Cyclic protein tyrosine kinase inhibitors

This invention relates to the use in connection of the formula IV or its salts for the manufacture of drugs intended for oral treatment of certain cancers.

[0003| Protein kinase tyrozynowe (PTK - protein tyrosine kinases) are enzymes which, in conjunction with ATP as a substrate fosforylują other tyrozynowe in peptydach and proteins. These enzymes are key elements in the regulation of cell signaling, including cell proliferation and cell differentiation. PTK include, among other things, receptorowe tyrozynowe kinase (RKT), including those that belong to the family of kinases of the epidermal growth factor (for example, 1IER1 and IIRR2), płytkopochodny growth factor (PDGF) and kinases plays a role in angiogenezic (lic-2 and KDR); and niereceptorowc kinase tyrozynowe, including family members, Hiss, and Src (e.g. Src, Langeland, Lin, Drug and Blk) (see ASP, J. B., Rowley, R. B., Spana, C., and Tsygankov, AY., "The src family of tyrosine protein kinases in hematopoietic signal transduction", FASFB J., 6, 3403-3409 (1992); Ulrich, A. has and schlessinger, J., "Signal transduction by receptors with tyrosine kinase activity", Cell, 61, 203-212 (1990) and 1hle, J. N., "The Janus protein tyrosine kinases in cytokine signaling hcmatcpoctlc", SCM. Immunol., 7, 247-254 (1995'"|0004| Increased activity of PTK it is associated with various malware and niezłośliwymi diseases rozrostowymi. Moreover, PTC plays a major role in the regulation of cells of the immune system. P TK inhibitors so they can affect a wide range of disorders, cancer and immune. This type of violation can be ameliorated by the selective inhibition of one or receptorowej niercceptorowej PTK, such as a Drug, or due to the homology among PTK classes, through the inhibition of more than one using the PTK inhibitor*.

|0005] in Particular, interesting PTK - Ixk, which occurs in T cells, where it participates in the phosphorylation of key protein substrates. It is necessary for the efficient transmission of the signal through the antigen receptor and activation of cells. If there is no activity the Drug, the zeta chain receptor T-cell (TCR) nothing fosforylowany, kmaza ^ZAP*-⁷0 mc is activated and me.^happly^and mobiHzacja Ca²¹ tameczną and^kt^ywacj^and

-2komórki T (see Weiss, A. and Littman, D. R., "Signal transduction by lymphocyte antigen rcceptors", Ccii, 76, 263-274 (1994); Iwashima, M., Irving?.?., van Oers, N. S. C., Chan, A. C. and Weiss, And "Sequenlial interaetions of Ihe TCR with two distinet eytoplasmie tyrosine kinases", Science, 263, 1136-1139 (1994) and Chan, A. C., Dalton, M., Johnson, R., Kong, G., Wang, T., Thoma, R. and Kurosaki, T., "Activation of ??? To 70 kinase activity by phosphorylation of tyrosine 493 is reauired for lymphocyte antigen receptor ftinction", EMBOJ., 14, 2499-2508 (1995)). Inhibitors the Drug is therefore useful in the treatment of disorders related to T cells, such as chronic diseases with a substantial component of the T cell, for example, rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases, which are diagnosed a key role of T-cells, for example acute transplant rejection and the reaction of delayed-type hypersensitivity (DTH).

|0006] WO 00/62778 Al shows cyclic compounds and their salts, including a compound of formula IV, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases associated with protein kinazami tyrozynowymi, such as disorder, immunological and cancer.

|0007| the present invention provides the use of the Association of the formula IV or salts thereof:

<img file="PL1610780T3_D0001.tif" />

for the manufacture of a drug intended for the oral treatment of cancer, where the cancer is chronic myelogenous leukemia (CML), cancer podścieliskowy the gastrointestinal tract (GIST), acute myeloid leukemia (AML), mastocytoza, tumor zarodkowy', small cell lung cancer (SCLC), melanoma, pancreatic cancer, prostate cancer or childhood sarcoma.

|0008] moreover, this' invention provides the use of the Association of the formula IV or its salts for the manufacture of drugs intended for the oral treatment of cancer, where the cancer is refractory to ST1-571.

|0009] the present description discloses a cyclic compound of the following formula i And their salts, for use as protein kinase inhibitors tyrozy new:

And

<img file="PL1610780T3_D0002.tif" />

where:

Qjest:

(1) 5-członowym ring hctcroarylowym;

(2) 6-członowym ring hctcroarylowym; or (3) ring arylowym;

additionally, a plant one or more Ri groups;

With:

(1) one anchor;

(2) R|sC=CH-; or (3) -(CH₂)_m-j, where m is from I to 2;

Xi and X2 are both wodorami or together form =0 or =S;

Ri:

(1) hydrogen or R*, where R/, alkilem, alkenylem, alkinylem, cykloalkilem, cykloalkiloalkilem, cykloalkcnylem, cykloalkenyloalkilem, arylcm, aralkilem, ring species or heterocykloalkilem, each of which is not substituted or substituted with Zi, Z2 or one or more (preferably one or two) groups Z3;

(2) -About kjb &lt;R*;

(3) -SH or SR$;

(4) -C(O)2, -C(O)qR$, or -O-C(O)qrn where q is 1 or 2;

(5) -SO3H or-S(O)qR";

(6) a group of halogen lamps;

(7) group cyjanową;

(8) group nitrową;

(9) Z4-n_?Year";

-4(1O)-Z4-N(R₉&gt;-Z5-n,oR";

(H) -Z4-N(R,₂&gt;Z5R";

(12) P(O)(OR6)2;

R2 and R3 each independently:

(And) wrołorem or R₆;

(2) -Z4R"; or (3), 3-No.₇R_s;

R4 and R5:

(1) let.dy independent hydrogen or R_ft;

(2) With₄-N(R₉)-S&lt;-NRioRh;

(3) N(R,)WITH₄R₆; or (4) together with the nitrogen atom to which they are attached complete a 3 - to 8członowy saturated or unsaturated ring heterocykliczny, not substituted or substituted with Zi, Z2 and Z3, which ring is heterocykliczny may wish to join a ring benzenowy, not substituted or substituted with Zi, ^With2 ^and3;

R?, R/, R9, Rio, Ru and R12:

(1) are each independently hydrogen or R";

(2) R7 and Rg leg both to be alkilencm, alkenylenem or heteroalkilem, as a 3 - to 8-membered saturated or unsaturated ring containing the nitrogen atom to which they are attached, which ring is not replaced or Zi, With₂ and Z3; or (3) any two of R9, Rio and Rn can be both alkilenem or alkenylenem complementary 3 - to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is not substituted, or Z|, Z2 and Z3;

R13:

(1) group cyjanową;

(2) group nitrową;

(3) -NH2;

(4) -NON-alkilcm;

(5) -Oh;

(6) -NON-arylem;

(7) -NllCOO-alkilem;

-5(8) -NHICOO-arylem;

(9) -NHSO₂-alkilem;

(10) -NHSO2-arylem;

(11) group arylową;

(12) gnjpą hctcroarylo VA;

(13) On-alkilem; or (14) -O-arrylem;

R14:

(1) -NO2;

(2) -COO-alkilem; or (3) -COO-arylcm;

R 15 is:

(1) hydrogen;

(2) alkilem;

(3) arylcm;

(4) aryloalkilem: or (5) cykloalkilem;

Zi, Z2 and Z 3 are each independently:

(1) hydrogen Feb Z5, where ?? (and) alkilem, alkcnylem, alkinylem, cykloalkilem, cykloalkiloalkilem, cykloalkenylem, cykloalkenyloalkilem, arylem, aralkilem, alkiloarylcm, cykloalkiloarylem, ring species or heterocykloalkilcm; (ii) group (s) which is itself substituted by one or more same or other groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) from the definition of??,?? 1Z3;

(2) OH or OZ₆;

(3) -SH or -SZ6 (4) -C(O)qH, -C(O)qZ6, or () ((0),/6,;

(5) -SO3II, -S(O)_qZ6; or S(0)h(C9)With_c;

(6) a group of halogen lamps;

(7) group cyjanową;

t (8) group nitrową;

(9) -Z4-NZ7Z₈;

-6(10) -Ζ4-?(Ζ9)-?₅-??₇-?₈;

(11) -Z4-N(C,₀)Hz₅-With";

(12) -Z4-N(C_1o)-With₅-H;

(13) group of the carbonyl carried;

(14) -O-C(O)-26;

(15) any two of Zi, Z2 and Z3 can both be alkilenem or alkenylenem complementary 3 - to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or (16) any two of the??, Z2 and Z3 can both be O-(n)r-O-, where r is to 5 as 4 - to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

Z4 and Z5 are each independently:

(1) pojcdynczym binding;

(2) With_n-S^(O)_qWith₂-;

(3) -,-C(O)-WITH_i2-;

(4) With rC(S)-S_n-;

(5) C,,-S. 2-;

(6) -S|,-S-Zi2-;

(7) -Zh-O-C(O)-Zi₂-; or (8) -C,,-C(O)-O-Zni2-;

Z7, ??, C9 And Uncle:

(1) are each independently hydrogen or Ζ5;

(2) Ζ7 and With or With and With_on can both be alkilenem or alkenyknem as 3 to 8)membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is nothing happens or replaced Z|, Z2 and Z3; or (3) Z7 or??, along with C9, can be alkilenem or alkenylenem to be completed in 3 to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is nothing happens, or zero Iony??, Z2 And Z3;

Zn and Z 2 are each independently:

(1) one anchor;

(2) alkIlcncm;

(3) alkcnylenem; or

-7(4)alkinylenem; and Zu j"ii:

(1) pojcdynczym binding;

(2) -Zn-S(O)_qWith₂-;

(3) -B,-C(O)-WITH_I2-;

(4) -,-C(S)-S₁₃-;

(5) -Zi,-O-C|₂-;

(6) -C,-C_I2-;

(7) -C-O-C(O)-C,₂-;

(8&gt; -, and-C(O-Oh-C,₂-;

(9) -C(NR|₃)-;

(10) -{ΧΟΪΚΗ) -; (11) -C(C(Ri₄)₂)-.

[0010] Relationships that meet the scheme 1 include compounds of the following formula U and their salts:

<img file="PL1610780T3_D0003.tif" />

where n is 1 or 2

And selected from carbon and nitrogen;

B is selected from nitrogen, oxygen and sulfur;

Xi is oxygen or sulfur; and

Ri, R₂| Ri, Rj and R5 are as described above.

Detailed description of the Invention [0011] the following are definitions of terms used in this specification. Preliminary determination delivered to the group or meeting, hereby apply to this group or meeting throughout this specification, individually or as part of another group, unless otherwise indicated.

-8 [0012] the Terms "hc" or "alkyl" refer to groups of simple or branched hydrocarbon chains containing from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms. The expression "lower alkyl" refers to groups alkilowych about 1 to 4 carbon atoms.

[0013] the Term "alkenyl" refers to a group of simple or branched hydrocarbon chain with 2 to 10, preferably 2 to 4 carbon atoms, having at least one of them a double. When the group alkenylowa attached to the nitrogen atom, preferably such a group was not connected directly using coal, creating a double tie.

