-ι-C₈alkylamino, e.g. dimethylamino-propylamino, Cι-C₈alkylsulfonyI, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, cyano, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N- methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4- piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;

R¹⁰ is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or butyl, hydroxy, cyano, hydroxyC C₈alkyl, e.g. hydroxyethyl or hydroxybutyl, halod-C₈alkyl, e.g. trifluoromethyl, C-ι-C₈alkoxy, e.g. methoxy or ethoxy, cycloalkylalkoxy, aryloxy, halod-C₈alkoxy, unsubstituted or substituted heterocyclylC-ι-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro; carboxy, carbamoyl, or unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; and each pair of adjacent substituents R⁷ and R⁸, or R⁸ and R⁹ or R⁹ and R¹⁰, are -NH-CH=CH-, - CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH₂-O- , -CH₂C(CH₃)₂0-, -CH=C(CH₃)O-, -OCH₂CH₂O-, -(Morpholinopropyl)N-CH=CH-, -CH=CH- O-, -O-CH₂-O-, or -0-CF₂-O-; preferably the pair of adjacent substituents R⁷ and R⁸ or R⁸ - 271 -

and R⁹ being -0-CH₂-0- or the pair of adjacent substituents R⁹ and R¹⁰ being -NH-CH=CH-, -CH=N-NH-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂- or -O-CF₂-O-.

3 use of a compound of formula I according to claim 1 or 2 wherein

R⁷, R⁸, R⁹, R¹⁰ and R'¹⁰are ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl- aminό-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, -XR-n, -C(O)Rn and -OXRn; wherein X is a bond, methylene or ethylene; R-π is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1 ,4-dioxa-8-aza- spiro[4.5]dec-8-yl; wherein R-n is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl- propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2- oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.

4.use of a compound of formula I according to claim wherein

R°or R² independently is hydrogen, d-C₈alkyl, e.g. methyl, ethyl or isopropyl, halod- C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro; preferably hydrogen, piperazino, N- methylpiperazino or 1-methyl-4-piperidyloxy, in particular hydrogen; R¹ is hydrogen, C C₈alkyl, e.g. methyl, ethyl or isopropyl, haloCι-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N- methylpiperazino, C C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro; preferably hydrogen, piperazino, N- - 272 -

methylpiperazino, morpholino, 1-methyl-4-piper.dinyloxy, 3-morphoiinopropoxy or 2- morpholinoethoxy, in particular hydrogen;

R³ is hydrogen, C C₈alkyl, e.g. methyl or ethyl, haloC C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, C C₈alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, C C₈alkylsulfonyl, e.g. methylsulfonyl, C₅- C₁₀arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2- trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl; preferably sulfamoyl, methylsulfamoyl or propylsulfamoyl; each pair of adjacent substituents R° and R¹, or R¹ and R², or R² and R³ are -CH₂-NH-CO-, -CH₂-NH-S0₂-, -CH₂-CH₂-SO₂-, -O-CH₂-O-, or -0-CF₂-O-, and such pairs wherein hydrogen in NH is replaced by d-C₈alkyI; preferably the pair of adjacent substituents R° and R¹, or R¹ and R² being -O-CH₂-O-, and the pair of adjacent substituents R² and R³ being -CH₂-NH- CO- or -CH₂-NH-S0₂-. R⁴ is hydrogen;

R⁵ is hydrogen, halogen, e.g. chloro or bromo, haiod-C₈alkyl, e.g. trifluoromethyl, or nitro; preferably hydrogen, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo; R⁶ is hydrogen; each of R⁷ and R⁹ independently is hydrogen, C C₈alkyl, e.g. methyl, ethyl or isopropyl, halod-C₈alkyl, e.g. trifluoromethyl, unsubstituted or substituted C₅-C₁₀aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N- methyipiperazino, Cι-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morphoiinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, - 273 -

trifluoromethyl, phenyl, o-, m- or p-methoxyphenyl, piperidino, piperazino, N- methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morphoiinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl; R⁸ is hydrogen, C_rC₈alkyl, e.g. methyl, ethyl or isopropyl, halod-Csalkyl, e.g. trifluoromethyl, C₅-Cιoaryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C₈alkoxy, e.g. methoxy, ethoxy or isopropoxy, halod-C₈alkoxy, e.g. trifluoromethoxy, Cs-doaryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyIoxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2- morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1- methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)- propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;

