EP2346881A1

EP2346881A1 - Novel compounds which modulate kinase activity

Info

Publication number: EP2346881A1
Application number: EP09778867A
Authority: EP
Inventors: Lutz Weber; Günther Ross; Michael Umkehrer
Original assignee: Priaxon AG
Current assignee: Priaxon AG
Priority date: 2008-10-10
Filing date: 2009-10-08
Publication date: 2011-07-27
Also published as: WO2010040527A1

Abstract

The present invention provides compounds (pyrazolothiazepines) of formula (I) that inhibit or modulate the enzymatic activity of protein kinases.

Description

Novel compounds which modulate kinase activity

The present invention provides compounds that inhibit or modulate the enzymatic activity of protein kinases for modulating cellular activities such as proliferation, differentiation, programmed cell death, and migration. In particular, the invention provides novel compounds (e.g. pyrazolothiazepines) which inhibit, regulate and/or modulate kinase related signal transduction pathways resulting in changes of cellular activities, compositions which contain these compounds, and methods of using them to treat diseases and conditions that are related to kinase activities. The present invention also provides methods for the preparation of these compounds, and compositions containing these compounds.

New agents used to treat cancer are of considerable interest because a large variety of these neoplastic diseases have only poor and insufficient treatments. Improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms, modulating cell signaling pathways.

Protein kinases catalyze protein phosphorylation. The consequences of this activity are for example cell differentiation and proliferation - cell function depends greatly on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a range of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely life threatening diseases such as brain cancer.

About 20 different subfamilies of receptor-type tyrosine kinases have been identified, for example the HER subfamily, the insulin subfamily, the PDGF subfamily and the FLK family. The PDGF and FLK families are usually considered as very similar.

The non-receptor type of tyrosine kinases comprises numerous subfamilies, including AbI, Src, Frk, Btk, Csk, Zap70, Fak, Jak, Ack, and LIMK. Each of these subfamilies contains a variety of kinases, for the Src subfamily includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, Yrk known to promote oncogenesis .

Deregulation of protein kinase enzymatic activity through overexpression, mutation and other pathways may lead to undesired cellular properties, such as proliferation, differentiation, programmed cell death, and migration. Altered kinase signaling is also included in immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases.

Therefore, protein kinases are attractive drug targets for small molecule drug discovery and several kinase inhibitors are effective therapeutics. For example, as demonstrated successfully with the approval of the c-Kit and AbI kinase inhibitor Gleevec for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers (GIST) .

Inhibition or modulation of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival, is an attractive goal for development of small -molecule drugs - antiproliferative agents are desirable to slow or stop the growth of tumors. In addition, antiangiogenic therapy may represent an important approach for the treatment of solid tumors and other diseases associated with overtly active vascularization, such as but not limited to ischemic coronary^' artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis.

Thus, kinases are biological targets for small -molecule modulation of angiogenic and proliferative activity, such as for example the receptor kinase c-Met. c-Met occurs in a wide variety of. cell types including epithelial, endothelial and mesenchymal cells inducing cell migration, invasion, proliferation and other biological activities associated with invasive cell growth. The hepatocyte growth factor (HGF), "scatter factor" (SF) , as the endogenous ligand for c-Met is a potent inducer of angiogenesis and tumor growth. Anti-HGF antibodies or HGF antagonists and gene therapy have been shown to inhibit tumor metastasis in vivo (Matsumoto and Nakamura Cancer Science 2003, 94, 321-327) .

Another attractive target for small-molecule modulation is c- Kit . c-Kit is expressed in mast cells, immature myeloid cells, melanocytes, epithelial breast cells and the interstitial cells. In mast cells, it is required for differentiation, maturation, chemotaxis, and for the promotion of survival and proliferation.

Flt-3 is a kinase that is constitutively activated via mutation in a large proportion of acute myeloid leukemia (AML) patients and correlated with poor prognosis in AML patients (Sawyers Cancer Cell 2002, 1, 413-415) .

Therefore, small -molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, including c-Met, KDR, c-Kit, Flt-3, and Flt-4, and others are desirable as agents to treat or prevent disease states associated with abnormal cell signaling through those kinases. Particularly interesting are those kinase inhibitors that exhibit a therapeutically useful inhibition profile and specificity against a range of kinases (Goldstein et al . Nature Reviews Drug Discovery 2008, 7, 391-397) .