(4)014] the Term "alkinyl" refers to a group of simple or branched hydrocarbon chain with 2 to 10, preferably 2 to 4 carbon atoms, having at least one triple. When the group alkinylowa attached to the nitrogen atom, preferably such a group was not connected directly using coal, creating a triple bond.

|0015| the Term "alkilen" refers to a bridge created using simple chain from 1 to 5 carbon atoms connected by single bonds (e.g.,- (ClbK-, where x is from 1 to 5), which may be substituted with 1 to 3 groups lower alkilów.

|0016] the Term "alkenylen" refers to a bridge created using simple chain of 2 to 5 carbon atoms having one or two double pairing, which is associated with dependency beds and can be substituted with 1 to 3 groups lower alkilów. Examples of groups alkenylenowym-CH=CH-CH=C1I-, -CH2-CH=CH-, -CH2CH=CH-CH2-, -C(CHj)2CH=CH - or-CH(C₂H_s)-CH=CH-.

|0017] the Term "alkinylen" refers to a bridge created using simple chain of 2 to 5 carbon atoms that contains the triple bond, are connected by tying to the bed and can be substituted with 1 to 3 groups lower alkilów. Examples of groups alkinylenowymi-C=C-, -CH2-C=C-, -CH(CH₃)-C^&gt; I-Cs C-CH(O2H₅)CH2.

|0018| the Terms "ar" or "aryl" refers to aromatic ring groups (e.g., 6-członowa jcdnopicrścieniowa or 10-membered ring system or dwupierścieniowy 14członowy system trójpierście.niowy) containing from 6 to 14 carbon atoms. Examples of the group arylowe include fenyl, naftyl, and antracen bifenyl.

|0019| Time "cykloalkil" and "cykloalkcnyl" refers to the group of hydrocarbon ring of 3 to 12 carbon atoms.

|0020] the Terms "halogen" and "Hello" refer to fluorine, chlorine, bromine and iodine.

|0t)211 the Term "insatiable ring" includes rings, partially unsaturated and aromatic.

|0022| the Terms "heterocykr, "heterocykliczny" or "heterocyklo" refer to fully saturated or unsaturated ring groups, including niearomatycznymi (for example, "hcterocykloalkil") and aromatic (e.g., "hctcroaryl") groups of the annular spring, for example, from 4 - to 7-członowych jednopicrścicniowych, from 7 - to 11-członowych dwupierścieniowych or 10 - to 15-członowych tricyclic systems, cyclic that have that

-9najmniej one heteroatom in at least one ring containing a carbon atom. Each ring heterocyklicznej group containing a heteroatom may have 1, 2, 3 or 4 heteroatomy selected from nitrogen atoms, oxygen and/or sulfur, and heteroatomy nitrogen and sulfur may optionally be oxidized, and heteroatomy nitrogen can optionally be kwaternizowane. The heterocyclic group may be attached via any heteroatom or carbon atom belonging to a ring or ring systems.

|0023| Sample jcdnopierścieniowe heterocyclic group include pirolidynyl, pirolil, pirazolil, oksetanyl, pirazolinyl, imidazolil, imidazolinyl, imidazolidynyl, oksazolil, oksazolidynyl, izoksazolinyl, izoksazolil, tiazolil, tiadiazolil, tiazolidynyl, izotiazolil, izotiazolidynyl, ftiryl, tetrahydrofuryl, tienyl, oksadiazolil, piperydynyl, a piperazine!, 2oksopipcrazynyl, 2-oksopiperydynyl, 2-oksopirolodinyl, 2-oksoazepinyl, azepinyl, 4piperydonyl, pirydynyl, pirazynyl, pirymidynyl, pirydazynyl, tctrahydropiranyl, morfolinyl, tiamorfolinyl, dimethyl tiamorfolinylu, sulfon tiamorfolinylu, 1,3-dioksolan and tetrahydro1,1-dioksotienyl, triazolil, triazynyl and the like.

|0024] the Sample dwupicrścieniowe heterocyclic group include indolil, benzotiazolil, bcnzoksazolil, benzodioksolil, benzotienyl, chinuklidynyl chinolinyl, tetrahydroizochinolinyl, izochinolinyl, benzimidazolil, benzopiranyl, indolizinyl, benzofuryl, chromonyl, kumarynyl, benzopiranyl, cynolinyl, chinoksalinyl, indazolil, pirolopirydyl, furopirydynyl (as it is[2,3-c|pirydynyl, it is[3,2-b|pirydynyl or he is[2,3-b]pirydynyl), dihydroizoindolil, dihydrochinazolinyl (such as 3,4-dihydro-4-oksochinazolinyl), tetrahydrochinolinyl and the like.

|0025| Examples of three-ring heterocyclic groups include karbazolil, bcnzydolil, fenantrolinyl, akrydynyl, fenantrydynyl, ksantenyl and the like.

[0026] the Term "hetcroaryl" refers to aromatic groups heterocyklicznych.

[0027| Example heteroarylowe include pirolil, pirazolil, imidazolil, oksazolil, izooksazolil, tiazolil, tiadiazolil, izotiazolil, furyl, tienyl, oksadiazolil, pirydynyl, pirazynyl, pirymidynyl, pirydazynyl, triazolil, triazinyl and the like.

|(HI2H When q-ynosi 1 or 2, ,,-C(O)"CH" means -€(O)-H or -C(O)-()H; ,,-C(O)_qR₆” or,- C(O)qZ6” mean, respectively,- C(O)-Ro-or -G(O)-OR6, or-C(O} -,, or -Cl(O)-O26; O-C(O)_qR6 or O-C(O)_qZ6” mean, respectively,- O-C(O)-R* or O-C(O)-R_n or OC(O)-Z-6 or -O-C(O)-O26; a ,,-S(O)qR&gt;¹ or-S(O)qZ6” means, respectively, SO-Rc or SO2-R6, or - SO-7&lt; or -Soy-Z6.

|0029] the Compound of formula l may in some cases form salts. The link with the formula 1 herein is understood to include reference to salts thereof, if that •zamączono differently. The term "salt (salt)" in this application means an acidic and/or alkaline salts formed with inorganic and/or organic acids and bases. Ions obojnacze (inner sole) fall under the term "salt (salt)" in this application and can be, for example, are formed when podstawniki Year contain an acidic functional group such as carboxyl group. Subject to this also from the group of Quaternary ammonium salts of ammonium, such as salts alkiloamoniowe. Preferred salts are pharmaceutically acceptable, i.e.

- 10nietoksyczne, physiologically acceptable, but other salts can be used, for example, in the stage of isolation or purification, which can be used during cooking. Solc compounds of formula I it is possible to create, for example, through przereagowanie regard with a certain amount of acid or alkali, such as an equivalent amount, in the center, in which salt it is precipitated, or in the center in an aqueous medium, after the reaction, in which the lyophilization.

|0030| Sample additive salts of acids include acetates, such as created with acetic acid or trihalooctowym, for example, trifluorooctowym, adypiniany, alginates, askorbiniany, asparaginiany. benzoesany, benzenosulfoniany, bisulfoniany, borates, buttery, citrates, kamforany, kamforosulfoniany, cyklopentanopropioniany, diglukoniany, dodccylosulfoniany, etanosulfoniany, fumarany, glukohcptaniany, glicerofosforany, hemisulfoniany, heptaniany, heksaniany, chlorowodorki, bromowodorki, jodowodorki, 2hydroksyctanosulloniany, mleczany, malciniany, metanosulfoniany, 2-naftalenosulfoniany, nikotyniany, nitrates, oxalates, pektyniany, persulfoniany, 3-fcnylopropioniany, phosphates, pikryniany, piwalany, propioniany, salicylates, bursztyniany, sulfates (e.g. sulfuric acid), sulfoniany (such as listed above), winiany, liocyjaniany, tolucnosulfoniany, undekaniany and the like.

|0031| the sole Sample of the rules created, for example, when podstawniki Year contain an acidic functional group, e.g. a carboxyl group include ammonium salts, salts of alkali metals such as sodium salt, lithium and potassium, salts of rare earth metals, alkali such as calcium salts and magnesium salts alkali organic substances, e.g. organic amines, such as benzalyny, dicykloheksyloaminy, hydrabaminy, N-methyl-S)-glukaminy, N-methyl-Dglukamidy, lerlbulyloaminy and salts of amino acids such as arginine, lysine and the like. Alkaline group containing nitrogen, can be kwatemizowane reagents, such as halides of lower alkili, for example, chlorides, bromides and iodides of methyl, ethyl, propyl and butyl, dialkili sulfates, e.g., sulfates sulfoxide, diethyl ether, dibutylu and diamylu, halogen long chain compounds, for example chlorides, bromides and iodides decylu, methacrylate, mirystylu and stearylu, Halogens aralkili, for example, the benzyl bromides and fenetylu and others.

|0032] Proleki and solwaty rówrnież compounds here disclosed. The term "prolek" in this application means a compound which after the introduction of the championship is subject to the chemical conversion by metabolic or chemical processes, providing the compound of formula I or a salt thereof and/or solwat. Solwaty connections' about the picture And profitable wodzianami.

|0033| stereoizomery All identified connections, such as those that may exist in result^regli asymmetric in podstawnikach Year, so in the picture, including forms cnancjomerycznymi and diastereoizomeryeznymi, was revealed. Bed stereoi/omery compounds can be, for example, essentially devoid of other isomers, or may contain an impurity, for example, as a mixture racemiczne, or all other individual stereoisomers of the Centers chiralne can have the S or R configuration, in accordance with the definition in the recommendations of the IUPAC 1974.

|0034| In all specifications, gmpy and podstawniki so chosen to provide a stable functional group and communication.

- II [0035] Disclosed here compounds of the formula i And their salts in which Q is tiazolem and in which one or more, and, in particular, all of the C, ??, Χ2, R|, R2, R3, R4 and Rs is selected from the following definitions:

With reference one;

Ri is selected from hydrogen, halogen, alkyl, arylu, group alkoksylowcj, alkoksykarbonylowej or aryloksykarbonylowej and is preferably hydrogen;

Xi and X2 together form =O or =S and more profitable =0;

R2 is hydrogen;

R3 is selected from -Z4-R0 or -Z13-NR7R8 and is more profitable-Zj-Ro, where" reference one, and R₆ it arylem or hctcroarylem, which is not replaced or??, Z2 and one or more (preferably one or two) groups Z3; R4 is hydrogen; and

Rj is selected from the group arylowych or heteroarylowych, which are substituted Z|, Z2 and one or more, such as one or two groups Z3.

Methods of Preparation [0036] Compounds of formula I can be obtained by methods such as presented in the following Schemes A through E and I through XI. Solvents, temperatuiy, pressure and other reaction conditions can be easily selected by a specialist. All cited documents are fully incorporated in this description by reference. Weekend materials are commercially available or easy to prepare specialist. The components of the connection are such as defined in this specification, or, as in particular defined in the schema.

|0037| methods Described here can be applied by using the original materials and/or reagents in solution or alternatively, where appropriate, using one or more starting materials or reagents¹ about tassociated with permanent base (see (1) (1) Thompson, L. A., FJlman, J. A., Chemical Rcviews, 96, 555-600 (1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W., Kobyłecki R. J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3) Gallop, ?. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon,

E. M., Journal of Medicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, F. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gallop, M. A., Journal of Medicinal Chemistry, 37, 13851401 (1994); (5) Balkcnhchl, F., Bussche von dcm-IIiinnefeld, Lansky, A., Zcchcl, C., Angewandte Chemie International Edition in English, 35, 2288-2337 (1996); (6) Balkenhohl,

F. , von dem Bussche-IIiinnefeld, Lansky, A., Zechel, C., Angewandte Chemie, 108, 24362487 (1996); and (7) Sofia, M. J., Drugs Discovery Today, 1,27-34 (1996)).