R¹⁰ is C C₈alkyl, e.g. methyl, ethyl or butyl, haloC C₈alkyl, e.g. trifluoromethyl, d- C₈alkoxy, e.g. methoxy or ethoxy, unsubstituted or substituted heterocyclyld-C₈alkoxy, e.g. 2-(1-imidazolyl)ethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro; preferably methyl, butyl, methoxy, ethoxy, 2- (l-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; and each pair of adjacent substituents R⁷ and R⁸, or R⁸ and R⁹ or R⁹ and R¹⁰, are -NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -0-CH₂-O-, or -O-CF₂-O-; preferably the pair of adjacent substituents R⁷ and R⁸ or R⁸ and R⁹ being -O- CH₂-O- or the pair of adjacent substituents R⁹ and R¹⁰ being -NH-CH=CH-, -CH=N-NH-, - CH2-CH2-CH2-. -CH2-CH2-CH2-CH2- or -O-CF₂-O-.

5. Use of a compound of formula I wherein the compound is selected from a compound of examples 1 to 53.

6. a compound of formula I' with the proviso that this does not include any of the compounds of examples 1 to 52 inclusive. - 274 -

in which: n' is selected from 1 , 2 and 3;

R'ι is selected from C₆.₁₀aryl, C₅-₁₀heteroaryl, C₃-ι₂cycloalkyl and C₃- oheterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R'ι is optionally substituted by 1 to 3 radicals independently selected from Ci-ealkyl, Ci-ealkoxy, alkoxy- substituted-Cι-₆alkyl, halo-substituted-Cι-₆alkyl, halo-substituted-Cι-₆alkoxy, -C(0)NR^, ₅R'₆, - S(O)o-₂NR^*5R^*6. -S(O)₀-₂R'₅, -C(O)R'₄, -OXR'₄₎ -NR'sXNR'sR', -OXNR'gR'e, -OXOR'₅ and -XR'₄; wherein X' is a bond or Ci-ealkylene; R'₅ is selected from hydrogen and C_halky!; R^* ₆ is selected from hydrogen, d-₆alkyl and C₃-i₂cycloaIkyl-Cι-₄alkyl; and R'₄ is independently selected from C₆-ιoaryl, Cs-^heteroaryl, C₃-₁₂cycloalkyl and d-ioheterocycloalkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R'₄ is optionally substituted by 1 to 3 radicals independently selected from Ci-ealkyl, C-₃-ιoheterocycloaIkyl-Co^alkyl optionally substituted with d-ealkyl, -C(O)NR^* ₅R^' ₆, -XNR'₅R'_6l -NR'gXNR'gR'e and -NR'₅C(0)R'₆; wherein X is a bond or C^alkylene; R'₅ and R'₆ are independently selected from hydrogen and d-ealkyl;

R'₃ is selected from halo, -S(0)o-2NR'₅R^*6, -S(O)o-₂R'6, -NR'₅S(O)₀-2R'6. - C(O)NR'₅R'_6ι -C(0)R'₆and -C(O)OR'₆; wherein R'₅ is selected from hydrogen and Ci-ealkyl; and R'₆ is selected from hydrogen, d-₆alkyl and C₃-ι₂cycloaIkyl; and the pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof.

7. A compound of fomula I' according to claim 6 in which: n' is selected from 1 and 2; - 275 -

R'ι is selected from C₈-ιoaryl and C₅- ₀heteroaryl; wherein any aryl or heteroaryl of Ri is optionally substituted by 1 to 3 radicals independently selected from d-₆alkyl, C^alkoxy, - C(0)NR'₅R'₆, -OX'R'₄, -C(O)R'₄, -NR'₅X'NR'₅R'₆, -OX'NR'₅R'₆, -OX'OR's and -X'R'₄; wherein X' is a bond or Cι-_ealkylene; R'₅ is selected from hydrogen and d-₆alkyl; R'₆ is selected from hydrogen, d-₆alkyl and Cs-^cycloalkyl-d^alkyl; and R'₄ is C₃-ι₀heterocycloalkyl optionally substituted by 1 to 3 radicals independently selected from Ci-ealkyl, halo-substituted-Ci-ealkyl, Ca-ioheterocycloalkyl-Co^alkyl optionally substituted with d-₆alkyl, -C(O)NR'₅R'6, -X'NR'sR'e, - NR'sX'NR'sR'e and -NR'₅C(0)R'₆; wherein X' is a bond or d-₆alkylene; R'₅ and R'₆ are independently selected from hydrogen and Ci-ealkyl;