Many chemical compounds, belonging to particular scaffolds have already been described as kinase inhibitors (Ghose et al . Journal Medicinal Chemistry 2008, 51, September 11) - however, especially desired are novel scaffolds that permit to achieve desired specificity, low toxicity and other therapeutically useful properties that allow the application of such compounds as therapeutically useful agents.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides one or more compounds for modulating kinase activity and one or more methods of treating and/or preventing one or more diseases mediated by kinase activity utilizing the compound (s) and pharmaceutical composition (s) thereof. Diseases mediated by kinase activity include, but are not limited to, diseases characterized in part by cell migration, invasion, proliferation and other biological activities associated with invasive cell growth. In particular this invention relates to modulation, especially inhibition, of c-Met, KDR, c-Kit, flt- 3, and flt-4.

In another aspect, the invention also provides one or more pharmaceutical formulations comprising one or more compounds and/or pharmaceutical compositions of the present invention, as described herein. Such pharmaceutical formulations can also include one or more other compounds or compositions (for example diluents, permeation enhancers, lubricants, and the like) .

In yet another aspect, the present invention provides a process for making a compound, and pharmaceutical composition thereof, for modulating kinase activity and treating diseases mediated by kinase activity. In particular this invention also relates to a method for making a pyrazolo [3 , 4- e] [1 , 4] thiazepine used for modulation of kinase activity, even more particular inhibition of kinase activity, and yet even more particular inhibition of c-Met, KDR, c-Kit, flt-3, and flt-4.

The composition of the invention is used to treat one or more diseases related to abnormal cellular activities. Diseases which can be treated by the methods and compositions provided herein include, but are not limited to, various forms of neoplastic diseases, immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, macular degeneration and diabetic retinopathy.

It is appreciated that in some disease cases the cells may exhibit abnormal cellular activities and still require treatment. For example, during wound healing, cells may be proliferating "normally", but proliferation and migration enhancement may be desired. Alternatively, reduction in "normal" cell proliferation and/or migration rate may be desired.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides one or more compounds of formula (I)

(D wherein

X is S, SO or SO₂;

R¹ is a hydrogen atom or an alkyl, alkenyl, alkynyl, hetero- alkyl, aryl , heteroaryl, cycloalkyl, alkylcycloalkyl , heteroalkylcycloalkyl , heterocycloalkyl , aralkyl or hetero- aralkyl radical;

R² is a hydrogen atom or an alkyl, alkenyl, alkynyl, hetero- alkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl , heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;

R³ is a hydrogen atom or an alkyl, alkenyl, alkynyl, hetero- alkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical;

R⁴ is a hydrogen atom or an alkyl, alkenyl, alkynyl, hetero- alkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical; and R⁵ is a hydrogen atom or an alkyl, alkenyl , alkynyl, hetero- alkyl, aryl , heteroaryl , cycloalkyl, alkylcycloalkyl , heteroalkylcycloalkyl, heterocycloalkyl , aralkyl or heteroaralkyl radical;

wherein all of the above radicals may be substituted;

or a pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate or a pharmaceutically acceptable formulation thereof .

The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert -butyl, n-pentyl, iso-pentyl, n-hexyl, 2 , 2-dimethylbutyl or n-octyl group.

The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to 6 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl) , propenyl

(allyl) , iso-propenyl , butenyl , ethinyl, propinyl, butinyl, acetylenyl, propargyl , isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s) , and alkynyl groups have one or two

(especially preferably one) triple bond(s) .

Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced e.g. by a halogen atom (preferably F or Cl) such as, for example, a 2 , 2 , 2-trichloroethyl or a trifluoromethyl group.

The expression heteroalkyl refers to an alkyl , alkenyl or alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms, each independently, have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) . The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl , acylalkyl, alkoxycarbonyl , acyloxy, acyloxyalkyl , carboxyalkylamide or alkoxycarbonyloxy.

Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen) . Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2 or 3 (especially 1 or 2) hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen) .