<img file="PL1610780T3_D0004.tif" />

|0038| the Scheme? illustrates a common way of creating connection la, which is a compound of formula I, where X] and X₂ together form =O, As shown in the diagram And the link-La, where Rt and R3 are hydrogen, can be created zmydlcnie and (R# karboksylcm protected groups, such as alkyl or aryloalkil) followed by reaction with amine iii by known methods of languishing equipment. Alternatively, and maybe przereagować with R₂L, where L is a group that came out such as halogen (e.g., równomolowych quantities), and then, if necessary, reaction may occur with R3Ł (e.g. równomolowych amounts), to create ii. Also in the alternative, and may be subjected to directed at aminacji using the appropriate aldehyde or ketone to create ii. Compound ii can be the fact /.mydlony and in conditions known in the art przereagować with Amin ni to create La, where R₂ and/or R3 is other than hydrogen.

|0039| the preparation Methods useful podstawników compounds And are illustrated in the following Schemes 1 to XI.

- 13 Scheme B

<img file="PL1610780T3_D0005.tif" />

|0040| Scheme B illustrates a General method of establishing communication Ib which is a compound of formula 1 where Z is -CH=CH - X - | and X2 together form =O, As shown in Scheme B, the compound 2-Hey - yi can be prepared in the reaction, respectively, person, when 2-amino - halogenkiem ia with copper (ii) and azotynem-alkyl, such as nitrite, tert-butyl in a solvent such as aprotycznym acctonitryl, to link 2-Hello - iv (see J. Het. Chem. 22, 1621 (1985)). Compound iv can be reduced by a factor of a reducing agent such as sodium borohydride in ethanol or aqueous tetrahydrofuran, to generate alcohol which can be oxidized oxidizing factor, such as chlorochromian dichromian pyridine or pyridine to generate aldehyde y. The ratio y can be przcrcagować acetate alkilo(trifenylofosfozylidenu) to create karboksylanu yi. The relationship yi can be.e to be zmydlony and then przcrcagować with amine iii by methods known in the art, in order to create a vii. Compound vii can przereagować of Amin And^RjNH to create Ib where Z is -CH=CH -, and??, X2 together form =0.

- 1 alternatively, a compound of formula Ib, where R2 and Rj are H, can be created by przereagowanic connection vii with its amendments substituted amine of benzyl, such as 4metylobcnzyloamina to create the link ix, which can be hydrogenolizowany or exposed to acids such as acid and acid trifluorometanosulfoniowy trifluorooctowy in the presence anizolu to create Ib, where R2 and R3 are wodorami.

[0041] Methods for preparing compounds useful podstawników And illustrated in the following schemes I-XI.

Scheme C

<img file="PL1610780T3_D0006.tif" />

[0042[ Scheme C illustrates a General method of creating a communication Ic, which is a compound of formula I, where Z -R|jC=CH - Xi and X2 together form =O, As shown in Scheme C, the compound 2-amino - ia will przereagować with chloroformianem or pirowęglanem for

- 15utworzenia x, which can be zmydlony and subjected to a reaction with the reagent organolitowym to create xi. Relations xi can przereagować acetate alkilo(trifcnylofosfozylidenu) with the following inclusion covering group karbaminianowej to create xii. In addition, the relationship of lc, where R2 and R3 are wodorami can be created zmydlenie xii followed by reaction of the amine with RiRńNH ways known in the art. In addition, the relationship may przereagować xii with R₂L, where L is the opuszczająca group such as halogen (e.g., równomolowych amounts) optionally followed by reaction with R3L (for example, in równomolowych quantities) to create xiii, which can be zmydlony and przereagować with the amine R₄R;NH of ways known in the art, to create La where R2 and/or R3 is other than hydrogen.

|0043| the preparation Methods useful podstawników compounds And are illustrated in the following schemes l to XI.

Scheme P

<img file="PL1610780T3_D0007.tif" />

|0044| Scheme D illustrates a General method for creating connection Id, which is a compound of formula I, where X, and X₂ together form =S. the Compounds of the formula la obtained in the Scheme, And can be converted to the appropriate tioamid Id using a reagent such as Lawessona reagent (2,4-bis-(4-metoksyfcnylo)-l,3-ditia-2,4-difosfctan-2,4-disulfide (see meanwhile. Soc. Chim. Belgian., 87, 223 (1978)).

|0045] Methods for preparing compounds useful podstawników And illustrated in the following schemes I-XI.

Diagram Of The Electronic

<img file="PL1610780T3_D0008.tif" />

|0046| Scheme E illustrates a General method for creating connection Ie, which is a compound of formula I, where Xi and X₂ each hydrogen. As shown in Scheme E, the compound of formula Id obtained in Scheme D may be converted to the corresponding aminę Ie reduction, for example by reaction with Nickel Raneya.

- 16|fl047) Methods for preparing compounds useful podstawników And illustrated in the following schemes I-XI.

Scheme 1

?.

cocrr

Rj.COOPo (1)Princip R. X

X "is halogen, R" alkyl, aryloalkil

COM or cykloalkil (2) KOH

OOO

COOK (A) synthesis setting peptydowego, ie a connection to

And

H

OR a (B) synthesis via acid chloride, i.e.,

(1) chloride or chloride tionylu oksalilu

And

H li

<img file="PL1610780T3_D0009.tif" />

Rj = COORi starting at 2: R " is alkyl, aryloalkil or cykloalkil since 2: R · H

- 17 |((((48], As shown in the Diagram And karboksylan and can przereagować with chloroformiancm or pirowęglanem to create?. The ratio X can be subjected to alkali, such as sodium wodorek, heksametylodisilazan sodium/potassium or lithium diizopropyloamid (LDA), and factor alkilującego ^?, where X is halogenem, And&lt;2 is preferably alkilem, aryloalkilem or cykloalkiloalkilem, and then zmydlony aqueous solution of alkali such as potassium hydroxide, to obtain 2. Alternatively? may be subjected to reduktywnej aminacji with the appropriate aldehyde or ketone and zmydlony aqueous solution of alkali such as potassium hydroxide, to obtain 2. In addition, the ratio X may be just zmydlony aqueous solution of alkali such as potassium hydroxide to obtain 3, where R2 is hydrogen.

|0049| Acid 2 can przereagować with amine iii under the reaction conditions well known in the field of synthesis of mate pcptydowych (see, e.g., Bodanszky and Bodanszky, The Practicc of Pcptidc Chcmistry, Springer-Verlag, 1984; Bodanszky, Principlcs of Peptide Synthesis, Springer-Verlag, 1984) with the creation of the Id, which is a compound of formula I, where X] and X2 together form =0, R3 is - COOR*, but because 2 is the starting material, R2 is preferably alkilem, aryloalkilem or cykloalkiloalkilem. For example, reagents which activate the karboksylową group of 2 for reaction with the amine IV include the acid chloride bis(2-oxo-3oksazolidynylo)-fosfïnowego (BOP chloride), benzotriazol heksafluorofosforan-l-iloksytris(dimctyloamino)fosfoniowy (BOP reagent), heksalluorofosforan O-(7-azaibenzotriiz^|’.oll-ilo)-lll,3,3 tterrcmietyluroniiowy (HATU) and karbodiimidy such as dicykloheksylokarbodiimid (DCC) or 3-ethyl-3’-(dimetyloamino)propylokarbodiimid (EDCI) either alone or in combination with hydroksybenzotriazolem. In addition, an activated ester of transition can be identified and then subjected to the action of the corresponding amine iy aprotycznym in a solvent such as tetrahydrofuran (TI II·); or - dimethylformamide (DMF) in the presence of rules, for example, organic rules, such as heksametylodisilazan sodium/potassium trietyloamina, diizopropyloetyloamina 1.8-diazabieyklo(5.4.0)undek-7-ene (DBU), or a rule, inorganic such as sodium carbonate, potassium or cesium or wodorek sodium or potassium. In addition, you can prepare a halide of the acid 2 in the reaction with chloride or chloride tionylu oksalilu, following after her, with the reaction of amine iii and the creation of the If, which is the Union of wznrze in common, And where R3 is COOR*, X| and X2 together form =O, R2 is a alkilem, aryloalkilem or cykloalkiloalkilem.

]0050] the Similar reaction as used above for the conversion of 2 to If may be used for the transformation of 3 to If where R3 is COOR^, Xi and X2 together form =O, R2 is a hydrogen.

- IR

<img file="PL1610780T3_D0010.tif" />

|0051] As shown in Scheme II, acid 4 where R₂ R3 and nothing they wodorami and choose Polish to the nitrogen to which they are attached to, was not alkaline, is reduced to the aldehyde 5 by means well known in the state of the art (see March, Advanccd Body Chemistry, Wilcy, 1985). For example, the acid 4 may be converted to the corresponding ester, which can then be reduced wodorkiem diizobutyloglinu. In addition, the acid 4 may be reduced to the corresponding original alcohol, for example, through the performance of actions, he made it/TI IF, L1AIH4 or decrease mixed bezwodnikiem with following oxidation to the aldehyde 5 with the use of Cr(IV) (for example, chlorochromianem pyridine, "PCC") or under Swcrna or Moffatta (for example, (COClh&gt;/dimctylosulfotlenkiem). Output acid 4 may be obtained, for example, by zmydlenie ii.

|0052| Reduktywna aminacja (see And ludlicky, Rcductions in Body Chemistry, Wilcy, 1984) of aldehyde 5 amine iii in the presence of a factor in the reduction, such as NaBH.iCN NaBFROAch (Ac = group acctylowa) or water and a catalyst palladowego gives as a product of the relationship of IG amine which is a compound of formula I, where X - | and X2 each hydrogen, and R2 and R3 is not hydrogen.

- 19Schemat III

<img file="PL1610780T3_D0011.tif" />

|0053|, As shown in Scheme LII, reduction of the acid 4 to a primary alcohol (for example, through the performance of actions boranu/tetrahydrofuranu, LiAlHą or decrease mixed bezwodnikiem), and the subsequent transfer by methods well known in the languishing art (see March, Advanced Body Chemistry, Wilcy, 1985), provides 6. which contains a group that came out, such as halide, tosylan (OTs), mesylan (OMs) or trifluoromctanosulfonian (oti). Groups R2 and Rj are selected to the nitrogen to which they are attached, nothing was alkaline. The connection 6 may then be converted into compound Ih, which is a compound of formula I, where Xi and X2 each hydrogen, and R2 and R3 is not hydrogen, by the reaction of substitution of the amine iii, preferably, when the amine iii is given in excess.

-20Schemat IV

R2· any defined group patented, dermatological or tioacyl

<img file="PL1610780T3_D0012.tif" />

(Xi,X₂*H] .

|0054| Scheme IV illustrates methods which may be used to prepare compounds' Ij, Ik, II, Im and In. Ik, II, Im and In are compounds of the formula I where R2 is any group in accordance with the definition, Rj is a group acylową or tioacylow-a, X| and X2 are not wodorami, and R| is not Amina pierwszorzędową no drugorzędową. Ij, Ik, II, Im and In have other particular podstawniki described in this Scheme and below. The output connection Ii can be prepared by methods described in Schemes A and S).

|0055| Amide Ij can be obtained using the relationship representation aminowego Ti action) substituted aromatic carboxylic acid 7_w the presence of reagents which activate the karboksylową group for reaction as described above, for example BOP reagent, IIATU and karbodiimidów such as DCC or EDCI or in combination with hydrokśybcnzotriazolem. Alternatively, the halide material 8 may be a reaction with the Union aminowym Ii in the presence of acid

-21 destroyer, such as diizopropyloetyloamina. Suitable tioamid Ik can be prepared via submission amide Ii (where X|,X₂#O) the action of the reagent Lawcssona as described above.

|0056| Karbaminian II can be prepared via the action on the relations of the amine Ii chloroform pirowęglanem Jan 9 or 10 in the presence of an acid breaker such as diizopropyloetyloamina.

|0057| Urea Im may be prepared presentation of aminowego Ii when the actions of one of the following: 1) chloroformianu 9, such as fenylochloroformian, and then the reaction of the amine with n 2) karbamoilu chloride 12 in the presence of an acid breaker such as diizopropyloetyloamina, or 3) reaction with isocyano 13A (where Rc Im = H). Suitable dynamic In can be prepared manual for tioizocyjanianem 13b on the relations of amine Ii.

|0058| G._and selected from the group covered by the definition of R&lt;, Yes, zc group G(=A)-R_and this group acylową or tioacylową lying in the definition of Rj. Rb and R_c they are selected from the groups included the definitions of R7 and RG so that the group -C(=A)-N(Rb)(Rc) is a group acylową or tioacylową lying in the definition of Rj.