R'₂ is selected from hydrogen and halo;

R'₃ is selected from halo, -S(O)₀-₂NR'₅R'6, -S(O)₀-₂R'₆. -NR'₅S(0)o-₂R'6, - C(O)NR'₅R'e and -C(0)OR'₆; wherein R'₅ is selected from hydrogen and Cι-₆alkyl; and R'₆ is selected from hydrogen, d-₆alkyl and C₃-ι₂cycloalkyl.

8. A compound of formula I' according to claim 6 or 7 in which R'ι is selected from phenyl, pyridinyl, pyrazolyl and pyrimidinyl; wherein any aryl or heteroaryl of R^ is optionally substituted by 1 to 3 radicals independently selected from ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl-amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, -X'R'_4l -C(0)R' and -OX'R' ; wherein X' is a bond, methylene or ethylene; R'₄ is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1 ,4-dioxa-8-aza- spiro[4.5]dec-8-yl; wherein R'₄ is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl-propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.

9. A compound of of formula I' according to claim 6, 7 or 8 in which R'₂ is selected from hydrogen and halo; and R'₃ is selected from halo, dimethyl-sulfamoyl, isobutyl-sulfamoyl, methyl-sulfamoyl, ethyl-sulfamoyl, propyl-sulfonyl, ethyl-amino-carbonyl, 1 -ethyl-propyl- - 276 -

sulfamoyl, cyclopentyl-sulfamoyl, isopropyl-sulfamoyl, cyclohexyl-sulfonyl, cyclopropyl-methyl- sulfamoyl, cyclobutyl-sulfamoyl, isopropyl-sulfonyl,

10. A compound of formula I according to any one of claim 6 to 9 wherein the compound is a compound of example 53.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, as active ingredient together with one or more pharmaceutically acceptable diluents or carriers.

12. The use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of neoplastic diseases and immune system disorders.

13. A combination comprising a therapeutically effective amount a compound according to any one of claims 1 to 9 and one or more further drug substances, said further drug substance being useful in the treatment of neoplastic diseases or immune system disorders.

14. A method for the treatment of neoplastic diseases and immune system disorders in a subject in need thereof which comprises administering an effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition comprising same.

15. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease which responds to inhibition of FAK and/or ALK and/or ZAP-70 and/or IGF-IR.

16. The use according to claim 15, wherein the disease to be treated is selected from proliferative disease .

17. The use according to claim 16, wherein the proliferative disease to be treated is selected from a tumor of, breast, renal , prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro-intestinal tumours as well as osteosarcomas and melanomas.

18. The use according to claim 15, wherein the disease to be treated is an immune disease. - 277 -

19. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of inflammatory and/or an immune disorder.

20. Use according to claim 19- wherein the inflammatory and/or immune disorder is selected from transplant rejection, allergy and autoimmune disorders mediated by immune cells including T lymphocytes, B lymphocytes, macrophages, dendritic cells, mast cells and eosinophils.

21. The use according to any one of claims 14 to 19, wherein the compound is 2-[5-Bromo-2-(2- methoxy-5-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide or5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yI]-phenyl}-N*4*-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof.

22. The use according to any one of claims 14 to 19, wherein the compound is selected from 2- [5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yIamino]-N-methyl- benzamide, N²-(4-[1 ,4^']Bipiperidinyl-1 ^*-yl-2-methoxy-phenyl)-5-chloro-N -[2-(propane-1 -sulfonyl)- phenyl]-pyrimidine-2,4-diamine and 2-{5-Chloro-2-[2-methoxy-4-(4-methyl-piperazin-1 -yl)- phenylamino]-pyrimidin-4-ylamino}-N-isopropyl-benzenesulfonamide, or 5-Chloro-N*2*-{2- methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)- pheny!]-pyrimidine-2,4-diamine a pharmaceutically acceptable salt thereof.