Scheme V

R₂"any particular group other than acylowa

Rj· alkyl, cykloalkil, cykloalkiloalkil, cykloalkenyloalkil, aralkil or rich heteropierścień

<img file="PL1610780T3_D0013.tif" />

-22|0059] Scheme V illustrates a method that can be used for the preparation of Ip, which is a compound of formula I, where R₇ any particular group other than aeylowa and which is selected so that the nitrogen to which it is connected, was alkaline, R3 is alkilem, cykloalkilem, cykloalkiloalkilem, cykloalkenyloalkilem, aralkilcm or rich hctcropicrścieniem, and Xi and Χ2 nothing they wodorami. Output connections Io and Iq can be prepared by methods described in Schemes A and D.

|0060] As shown in Scheme V, the ratio of amine Io is subjected to reaction with ketonem aldehydem or £4 in the reduktywnej aminacji described above, to obtain the Ip. Ip communication can be done through the effect on the relationship of Amina Iq, where R? and R3 are wodorami, azotynem tert-butyl or azotynem sodium halide in the presence of copper (II), to obtain replaced halogenem connection 15, and then through substitution of the amine £6 in the presence of alkali, such as wodorek sodium or potassium or similar (see Lee et al., Yu And leterocyclic Chemistry, 22, 1621 (1985)).

|0061] Ra and R" are independently selected from hydrogen, alkyl, arylu, cykloalkilu or cykloalkcnylu, or both alkilenami or alkenylenami complementary 3 - to 8-membered ring, saturated or unsaturated, so that the group -CH(Rd)(Rc) is a group lying in the definition of R3.

Scheme VL

R2 = any particular group other than acylów^rand R3 = aryl, heteroaryl

<img file="PL1610780T3_D0014.tif" />

|0062| As shown in Scheme VI, when R2 is any of a certain group other than aeylowa and selected Polish to nitrogen, dn which are connected was alkaline, R3 is arylcm or hctcroarylcm, and X| and X2 are not wodorami, relationships amine IR can be reaction with a group halofenylową or haloheteroaromatyczną 17 in the presence of a catalyst palladowego (0) (see J. Am. Chem. Soe., 118, 7215 (1996)), to get aminę Is, which is a compound of formula I, in which special podstawniki described in this Scheme. Output' connection IK may be prepared by methods described in Schemes A and D.

Scheme VII

And&lt;2 = any defined group R3 = heteroaryl

<img file="PL1610780T3_D0015.tif" />

|0063] As shown in Scheme VII, when R2 is any group in accordance with the definition, and Ri is a group hetcroaromatyczną, relationships amine ll may, if necessary, in the presence of rules, to be reaction with 2-halopodstawionym Union hetcroaromatycznym 17, where Qi together with the atoms to which attached form a 5 - or 6-członową jednopierścieniowa or 10 - to 12-członową dwupicrścicniową group heleroaromatyczną (e.g., forming 2chloropirydynę or 2-chlorcpirymidynę) to obtain aminę lu where lu is the Union of the painting And special podstawnikach described in this Scheme. Output connection lt may be prepared by methods described in Schemes A and

D.

Scheme VIII

<img file="PL1610780T3_D0016.tif" />

ln (Χ1.Χ2* HJ |(Mli&gt;4|, As shown in Sciemacie VIII, the relationship tiomocznikowy ln, where X| and Χ2 wodorami nothing they can przcrcagować with the appropriate amine in the presence of the acid chloride bis(2-okso3-oksazolidynylo)-fosfinowego (BOP chloride), heksafluorofosforanu bcnzotriazol-1-iloksytris(diinetyloamino)fosfoniowcgo (BOP reagent), heksafluorofosforanu O-(7azabenzotriazol-l-yl)-l ,1,3,3-tetrametyluroniowcgo (HATU) and karbodiimidu such as dieykloheksylokarhodiimid (DCC), 3-ctylo-3’-dimctylamino)propylokarbodiimid (EDCI) or diizopropylokarbodiimid (D1C) in the presence of organic principles, such as trietyloamina, diizopropyloetyloamina or dimetyloaminopirydyna in solvents such as; - dimethylformamide, dichloromethane or tetrahydrofuran, to create the link lv is the compound of formula I, in which special podstawniki described in this Scheme.

|Q065| in addition, relationships can przereagować ln. appropriate amine in the presence of salts of mercury (II), such as mercury chloride, or other methods known in the literature, with the creation of the lv.

-24Schemat IX

<img file="PL1610780T3_D0017.tif" />

|0066|, As shown in Scheme IX, amine IR, where Xi and Χ2 wodorami nothing they can przereagować with difenylocyjanokarbonimidatem itself or in the presence of alkali, such as sodium wodorek, heksametylodisilazan sodium or dimetyloaminopirydyna in acetonitrile, tetrahydrofuranie or dimetyloformamidzie at room temperature or elevated, to create a transitional connection I. The Union And may przereagować with Amina RjReNII to link Iv, which is a compound of formula I, in which special podstawniki described in this Scheme.

-25 X Scheme

<img file="PL1610780T3_D0018.tif" />

|0067| As shown in Scheme X, the relationship IK, where X - | and X2 are not wodorami may przereagować with 18 or or In himself or in the presence of alkali, such as sodium wodorek, heksametylodisilazan sodium or dimelyloaminopirydyna in dimetyloformamidzie or tetrahydrofuranie at room temperature or higher, to generate, respectively, compounds Ix or ly, which can przereagować with amine R?R"NH at room temperature or elevated, to create, respectively, And, or, And*. Bond And the compound of formula I, which is a special podstawniki described in this Scheme. Union And* is the compound of formula I, in which special podstawniki described in this Scheme.

Scheme XI

R2 = aryl, heteroaryl, heteroaryl dwupierścieniowy

-26Ri = hydrogen, alkyl, aryl, hctcroaryl, dwupierścieniowy hctcroaryl

<img file="PL1610780T3_D0019.tif" />

|0068|, As shown in Scheme XI, compounds of formula 1 can be prepared from 15 by the action of a specific amine in the presence of acid catalyst (see, e.g., Gunzenhauser et al., Helv. Chim. Acta, 71,33 (1988)).

<img file="PL1610780T3_D0020.tif" />

in which:

each R|, R3 and R4 is independently a group heterocykliczną or arylową, optionally its substituted by one or more bases of columns; and R 2 is hydrogen or alkilem.

|0070| According to the present invention, the compound of formula IV or a salt thereof is used for the production of a medicinal product for oral treatment of certain types of cancer:

<img file="PL1610780T3_D0021.tif" />

Application |00711 Compounds disclosed in the present description inhibit protein kinase tyrozynowc, especially kinases of the Src family, such as a Drug, Langeland, Lyn, Src, Yes, Hck, Fgr and Blk, and are thus useful in the treatment, in the prevention and treatment of disorders associated with protein kinazami tyrozynowymi, such as disorder, immunological and cancer. These compounds also inhibit the kinase receptorowe tyrozynowe, including those of her1 and 1IER2, and thus useful in the treatment of disorders rozrostowych such as psoriasis and cancer.

-27Zdolność wonderful compounds for inhibiting IIER1 and other kinases receptorowych will also allow you to use them as factors, anti-angiogenicznych in the treatment of disorders such as cancer or diabetic retinopathy. "Disorders associated with protein kinazami tyrozynowymi" are violations which lead to incorrect tyrosine kinase activity and/or improved via inhibition of one or more of these enzymes. For example, inhibitors are the Drug valuable in the treatment of several disorders such as, for example, in the treatment of autoimmune diseases, because inhibition of Drug blocks the activation of t cells for the treatment of diseases involving T cells, including inhibition of activation and proliferation of T-cells, disclosed here. Preferred are compounds which selectively inhibit the activation and proliferation of t-cells, Compounds that block the activation of PTK. epithelial cells on oxidative stress, limiting surface expression of adhesion molecules that cause bondage ncutrofili, and which cause the inhibition of PTK required for the activation of neutrophils, are used, for example, in the treatment of ischemia and syndrome reperfuzyjnego.

|0072| In this description are disclosed methods of treating disorders associated with protein kinazami tyrozynowymi, including the step of supplying the first, if necessary, at least one connection to formula 1 in sufficient quantities. Other therapeutic factors, such as those described below can be applied together with the archives of trade unions in accordance with the described methods. According to these methods, such therapeutic factors therapeutic factors, may be before, during or as a result of the provision of publicly available communication of the identified compounds).

|0073| the Use of these compounds in the treatment of disorders associated with protein kinazami tyrozynowymi can be illustrated by, but is not limited to treat a number of disorders, such as transplant rejection, such as rejection of organ transplant, acute transplant rejection, rejection ksenograftu or homograflu such as is used for the treatment of burns; protection from ischemia or team reperfuzyjnym, as in the case of ischemia or group reperfuzyjnego produced during organ transplantation, myocardial infarction, stroke or other causes; induction of tolerance in transplantation; arthritis, such as rheumatoid arthritis, psoriatic arthritis, degenerative joint disease; multiple sclerosis; chronic obstructive pulmonary disease (COPD) such as emphysema; nonspecific intestinal inflammation, including inflammation of the large wrzodzicjącc gnibego and Crohn's disease; systemic lupus erythematosus, systemic lupus erythematosus (SLE); disease "graft versus host"; hypersensitivity of type IV, including contact hypersensitivity, delayed type hypersensitivity; disease with an extreme sensitivity to gluten - celiac disease; psoriasis; contact dermatitis, including caused by poison ivy; Hashimoto's thyroiditis; Sjogren's syndrome; hyperthyroidism, on the surface of autoimmune origin, such as illness Gravcsa'; Addisonapierwotna disease hypofunction of adrenal cortex; autoimmune wielogruczołowe team, also known as auto immune syndrome wielogruczołowy; alopecia on the basis of autoimmune origin; anemia of the Addison-Biermera; vitiligo acquired; we treat Simmondsa on the basis of autoimmune origin; Guillain-Barrcgo; other autoimmune diseases; tumors, including cancer, in which a Drug or other kinases

-28rodziny Src are activated or nadcksprymowanc, as in the case of colon cancer and grasiczaka, and cancer in which the activity of Src family kinases promotes growth or survival of the tumor; glomerulonephritis; serum sickness; urticaria; allergic diseases such as respiratory allergies - asthma, hay fever, rhinitis on the basis of Allergy or allergies; scleroderma; granuloma grzybiasty; acute inflammatory response - the same as acute respiratory distress syndrome and nicdokrwienic/zcspół reperfuzyjny; dermatomyositis; alopecia areata; chronic wypryskowe dermatitis; eczema; disease Behęeta; krostkowica hands and feet; piodermia zgorzelinowa; team Sćzary Potter; atopic dermatitis; systemic scleroderma and lupus erythematosus, scleroderma localized. In addition, in this description discloses a method of treating the aforementioned disorders such as atopic dermatitis, putting any relationship, capable of inhibiting protein tyrosine kinase.

|0074| the family of Src Kinases, than other Medications such as Hck and Fgr, are important in the reactions of the Fc gamma receptors of monocytes and macrophages. Compounds disclosed in the present description inhibit depending on FC gamma production of TNF-alpha in the communication line of monocytes THP-1, which is not eksprymuje Drug. The ability to inhibit the response of monocytes and macrophages' dependent receptor Fc gamma causes additional anti-inflammatory activity of these compounds beyond their effect on cells T. This activity is particularly valuable, for example, in the treatment of inflammatory diseases such as arthritis or nonspecific intestinal inflammation. In particular, these compounds are valuable in the treatment of glomerulonephritis on the basis of autoimmune origin and other cases of glomerulonephritis caused by deposition in the kidney immune complexes, which cause a reaction of Fc gamma receptors, leading to kidney damage.

|0075| in addition, kinases of the Src family than other Medications such as Lyn and Src, the actual recipe in the called Fc Epsilon degranulacji mast cells and basophils that plays an important role in asthma, nieżycie nose on the basis of allergic and other allergic diseases. The Fc Epsilon receptors are stimulated by complexes of IgE-antigen. Identified in the present compounds inhibit the reaction degranulacji sent Fc Epsilon, including communication lines RBL basophils, which is nothing eksprymuje Drug. The ability to inhibit depending on Fc Epsilon response of mast cells and basophils, which causes additional anti-inflammatory activity of these compounds beyond their effect on cells T. In particular, these compounds are valuable in the treatment of bronchial asthma, rhinitis, on the substrate, allergic and other cases of allergic diseases.

|0076| related to the activities of these associations focused on monocytes, macrophages, T-cells, etc. can be valuable in the treatment of any of the above violations.

|0077| the Compounds disclosed in this description, are useful in the treatment of the above listed examples of disorders irrespective of their etiology, for example, in the treatment of the impact of transplant, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, nonspecific inflammation of the bowel, lupus, the disease "graft versus host", of type IV hypersensitivity, psoriasis, inflammation of the thyroid gland And lashimoto, syndrome of Guillain-berry, cancer, contact dermatitis, diseases

-29alergicznych such as rhinitis on the basis of allergic, asthma, ischemia or syndrome reperfuzyjny or atopic dermatitis associated or not with PTK.

|0€78| Due to its ability of inhibiting kinase of her1 and IIER2, the compounds disclosed in the present description, can also be used in the treatment of diseases rozrostowych, including psoriasis and cancer. It has been shown that the janus kinase receptorowa IIER1 is eksprymowana and activated in many solid tumors, including niedrobnokomórkowym lung cancer, colon cancer and breast cancer. It was also shown that the janus kinase receptorowa IIER2 is nadeksprymowana in cancers of the breast, ovaries, lungs and the stomach. Monoclonal antibodies that reduce the number of receptors IIER2 or block signaling via the receptor of her1, przcciwguzową show efficacy in preclinical studies and clinical. Expecting, therefore, that kinase inhibitor of her1 and IIER2 be effective in the treatment of tumors dependent on signaling through one or both receptors. Hopes that these relations will be effective either as single factor or in combination with other chemotherapeutic factors, such as placlitaxel (Taxol), doxorubicin hydrochloride (adriamycyna) and cisplatin (Platinol). Cm. these documents and given them links: Cobleigh, ?. ?, Vogcl, C. L., Tripathy, D., Robert, N. J., Scholl, S., Fchrenbacher, L., Wolter, J. M., Paton, V., Shak, S., Lieberman, G. and Slamon, D. Yu., "Multinational study of the efficacy and safety of humanization of anti-IIER2 monoclonal antibody in women who havc HER2-overexpressing metastatic breast cancer that has progressed after chcmotherapy for metastatic discase", J. of Clin. Oncol. 17(9), pp. 26392648 (1999); Basclga, J., Pfister, D., Cooper, M. R., Cohen, R., Burtncss, B., Bos, M.. D'andrea, G., Simon, A. Norton, L., Gunnett K, Falcey, J., Anderson, V., Waksal, II., Mendelssohn, .1., "Phasc And studies of anti-epidermal growth factor receptor antibody C225 chimcric alonc and in combination with cisplatin", J. Clin. Oncol. 18(4), p. 904-914 (2000).

|0079| the Compounds disclosed in this description, are useful in the treatment of cancer, such as chronic myelogenous leukemia (CML), cancer podścieliskowy the gastrointestinal tract (GIST), small cell lung cancer (SCLC), niedrobnokomórkowy lung cancer (NSCLC), ovarian cancer, melanoma, mastocytoza, embryonal tumors, acute myelogenous leukemia (AML), for sarcomas, breast cancer, colon cancer, pancreatic cancer, prostate cancer and others which are known that they are associated with protein kinazami tyrozynowymi, such as, for example, SRC, BCR-ABL and c-KIT. Disclosed in the present description of the compounds are also useful in the treatment of tumors sensitive and resistant to factors chemoterapeutycznc directed to BCR-ABL and c-KIT such as Gleevec® (ST1-571).

|0080| in addition, in this description disclosed pharmaceutical composition, covering at least one of the compounds of formula I, which is able to treat disorders associated with protein kinazą tyrozynową effective for this purpose, the amount, and a pharmaceutically acceptable carrier or diluent. The compositions may contain other therapeutic factors, as described below, and can be designed, for example, by use of conventional solid or liquid carriers or rozpiJsy£zalnikWw'|, and additives, pharmaceutical preparations suitable for the desired method of administration (e.g., excipients, indicate, preservatives, stabilizers, flavors

-30etc.) in accordance with methods such as the methods well known in the field of pharmaceuticals.

|0081| Compounds of the formula I can be introduced in any suitable way, for example oral like tablets, capsules, granules or powders; sublingually; buccal; parenterally, by injection under the skin, intravenously, intramuscularly or machinery injection or infusion spinal (e.g., as sterile solutions or water suspensions or other than water intended for parenteral administration); to the nose, as a spray for inhalation; topically as a cream or ointment; rectally, in the form of suppositories; in single drugs for dispensing, containing non-toxic pharmaceutically acceptable carriers or solvents. These compounds can for example be submitted in the form suitable for immediate or sustained release. Immediate or prolonged release can be obtained by the use of appropriate compositions and pharmaceutical preparations including these compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or pump osmotycznc. Connections can also be provided in the form of liposomes.

|0082| Example compositions for oral administration include suspensions which can contain, for example, mikrokrystaliczną cellulose for imparting volume, alginowy acid or sodium alginate as a factor contributing to the maintenance of the suspension, metylocelulozę to improve kpkości and sweeteners or flavoring agents, such as known, languishing technology; tablets immediate release, which may include, for example, mikrokrystaliczną cellulose phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, bonding, support crushing, diluents and lubricants, such as known in the state of the art. Connections can also be submitted through the oral cavity by entering the sublingual and/or dopoliczkowe. Examples of forms that can be used, this tablet is extruded, pressed or dried or lyophilized. Example compositions include those that connect / relationship with fast rozpuszczającymi themselves solvent, such as mannitol, lactose, sucrose and/or cyclodextrin, these drugs can also be included auxiliary substances with high molecular weight, such as avicel cellulose, and polyethylene glycols (PEG). These preparations may also contain auxiliary substance, the auxiliary adhesion to the mucosa, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (IPMC), sodium salt karboksymetylocelulozy (PM), copolymer of anhydride maleinowego for example, Gantrez and the factors controlling the release such as copolymer of acrylic acid, for example, Carbopol 934. To facilitate the production and application can also be added lubricants, giving a slide, flavoring, colorants and stabilizers.

|0083| Example of compositions for intranasal administration of the dose via aerosol or by inhalation include solutions, in brine, which may contain, for example, benzyl alcohol or other suitable preservatives, substances that promote absorption, to enhance bioavailability, and/or other factors, or soluble dispersants, such as is well known, languishing technology.

-31 |0€84| Example of compositions for parenteral administration include solutions or suspensions, intended for injection, which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanodiol, water, ringer solution, isotonic sodium chloride solution or other suitable factors dispersing or moisturizing and lingering in suspension, including synthetic mono - and diglycerides and fatty acids including oleic acid.

|0085] the Sample compositions for the administration of enemas include suppositories which can contain, for example, suitable, nothing podrażniające excipients such as cocoa butter, synthetic esters glycyrrhizin or polyethylene glycols, which are solid at ordinary temperatures, but upłynniają and/or dissolve in the rectal cavity to release the drug.

|0086| Sample compositions for the local introduction include local media, such as Plastibase (mineral oil-generating gel with polyethylene).

|0087| Effective amount can be determined by an expert and includes an exemplary dose of the active substance for an adult is from about 0.1 to 100 mg/kg of body weight per day, this quantity can be given as a single dose or in separate doses porcjowanych, for example from 1 to 4 per day. It is clear that the exact dose and frequency of intake for each individual can be variable and depends on a number of factors, including the activity of the specific compound used, its metabolic stability and duration of work, type, age, body weight, General health, pici and diet of the subject, method and time of administration, rates wypróżniania, combination with other Ickami and how serious his condition is. Preferred people for treatment include animals, most preferably mammals such as humans, and domestic animals such as dogs, cats, etc., suffer from disorders associated with protein kinazami tyrozynowymi.

|0088| When applying intravenous disclosed here compounds, including the compound of formula IV, preferably served using the disclosed here of the drugs. In General, the compound of formula IV is administered via IV infusion over a period of time from about 10 minutes to about 3 hours, preferably from about 30 minutes to about 2 hours, preferably at about 45 minutes to 90 minutes, and most preferably okoto ¹ gódźmy. Typically, zw^iawith^Ki served dożytaie dose of okoto ^0,5m^gV /m ⁶⁵m^g/m ^, preferably with^d o^c ¹m^g/m ⁵⁰ mg/m ^korzystnicj from ototo ^2,5m^g/m ³⁰m^g/m ^, and najtarzysmiej ototo 25 m^g/m . Fachowtec without tru^du know, I^k przebcz.yc dose mg/kg or mg/m2, having the data or the height, or mass, or both the data for the patient.

|0089| As discussed above, the disclosed here compounds, including compounds of the formula IV, can be administered orally, intravenously, or both ways. In particular, disclosed here, the methods include procedures for dosing, such as once a day for 2 to 10 days, preferably from 3 to 9 days, more profitable, from 4 to 8 days and most preferably every 5 days. In one example implementation occurs in the period from 3 days to 5 weeks, preferably 4 days to 4 weeks profitable from 5 days to 3 weeks, and most preferably from 1 week to 2 weeks, in between cycles has no treatment. In another embodiment, the compounds, including compounds formula IV can be specified

-32doustnie, intravenously, or two ways once a day for 3 days. with a period of preferably 1 week to 3 weeks in between cycles where there is no treatment. In yet another example implementation of compounds, including compounds of the formula IV total, can be administered orally, intravenously, or two ways once a day for 5 days, with a period of preferably 1 week to 3 weeks in between cycles where there is no treatment.

|0090| treatment Cycle for filing disclosed here compounds, including compounds of the formula IV, may be once a day for 5 consecutive days, and the period between cycles of treatment may be from 2 to 10 days, preferably a week. The leak here is the link, for example, the compound of formula IV can be administered once a day for 5 consecutive days with following them after 2 days without treatment.

[0091J Disclosed here compounds, including compounds of formula IV may also be administered orally, intravenously or both ways from 1 to 10 weeks, preferably between 2 to 8 weeks, it is better every 3 to 6 weeks, and preferably every 3 weeks.

|0092| Disclosed here compounds, including compounds of the formula IV, can be enjoyed in the cycle 28dniowym, in which the compounds are administered intravenously on days 1, 7 and 14 and orally for 21 days. In addition, compounds, including compounds of the formula IV, can be flow in a loop 28dniowym.

I0093| Disclosed here compounds, including compounds of the formula IV, can be enjoyed until the moment when the patient shows a response, for example, the reduction of the roses.miaru of the tumor, or until, until you reach the dose limited by toxicity.

|0094| Disclosed here compounds can be used alone or in combination with each other and/or other relevant therapeutic factors useful in the treatment of related protein kinazami tyrozynowymi disorders such as PTK inhibitors other than the disclosed in the present description, anti-inflammatory drugs, przeciwrozrostowe, factors to chemotherapy, the anti-rejection drugs, anti-cancer factors and cytotoksycznc.

[0095| The examples of other therapeutic factors include the following: for example, cyclosporine, cyclosporin A, CTLA4-Ig, antibodies such as anti ICAM-3, the receptor przeciw1L-2 (Anti-Tac) against CD45RB, anti-CD2, przcciw-CD3 (OKT-3), vs'-CD4, anti-CD80, against'-CD86, monoclonal antibody OKT3, the factors blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and gp39 or for example, 54 CDI, protein synthesis, generated from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as inhibitors of the' nuclear translocation, about the function of NF-kappa B, such as deoksyspergualina (DSG), a nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen, steroids such as prednisolone or dexamethasone, gold compounds, factors przeciwrozrostowe such as methotrexate, FK506 (tacrolimus, prograf), mycophenolate mofctylu, medication cytotoksycznc such as azatiopiryna and cyclophosphamide, inhibitors of' TNF -?, such as tenidap, antibodies against TNF or soluble TNF receptor, such as ctanercept (Enbrel), rapamyeyna (sirolimus or Rapamune), leflunomid (arava), and cyclooxygenase-2 inhibitors (COX-2) such as celecoxib (Celebrex) and rofckoksyb (Vioxx), or derivatives thereof, and the PTK inhibitors disclosed in the following U.S. Patent Applications are hereby included in full

-33przez reference: Serial Number 60/056,770, complex 8/25/97 (Attorncy Case No. QA202*), Serial No. 60/069,159, complex, 12/9/97 (Attomey Case No. QA202a*), Serial No. 09/097,338, complex 6/15/98 (Attomey Case No. QA202b), Serial No. 60/056,797, complex 8/25/97 (Attomey Case No. QA205*), Serial No. 09/094,797, complex 6/15/98 (Attomey Case No. QA205a), Serial No. 60/065,042, complex 11/10/97 (Attomey Case No. QA207*), Serial No. 09/173,413, complex 10/15/98, (Attomey Case No. QA207a), Serial No. 60,076,789, complex 3/4/98 (Attomey Case No. QA208*) and Serial Number 09,262,525, complex 3/4/99 (Attorncy Case No. QA208a). Cm. these documents and given them links: Holłcnbaugh, D., Douthwright, J., McDonald, V., and Arufio A., "Cleavablc CD40Ig fusion proteins and the binding is sgp39”, J. Immunol. Methods (Nethcrlands), 188(1), str. 1-7 (Dcc 15 1995); Hollcnbaugh, D., Grosmaire, L. S., Kullas C. D., Chalupny, N. J., Braesch-Andersen, S., Nocllc, R. J., Stamenkovic, I., Ledbctter, J. A., and ArufTo, A., "The human T cell antigen gp39, a member of the TNF gcnc 1'amily, is a ligand for the CD40 receptor: exprcssion of a soluble form of gp39 with B cell co-stimulatory activity", EMBO J (England), 11(12), pp. 4313-4321 (Dec 1992); Moreland L. W. et al., "Treatment of rheumatoid arthritis with a recombinant human edema necrosis factor receptor (p75)-Fc fusion protein, New England J. of Mcdicinc, 337(3), pp. 141-147 (1997).

|0096| Examples of factors against cancer and cytotoxic factors include the way nieograniczający: factors alkilujące iperyty such as nitrogen, sulfoniany alkyl, nitrozomoczniki, etylcnoiminy and triazeny; antimetabolites such as folate antagonists, purine analogues, and analogues pirymidyn; antibiotics such as anthracyclines, blcomycyny, mitomycin, daktynomycyna and plikamycyna; enzymes, such as Lasparaginaza; inhibitors famezylowo transferase proteins; hormonal factors such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and antagonists releasing hormone luteinizing hormone, acetate oktreotydu; factors dezorganizujące mikrotubule such as ekteinascydyny or their analogs and derivatives; stabilizing factors mikrotubule such as paklitakscl, docetaxel and epotilony?-F or their analogs or derivatives, herbal products such as the Vinca alkaloids, cpipodofilotoksyny, taksany; and inhibitors* topoisomerase; prcnylowobiałkowej transferase inhibitors; and miscellaneous factors such as hydroksymocznik, prokarbazyna, mitotan, hcksamctylomelamina, coordination complexes of platinum, such as cisplatin and carboplatin; and other factors that are used as factors przeciwr-akowe or cytotoxic factors such as biological response modifiers, growth factors; immunological modulators and monoclonal antibodies. Relationships identified in the present can be too.used in conjunction with therapy radiacyjną.

|0097| Representative examples of these classes of factors, anticancer and cytotoxic factors include the way nieograniczający: mechlorclaminy hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamid, busulfan, karmustynę, lomustynę, semustynę, streptozocynę, tiotepę, dakarbazynę, methotrexate, thioguanine, merkaptopurynę, fludarabinę, pentastalynę. kladrybinę, cytarabinę, fluorouracil, hydrochloride doksorubieyny, daunorubicynę, idarubicynę, sulfate blcomycyny, mitomyeynę C, D aktynomycynę, safracynę, saframycyny, chinokarcyny, diskodermolidy, winkrystynę,

-34 winblastynę, winian winorebiny, etoposide, tenipozyd, paklitaksel, tamoksyfcn, cstramuslynę, salt largest phosphate cstramustyny, flutamid, buzerelinę, lcuprolid, pterydyny, diyncscs, Iewamizol, aflakon, interferon, inlerleukiny, aldeslcukinę, the drug filgrastim, sargramostym, rituksymab, BCG, tretinoinę, irinotekanu hydrochloride, betamethasone, gemcitabine hydrochloride, and altrctaminę topotekan, and any of their analogs or derivatives.

|0098| Priority members of those classes include the method nieograniczający paklitaksel, cisplatynę, karboplatynę, doksorubicynę, karminomycynę, daunorubicynę, aminopterynę, methotrexate, metopterynę, mitomycynę C, ekteinascydynę 743, porfiromycynę, 5iluorouracyl, 6-merkaptopurynę, gemcytabinę, arabinazyd cytozyny, podofilotoksynę podofilotoksyny or derivatives such as etoposide. phosphate etopozydu or tenipozydu, melphalan, vinblastine, vincristine; leurozydynę, windezynę and leurozynę.

|0099| Examples of factors to push iwrakowych and other factors cytotoxic agents include the following: derivatives epotilonu who are in U. S. a Serial Number. 09/506,481, made on 17 February 2000 (Attomey Case No. LD186); German Patentcie No. 4138042.8; 97/19086 WO, WO 98/22461, 98/25929 WO, WO 98/38192, 99/01124 WO, WO 99/02224, 99/02514 WO, WO 99/03848,

W099/07692,W099/27890,W099/28324,W099/43653,W099/54330,W099/54318,W099/5 4319,WO99/65913, WO 99/67252, WO and WO 99/67253 00/00485; inhibitors of kinase-dependent cyklin who are in GRIEF 99/24416; and prenylowo transferase inhibitors, proteins that are located in MOUNT 97/30992 and WO 98/54966.

|0100| the Above factors therapeutic used in combination with the compounds of the archives in the present description, can be used, for example, in the amounts indicated in the Physicians' Desk Refcrence (PDR) or otherwise determined by the specialist.

|0101] the Following attempts can be used to determine the degree of activity relationship ("relationship test") as a PTK inhibitor. Compounds described in the following Examples were tested in one or more of these tests and showed activity.

Attempt enzymatically with the use of the Drug, Langeland, Lyn, Hck, Fgr, Src, or Yes lilk |0102| the Next attempt was carried out using the protein tyrosine kinase Preparation, Langeland, Lyn, Hck, Fgr, Src, Blk and Yes.

|0103] Protein kinazę tyrozynową that is the subject of interest is kept in kinazowym buffer (20 mm MOPS, pH7, 10 mm MgCb) in the presence of the compounds tested. The reaction is initiated by adding substrate to a final concentration of 1 ?? ATP, 3.3 V pCi/ml [33P] gamma-ATP, and 0.1 mg/ml zdenaturowanej in the enolazy acid (prepared as described in Cooper, J. A., Esch, F. S., Taylor, S. S., and Hunter, T., "Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro", J. Biol. Chem., 259, 7835-7841 (1984)). The reaction is stopped after 10 minutes add 1.0% of" acid triiluorooctowego, 100 mm sodium pyrophosphate followed by 2 mg/ml bydlęcej of albumin in plasma. Protein substrate znakowanej enolazy precipitated at 4 degrees, gathers Packard Unifilter plates and counted in the Topcount counter scyntylacyjnym to determine the activity inhibicyjną protein tyrosine kinase of the test compound (activity Vice versa

-35proporcjonalną to the number of received znakowanej cnolazy). The exact concentration of reagents and the number of tags can be changed as needed.

|0104| this Test is positive, as it uses egzogenny substrate (enolazę) for more accurate enzyme kinetics, and can be held in the format of 96-studzienkowym that can be easily automated. In addition, His-tagowanc protein kinase tyrozynowe (described below) offer much higher performance and purity compared to the protein fuzyjnym GST-białkowa janus kinase tyrozynowa.

|0105| Białkowa janus kinase tyrozynowa can be obtained from commercial sources or recombinant methods described in the present description. For the preparation of a recombinant Drug is preparing a human Drug as a His-tagged protein using the vector pFastBac bakulowirusowego lita in insect cells commercially available from Life Technologies (Gibco). The Drug label human cDNA isolated by PCR (polymerase chain reaction; polymerase chain reaction) is introduced to illustrate and cksprymowano proteins using the methods described by the manufacturer. The product was purified via chromatografię affinity. In order to produce the Drug in insect cells using bakulowirusa. Spana, C.,'Rourkc, E. C., Chub, J. B., and Fargnoli, J., "Analysis of the p561ck tyrosine kinasc expresscd and antioxidant action regenerates S-lransferase protein in Spodoptera frugiperda cells," Protein expression and purification, Vol. 4, p. 390-397 (1993). Similar methods can be used for recombinant production of other Src family kinases.

Attempt enzymatically using IT AND or HER2 |0106] the Relationship that is the subject of interest was conducted in kinazowym buffer that contained 20 mm Tris.HCl, pil of 7.5, 10 mm MnCh, 0.5 mm diliotreitolu, cow albumin plasma concentration of 0.1 mg/ml poly(glu/Tyr, 4:1) with a concentration of 0.1 mg/ml, 1 mm ??? and 4 mCi/ml gamma^{33 P}]^ATP. ⁴J) s^yn^tc^youü^ym poHmerem., ^kt^onry slime^y shed the coin slot fosforytu and ordered from Sigma Chemicals. The kinase reaction results in the addition of enzyme, and the reaction mixture is kept at 26°C for 1 h. The reaction is stopped by adding EDTA to a concentration of 50 mm and proteins are precipitated by adding acid triiluorooctowego in 5% concentration. Separated proteins are recovered by filtration on Packard Unifiltcr plate, and the amount of radioactivity measured on a built-in counter scyntylacyjnym Topcount.

(0107] For preparation of recombinant IIER1, cytoplazmatyczną sequence cksprymowano receptor in insect cells in the form of a fusion protein GST, which oczyszczano chromatografią affinity, as described above for the Drug. Cytoplazmatyczna sequence IIER2 was wklonowana to bakulowirusowego expressive vector pBlueBac4 (Invitrogen) and cksprymowana as devoid of the marker protein in insect cells. Rekombinowanc protein was partially purified through chromatografię jonowymienną.

Attempts phones

3. Phosphorylation of cellular tyrosine |0108| T-Cell Jurkat incubate with the tried and tested Union, and then stimulated by adding antibodies against CD3 (monoclonal antibody G19-4). After 4 minutes

-36lub other desired time cells were lizic by adding lizującego buffer containing the detergent NP-40. Phosphorylation of proteins was detected by using immunoblotting directed against fosfotyrozynie. Phosphorylation of certain proteins of interest such as ZAP-70 was detected by using immunoprecypitację with the current against ZAP-70, and then immunoblotting directed against fosfotyrozynie. Such procedures are described in Schieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., ASP, J. B., Kanner, S. B., and Ledbetter, J. A., "ZAP-70 tyrosine kinase, CD45 and T cell receptor involvemenl in l JV and H2O2 induccd T cell signal transduction", J. Biol. Chem., 269, 20718-20726 (1994) and their attached links. Inhibitor the drug inhibits the phosphorylation of tyrosine in the proteins of phones called antibodies przcciwCD3.

|0109] for the preparation of G19-4, see Hansen, J. A., Martin P. J., Beatty, R. G., Clark, E. A., and Ledbetter, J. A., "Human T lymphocyle cell surface molecules defined by the workshop monoclonal antibodics," in Leukocytc And Typing, A. Bernard, J. Boumscll, J. Dausett, C. Milstein, and S. Schlossman, EDS (New York: Springer Vcrlag), str. 195-212 (1984); and Ledbetter, J. A., Junc, C. H., Rabinovitch, P. S., Grossman, A., TSU, T. T., and Imboden, J. B., "Signal transduction through CD4 receptors: stimulatory vs.. inhibitors* activity is regulated by CD4 proximity to the CD3/T cell receptor", Eur. J. Immunol., 18, 525 (1988).

3. Attempt calcium |0110] the Inhibitors' Drug blocks the calcium mobilization in T cells stymulowanych antibodies anti-CD3. In cells injected dye proportion of calcium Indo-1 and antibodies anti-CD3, such as the monoclonal antibody G19-4, and then measured cytomctrem natural conditions the mobilization of calcium for registration changes colors blue/violet Indo-1 as described in Schieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., ASP, J. B., Kanner, S. B., and Ledbetter, J. A., "ZAP-70 tyrosine kinase, CD45 and T cell receptor iDYo^emcnt in UV and H2O2-induced T cell signal transduction", J. Biol. Chem., 269, 20718-20726 (1994) and the references attached, there is a link.

3. Attempts proliferacyjne |01111 Inhibitor the Drug inhibits the proliferation of normal human peripheral T-cells in the blood, stymulowanych to increase antibodies anti-CD3 and anti-CD28. Plate 96-studzienkową the same, the current monoklonalnym against CD3 (for example G194), allows you to associate przeciwciału, and then washed the plate. Antibodies associated with cost, used to stimulate cells. Normal human peripheral T-cells from the blood are added to wells together with tested composition and acting against CD28 to provide kostymulację. After the desired time (e.g. 3 days) is administered in cells [3HJ-tymidynę, and after further incubation embeds the labels to re-syntetyzowanego the BOTTOM, collect the cells and counted in the counter scyntylacyjnym to measure cell proliferation.

|0112J abbreviations used in the Examples are defined below. Compounds in Examples identificeret for example, the move serves (e.g. "1A"

-37oznacza in the title compound in step? Example 1) or example, when the relationship is a relationship heading for this example (e.g., "2" indicates the connection header Example 2).

Labels |0113| aq. = water (eng. aąueous) conc. = concentrated (eng. concentrated)

DMSO = dimetylosulfotlenek (eng. dimethyłsulfoxide)

EtOAc = ethyl acetate (eng. ethyl acetate)

Et2O = diethyl ether. ether diethyl phthalate (dep) CH = hours

HATU = heksafluorofosforan N-oxide N-ldimetyloamino-lH-l,2,3-triazolo-[4.5 b (pirydyn-1-yl-metylenoJ-N-metylometanoamoniowy Methanol = methyl alcohol

Pug = acid 4-morfolino-propanosulfonowy MS = mass spectrometry Ret Time = retention time

RT' = room temperature (from the English. room temperature) satd. = rich (English. saturated)

TFA = trifluorooctowy acid THF = tctrahydrofuran DMF= N,N -; - dimethylformamide

Example 1 (Reference)

Przygotowanie_estru_1, 1-dimctyloctylowego_kwasu_|5-H(2,4,6 trimetylofcnylojaminolkarbonyloM-methyl^-tiazolilolkarbaminowego |0114|

<img file="PL1610780T3_D0022.tif" />

3. Ethyl^-fgjrf-butoksykarbcinylooksyamijKM-inetylo-tiazpio-S-karhoksylan

-38[0115| Suspension of ethyl 2-amino-4-methyl-tiazolo-5-karboksylanu (18.6 g, 100 mmol), diwęglanu-di-tert-butyl (26.2 g, 120 mmol) and 4-dimetyloaminopirydyny (800 mg, 6,55 mmol) in dry tctrahydrofuranie (300 ml.) was stirred in an atmosphere of nitrogen for 18 hours. The solvent is evaporated in vacuum. The residue is suspended in dichlorometanie (1 L) and filtrowano through celit. The filtered substance was washed with 1 N aqueous HC1 (300 ml, 2x), water and brine, dried (MgSO₄) and concentrated in vacuo. The rest rozdrobniono with heksanami. Odfiltrowano permanent sediment and vacuum dried to obtain the title compound (20 g, 72%) as a brown solid.

B. Acid 2-This-butoksvkarbonvloksvamino-4-mctyk&gt;-tiazolo-5-carboxylic [01 16] the Prepared solution of ethyl-2-Zeros/-butoksykarbonylooksyamino-4-mctylo-thiazolo-5karboksylanu (10 g, 34,95 mmol) in tetrahydrofuranic-ctanolu (250 ml, 2:3) was subjected to the action of a solution of 6N KOI! (250 ml). The mixture podgrzewano to 55°C over night. The solution was cooled to 0°C and acidified by concentrated HCl to pH 1. The solvent is evaporated in vacuum. The residue is washed with water and ether dictylowym, and dried in vacuum over anhydrous pentallenkiem phosphorus to obtain the title acid (6 g, 89%) as a white solid.

C. the acid Chloride of 2-Ter/-butoksykarbonyloksyamino-4-mctylo-tiax.olo-5-karhoksylowcgo |0117] a 2 M solution of chloride oksalilu in dichlorometanie (22.5 ml, 45 mmol) is added dropwise to a suspension of the mixed acid 2-ter7-butoksykarbonyloksyamino-4-metylotiazolo-5 -) - substituted aromatic carbon (10 g, 38 and 72 mmol) in dichlorometanie (150 ml) and N,Ndimctyloformamidzic (150??) at 0°C. the Suspension gradually became homogeneous when the addition was completed. Solution pozostawnono to warm to room temperature and stirred it in rl for 1.5 h. the Solvent was evaporated in vacuum and the residue was evaporated with toluene (2x 300 ml) and then dried in vacuum to obtain the title acid chloride (10.7 g, 99%) as a brown solid.

D. Lster 1,1-dimetvłoelyłowy acid [5-|f(2.4,6-trimełylofenylo)aminolkarbonyloł-4-mclylo2-liazoliloł karbaminowego |0118| In a stirred solution of acid chloride 2-This-butoksykarbonyłoksyamino-4metylo-tiazolo^ -) substituted aromatic carbon (10.7 g, 33,66 mmol) in dichlorometanie (150 ml) at 0°C dropwise added 2,4,6-trimetyloalaninę (6,3 ml 38,66 mmol). After 20 min dropwise added diizopropyloełyloaminę (8,8 ml, 44,88 mmol). Leave the solution to warm to rt and stirred it for an additional 2 hours. The solvent is evaporated in vacuum. The residue is suspended in EtOAc (700 ml), washed with 1 N aq HC1 solution. (300 ml, 2x), water and brine; dried (MgSO₄), przefiltrowano and concentrated. The rest rozdrobniono with ether to obtain the same compound (12.5 g, 86%) as a brown solid.

Example 2 (Odn iesienie)

Preparation of 2-Amino-N-|2,4,6-trimelylofenylo)-4-methyl-5-liazolokarhoksyamidu |0119|

?₂?

And

<img file="PL1610780T3_D0023.tif" />

CH |012ϋ] a Solution of 1,1 ether-dimctyloctylowego acid [5-[[(2,4,6 trimctylofcnylo)amino]karbcnyloJ-4-mctylo-2-tiazo1ilo]karbaminowcgo (10 g, 26,63 mmol) in kwasic trifluorooctowym (100 ml) was stirred at rt for 3 h. the Solution was concentrated under vacuum and the residue was diluted with EtOAe (700 ml), washed with 5% solution of KHCO_Have aq. (400 ml, 2x), water and brine; dried (MgSO₄), experience filtrowano and concentrated. The residue is washed with ether (200 ml) and acetonitrylem (100 ml) to obtain the title compound (6.7 g, 91%) as a white solid.

Example 3 (Link)

Preparation___ether__1,1 -dimetyloetylowego__kislota_|5-N(2.4.ńtrimęlylofenyIo)aminoIkaibonyloj_-4l^I^1ijorc^nietil]o-^-tjizo2^odkaibaminowego |0121|

<img file="PL1610780T3_D0024.tif" />

3. Ety1o-2-/e/-butoksykarbony1ooksyamino-4-tri11uorcmclvlo-tiazo1o-5-k arboksylan |(H22| Suspension of ethyl 2-amino-4-trifluoromctylo-tiazolo-5-karboksylanu (of 5.05 g, 21,02 mmol), diwęglanu-di-tert-butyl (4,82 g, 22,07 mmol) and 4-dimetyloaminopirydyny (260 mg, 2.1 mmol) in dichlorometanie (209 ml) was stirred under nitrogen atmosphere for 1.5 h. the Solvent is evaporated in vacuum. The residue is purified by chromatografię on a column of silica gel. Elucja 5% EtOAe in heksanach, and then 15% EtOAe in heksanach gave the name of the relationship (6,57 g, 92%) as a white solid.

B. Acid 2-fer/-hutoksykarbcnv1oksyamino-4-trifluoromcty1o-liazok)-5-karhoksylowy |0123| Prepared with a solution of ethyl-2-/ć7/-butoksykarbonylooksyamino-4-trifluorometylotiazolo-5-karboksylanu (6.5 g, 19,1 mmol) in methanol (100 ml) was subjected to IN NaOH aq. (573 ml). The mixture was stirred at rt over night. Solution oziębiono to 0°C and acidified by 6 M aq solution of IIC1. for pil 1 and extracted with chloroform (150 ml, 6x). Chloroformowe extracts combined, dried (At₂SO₄), odfiltrowano and concentrated under reduced pressure and in vacuo to obtain the title acid (5.75 g, 96%) as a white solid.

-40C. Ether 1,1-dimetyloetylowy acid b-if^AO lrimetylofenylojaminolkiutionylol-^ltriiluorometylo^-tiazolilolkarbaminowego |0124] In a mixture of acid 2--L er-buloksykia-bonyloksyamino-4-trif uoromctylo-tiazolo-5karboksylowego (100 mg, 0,32 mmol), 2,4,6-trimetyloalaniny (45 Rus, 0,32 mmol) and heksafluorofosforanu ben2otriazol-l-iloksy-Tris(dimetyloamino)fosfoniowego (BOP reagent, 380 mg, 0.4 mmol) in DMF (2 ml) was added 4-metylomorfolinę (40 blonde, 0.39 mmol). The solution was stirred at rt for 72 h, diluted dichlorometanem and washed with 0.25 M solution KIISO,and aq., and then with a solution of saturated KHCO3 aq. Extract dichlorometanowy separated, dried (Na2SCO)₃, odfiltrowano and concentrated. The residue was separated chromatografią on the column with silica gel and cluowano 5% EtOAc in heksanach, and then 10% EtOAc in heksanach to receive the same compound (90 mg, 65%) as a white solid.

Example 315 (Link)

Przygotowanie_N-^?s^hl^rQ-6-metyloifenylo)-:2-ficyklopropylokarb9nylo)amijio]25tiazolokarboksyamidu

101251

<img file="PL1610780T3_D0025.tif" />

3. Ethyl-2--erv-butoksykarbonyloksyamino-4-mctylotiazolo-5-karboksvlan |"I26| Suspension ctylo-2-amino-tiazolo-5-karboksylanu (972 mg, 6 mmol, B. Plouvler, S. Bailly, R. Houssin, J-P. Hcnlchart Heterocyles 32(4), 693-701, 1991 and H. J. Becker, J. de Jonge, Rec. Trav. Chim, 61, 463, 1942), d-carbonate-di-tert-butyl (1,94 g, 9 mmol) and 4dimetyloaminopirydyny (73 mg, 0.6 mmol) in dry tetrahydrofuranie (75 ml) was stirred under nitrogen atmosphere for 24 h. the Solvent is evaporated in vacuum. The residue is suspended in ether (50 ml). Solid was washed with ether (10ml, 3x) and dried in vacuum to obtain the title compound (1.1 g, 70%).

B. Acid 2-/e/-bbtokkykarrb)nvloksvamino-tiazolo-5-carboxylic [0127] the Prepared solution elylo-2--?’/7-bbto0kyykrbonyloksyamino-4-metylotiazolo-5karboksylanu (1.1 g, 4.2 mmol) in tctrahydrofuranie-mctanolu (80 ml, 1:1) was subjected to 6 N solution of NaOI l aq. (20 ml, 120 mmol). The mixture was stirred at rt for 24 h. Most of THF and methanol jsunięto by distillation under reduced pressure, and the aqueous solution is acidified by 6 N IIC1 solution (22 ml). Odfiltrowano the precipitate, washed with water and ether, dried in air, then in vacuum to obtain the title acid (940 mg, 96%) as a whitish solid.

.41 C. Broadcast-dimetyloetylowy acid |5-[[(2-chloro-6-metylofcnylo)amino1karbonyioj-2tiazoliloikarbaminowego |0128| In a stirred solution of acid 2-/e/-butoksykarbonyioksyamino-tiazoio-5karboksyiowego (234 mg, 1 mmol) in THF (10 ml) and?,?-dimetyioformamidzie (a few drops) was added dropwise 2 m solution of chloride oksalilu in dichlorometanie (1 ml, 2 mmoi). The mixture was stirred at rl for 4 h. the Solvent was evaporated under reduced pressure and in vacuo to obtain crude acid chloride.

|0129| In a stirred solution of crude acid chloride 2-tertbutoksykarbonyloksyamino-tiazoio-5-karboksylowcgo (And mmol) in dichlorometanie (10 ml) at 0°C was added dropwise 2-chioro-6-metyloalaninę (2I2 mg, 1.5 mmol). Added diizopropyloctyloaminę (516 mg, 4 mmol). The solution was allowed to warm to rt, stirred for 24 h, diluted dichlorometanem (60 ml) and washed with 2 N aq solution I1CI. (15 ml). The organic extract was dried (MgSOOa, odfiltrowano and concentrated. The residue was dissolved in EtOAc-etcrze (25 ml, 1:4), and the residue odfiltrowano and washed with ether (5 ml, 4 times) and dried in vacuum to obtain the title compound (175 mg, 48%) as a brown solid.

D. 2-Amino-N-(2-chloro-6-methylphenyl)-5-tiazolokarboksyamid |0130| Relationships 3151) a method similar to 2, except for the use of communications 3I5C to receive communication 3151 of the same name) as a brown solid.

E. 2-f(Cyklopropylokarbonyio)amino|-N-(2-chloro-6-metylofcnylo)-5-tiazolokarboksyamid

1)11311 Solution of 315D (50.6 per mg, 0,19 mmol) and anhydride acid cyklopropanokarboksylowego (302 mg, 1,96 mmol) in dioksanie (2 ml) podgrzewano to 93°C during the night. The mixture was concentrated in vacuo, diluted with EtOAc and washed with saturated solution KIICO^j aq. (2x). The organic extract was dried (Na^SO^), and concentrated odfiltrowano. The rest rozdrobniono with ether to obtain the title compound (11 mg, 17%) as a white solid.

For Example, 444 (Link)

Preparation _tN-(2-Chloro-6-methylphenyl)-2-[i2-metvlo-6-||2-(4morfolinylo)etylolamino1-4-pirimidynylolaminol-5-tiazolokarboksyamidu j0132|

<img file="PL1610780T3_D0026.tif" />

<img file="PL1610780T3_D0027.tif" />

|0133| To a slurry of NaH (148 mg, 6,17 mmol) in THF (20 ml) was added the solution of communication 3151) (551 mg, of 2.06 mmol) in THF (10 ml) and the mixture was stirred at RT for 0.5 h. a Solution of 4,6 dichloro-2-metylopirymidyny (671,6 mg, 4,12 mmol) in THF (10 ml) and the mixture was stirred at RT for Noah. The reaction was quenched with acetic acid and the solvent was removed in vacuum. To the residue added water and saturated Nal 1COj and extracted with CH2CL2. The organic phase was removed in vacuum and the crude material was purified by chromatography on a column getting 444A (494 mg).

B. the Communications Header |0134| In connection 444Λ (30 mg) was added N-(2-aminoetylo)-morfolinę (300 gigabytes) and the mixture podgrzewano to 80°C for 2 h. To the reaction was added water and the product collected by filtration. HPLC Ret. Time 2,357 minutes.

Examples of the thighs 445 to 461

General Procedure |0135| Relationship from 445 to 461 prepared by the method similar to 444B

<td>through</td><td colspan="3">substitution of the appropriate amine.</td>

<td>EX. WELL.</td><td>The Communication Structure</td><td>The name Zw iązku</td><td>HPLC Ret. Time (min)</td>

<td> 445*</td><td></td><td>'N-(2-Chloro-6-metylofcnylo)2-[[2-methyl-6-[[3-(4morfol inylo)propylojam and trihofitii-4pirymidynylolaminoj-5tiazolokarboksyamid</td><td> 2,253</td>

<td>?? . WELL.</td><td>The Communication Structure</td><td>The Relation Name</td><td>HPLC Ret. Time (min)</td>

<td> 446*</td><td></td><td>'N-(2-Chloro-6-metylofenyIo)2-[[2-mctylo-6-[metylo[3(mctyloamino)propylojamino]4-pirymidynylojamino|-5tiazolokarboksyamid</td><td> 2,493</td>

<td> 447*</td><td>et</td><td>’N-(2-Chloro-6-methylphenyl)2-[ [2-mctylo-6- [ |2-(tetrahydro2-oxo-1 H-imidazolo-1 yl)ethyl]-aminoj-4pirymidynylo|amino|-5tiazolokarboksyamid</td><td> 2,71</td>

<td> 448*</td><td>^£In⁰WHAT here</td><td>’N-(2-Chloro-6-methylphenyl)2-[[2-mctylo-6-[(2-lHim idazolo-4-yloctylo)and am trihofitii-4pirymidynylo|aminol-5tiazolokarboksyamid</td><td> 2,303</td>

<td> 449*</td><td></td><td>’ N-(2-Chloro-6-mctylofcny lo)2-[[2-methyl-6-(4-morfolinylo)4-pirymidynylolaminoJ-5tiazjolokarboksyamid</td><td> 3,337</td>

<td> 450*</td><td></td><td>’N-(2-Chloro-6-metylofcnylo)2-[[6-[[[(2R)-l-ctylo-2pirrolidynylo]metylojamino|-2metylo-4-pirymidynylo|amino]5 azol okarbok syam id</td><td> 2,703</td>

<td> 451*</td><td></td><td>’N-(2-Chloro-6-metylofenylo)2-[[6-[[[(2S)-l-clylo-2pirrolidynylo|metyloJamino|-2metylo-4-pirymidynyloJamino|5-tiazolokarboksyamid</td><td> 2,717</td>

<td> 452*</td><td>About\</td><td>’2-[[6-[(2S)-2(Aminokarbonylo)-1 pirrolidynyloj-2-melylo-4pirymidynylo]aminol-N-(2-</td><td> 2,81</td>

<td>?? . WELL.</td><td>The Communication Structure</td><td>The Relation Name</td><td>HPLC Ret. Time (min)</td>

<td></td><td></td><td>chloro-6-methylphenyl)-5tiazolokarboksyamid</td><td></td>

<td> 453*</td><td></td><td>’N-(2-Chloro-6-mctylofenylo)2-[l6-| (2-hydroxyethyl)amino]2-methyl-4pirymidynylo|aminol-5tiazolokarboksyamid</td><td> 2,677</td>

<td> 454*</td><td></td><td>’N-(2-Chloro-6-mctylofcnylo)2-[[6-[4-(hydroksymetyio)·1 pipcridynylol-2-methyl-4pirymidynylolamino]-5tiazolokarboksyamid</td><td> 3,05</td>

<td> 455</td><td></td><td>'N-(2-Chloro-6-methylphenyl)2-[[6-[4-(2-hydroxyethyl)-1 piperazynylo]-2-mctylo-4pirymidynylo|amino]-5tiazolokarboksyamid</td><td> 2,717</td>

<td> 456*</td><td>x&gt;x£ "?</td><td>’l-[6-[(5-[[(2-Chloro-6metylofenylo)amino|karbonylo]2-tiazol and lojamino |-2-methyl-4pirymidynylo|-4pipcrydynokarboksyamid</td><td> 2,863</td>

<td> 457*</td><td>&lt;n</td><td>’N-(2-Chloro-6-metylofenylo)2-[[2-metylo-6-[(3S)-3-metylo1-piperazynyloJ-4pirymidynylo]amino]-5tiazolokarboksyamid</td><td> 2,823</td>

<td> 458*</td><td></td><td>’2-[[6-[3-(Acetylamino)-1pirrolidynylo|-2-methyl-4pirymidynylo]amino]-N-(2-1oro-6-metyiofenylo)-5 tiazolokarboksyamid</td><td> 2,78</td>

<td>EX. WELL.</td><td>The Communication Structure</td><td>The Relation Name</td><td>HPLC Ret. 'lime (min)</td>

<td> 459*</td><td></td><td>’N-(2-ChIoro-6-melylofenylo)2-[(6-[[2-(l-mctylo-2pirrolidynylo)etylo]amino]-2metylo-4-pirymidynylo]amino]5-tiazolokarboksyamid</td><td> 2,383</td>

<td> 460*</td><td></td><td>'N-(2-Chloro-6-melyłofenylo)2-[[2-metylo-6-[[(5-mctylo-2pirazynylojmelylolaminol^pirymidynylolamino]-5tiazolokarboksyamid</td><td> 3,027</td>

<td> 461*</td><td></td><td>'N-(2-Chloro-6-methylphenyl)2-[[2-methyl-6-[ [2-(LH-1,2,3 triazolo-1 -yl)ethyl]ami no]-4pirymidynylo]amino|-5liazołokarboksyamid</td><td> 2,78</td>

<td colspan="4">* Link</td>

<td></td><td></td><td>. J made and iweifyl</td><td>r Pikowała:</td>

<td></td><td></td><td>\ \ ? Dorothy?"</td><td>zażewską</td>

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