Examples of heteroalkyl groups are groups of formulae: R^a-O-Y^a-, R^a-S-Y^a-, R^a-N(R^b) -Y^a-, R^a-CO-Y^a-, R^a-O-CO-Y^a-, R^a-CO-O-Y^a-, R^a-CO-N(R^b) -Y^a- , R^a-N (R^b) -CO-Y^a- , R^a-O-CO-N (R^b) -Y^a- , R^a-N (R^b) -CO-O-Y^a- , R^a-N (R^b) -CO-N (R^c) -Y^a- , R^a-0-CO-O-Y^a- , R^a-N(R^b) -C(=NR^d) -N(R^C) -Y^a-, R^a-CS-Y^a-, R^a-O-CS-Y^a-, R^a-CS-O-Y^a-, R^a-CS-N(R^b) -Y^a-, R^a-N(R^b) -CS-Y^a-, R^a-O-CS-N (R^b) -Y^a- , R^a-N(R^b) -CS-O-Y^a-, R^a-N(R^b) -CS-N(R^C) -Y^a- , R^a-O-CS-O-Y^a- , R^a-S-CO-Y^a-, R^a-CO-S-Y^a-, R^a-S-CO-N(R^b) -Y^a-, R^a-N (R^b) -CO-S-Y^a- , R^a-S-CO-O-Y^a-, R^a-O-CO-S-Y^a-, R^a-S-CO-S-Y^a- , R^a-S-CS-Y^a-, R^a-CS-S-Y^a-, R^a-S-CS-N(R^b) -Y^a- , R^a-N (R^b) -CS-S-Y³- , R^a-S-CS-O-Y^a- , R^a-O-CS-S-Y^a-, wherein R^a being a hydrogen atom, a C₁-C₆ alkyl, a C₂ -C₆ alkenyl or a C₂-C₆ alkynyl group; R^b being a hydrogen atom, a Ci-C₆ alkyl , a C₂-C₆ alkenyl or a C₂-C₆ alkynyl group; R^c being a hydrogen atom, a C₁-C₆ alkyl, a C₂-C₆ alkenyl or a C₂-C₆ alkynyl group; R^d being a hydrogen atom, a Ci-C₆ alkyl, a C₂-C₆ alkenyl or a C₂-C₆ alkynyl group and Y^a being a direct bond, a Ci-C₆ alkylene, a C₂-C₆ alkenylene or a C₂-C₆ alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms.

Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl , ethoxymethyl , -CH₂CH₂OH, -CH₂OH, methoxyethyl , 1-methoxyethyl , 1-ethoxyethyl , 2 -methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropyl- ethylamino, methylamino methyl, ethylamino methyl, diiso- propylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl , ethoxy- carbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl , carboxyethyl or carboxypropyl , N-ethyl-N- methylcarbamoyl or N-methylcarbamoyl . Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thio- cyanate, isocyanate, isothiocyanate and alkylnitrile groups.

The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH₂, =NH, N₃ or NO₂ groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopenta- none . Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro [4 , 5] decanyl , norbornyl , cyclohexyl, cyclopentenyl , cyclohexadienyl , decalinyl, bicyclo [4.3.0] nonyl , tetraline, cyclopentylcyclohexyl , fluorocyclohexyl or cyclohex-2-enyl group .

The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms, each independently, have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) . A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably secected from C, 0, N and S) . The expression heterocycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH₂, =NH, N₃ or NO₂ groups. Examples are a piperidyl, prolinyl, imidazolidinyl , piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl , tetra- hydrothiophenyl, tetrahydropyranyl , tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.

The expression alkylcycloalkyl refers to a group that contains both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl , alkylcycloalkenyl , alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms .

The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1, 2 or 3) carbon atoms, each independently, have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) . A heteroalkylcycloalkyl group preferably contains 1 or 2 ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl , alkylheterocycloalkenyl , alkenylheterocycloalkyl , alkynylheterocycloalkyl , heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and hetero- alkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri -unsaturated.

The expression aryl or Ar refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. The expression aryl (or Ar, respectively) refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH₂, N₃ or NO₂ groups. Examples are the phenyl, naphthyl , biphenyl , 2-fluorophenyl , anilinyl, 3 -nitrophenyl or 4 -hydroxyphenyl group .

The expression heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, and contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N) . The expression heteroaryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N₃, NH₂ or NO₂ groups. Examples are pyridyl (e.g. 4-pyridyl) , imidazolyl (e.g. 2-imidazolyl) , phenylpyrrolyl (e.g. 3- phenylpyrrolyl) , thiazolyl, isothiazolyl , 1 , 2 , 3-triazolyl , 1 , 2 , 4-triazolyl , oxadiazolyl , thiadiazolyl , indolyl , indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl , pyridazinyl, oxazolyl , isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl , benzoxazolyl , benzisoxazolyl , benzthiazolyl , pyridazinyl, quinolinyl, isoquinolinyl , pyrrolyl, purinyl , carbazolyl, acridinyl , pyrimidyl, 2,3'- bifuryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups .

The expression aralkyl refers to a group containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, an arylalkyl, arylalkenyl , arylalkynyl, aryleye1oalkyl , aryl- cycloalkenyl , alkylarylcycloalkyl and alkylarylcycloalkenyl group. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, lH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl , cumene, cyclohexylphenyl , fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 6 to 10 carbon atoms and one or two alkyl , alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms .

The expression heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms, each independently, have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen) , that is to say to a group containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms.

Examples are arylheteroalkyl , arylheterocycloalkyl , aryl- heterocycloalkenyl , arylalkylheterocycloalkyl , arylalkenyl- heterocycloalkyl , arylalkynylheterocycloalkyl, arylalkyl- heterocycloalkenyl , heteroarylalkyl , heteroarylalkenyl , heteroarylalkynyl, heteroarylheteroalkyl , heteroaryl - cycloalkyl, heteroarylcycloalkenyl , heteroarylhetero- cycloalkyl, heteroarylheterocycloalkenyl , heteroarylalkyl - cycloalkyl, heteroarylalkylheterocycloalkenyl , heteroaryl - heteroalkylcycloalkyl , heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri -unsaturated. Specific examples are a tetrahydroisoquinolinyl , benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl , 4-ethoxyphenyl , 2-, 3- or 4-carboxy- phenylalkyl group.

As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH₂, =NH, N₃ or NO₂ groups.

The expression "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH₂, =NH, N₃ or NO₂ groups. This expression refers furthermore to a group that are substituted by one, two, three or more (preferably unsubstituted) Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl , Ci-C₆ heteroalkyl, C₃-Ci₀ cycloalkyl, C₂-C₉ heterocycloalkyl, C₂-Ci₂ alkylcycloalkyl , C₂-Cn hetero- alkylcycloalkyl C₆-Ci₀ aryl , Ci-C₉ heteroaryl, C₇-Ci₂ aralkyl or C₂-Cn heteroaralkyl groups.

Preferably, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl , heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.

Preferred are compounds of formula (I) wherein X is S or SO₂, especially S.

Further preferred are compounds of formula (I) wherein R¹ is an optionally substituted aryl or heteroaryl or an alkyl radical.

Moreover preferred are compounds of formula (I) wherein R¹ is an optionally substituted phenyl radical or an optionally substituted heteroaryl radical containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from 0, S and N.

Especially preferred are compounds of formula (I) wherein R¹ has the following structure wherein the groups R⁶ are independently from each other a halogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl , heteroaryl , cycloalkyl, alkylcycloalkyl , heteroalkylcyclo- alkyl, heterocycloalkyl , aralkyl or heteroaralkyl radical and m is 0, 1, 2, 3, 4 or 5 (especially 0 or 1) .

Further preferred, R⁶ is F, Cl, Br, CN, NHCOMe, Me, OMe, CF₃ or OCF₃.

Further preferred are compounds of formula (I) wherein R² is an optionally substituted aryl or heteroaryl radical .

Moreover preferred are compounds of formula (I) wherein R² is an optionally substituted phenyl or naphthyl radical or an optionally substituted heteroaryl radical containing 5 or 6 to 10 ring atoms (i.e. one or two rings) and 1, 2, 3 or 4 heteroatoms selected from 0, S and N.

Especially preferred are compounds of formula (I) wherein R² has the following structure wherein the groups R⁷ are independently from each other a halogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcyclo- alkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical and o is 0, 1, 2, 3, 4 or 5 (especially 0, 1 or 2) .

Further preferred, R⁷ is F, Cl, OMe, Me, SO₂Me, NHCOMe, COOH, COOMe, OCH₂COOMe, OCH₂COOH, benzyl, a heterocycloalkyl (e.g. a morpholinyl or a piperazinyl) radical, or an heteroalkylcycloalkyl (e.g. a -CH₂ -morpholinyl, -CH₂- piperazinyl, -CH₂-N-Methylpiperazinyl or an N-methyl- piperazinyl) radical.

Moreover preferred are compounds of formula (I) wherein R³ is a hydrogen atom or Ci-C₄ alkyl, especially hydrogen.

Further preferred are compounds of formula (I) wherein R⁴ is a hydrogen atom or an alkyl, heteroalkyl or a heteroalkylcycloalkyl radical .

Especially preferred are compounds of formula (I) wherein R⁴ is hydrogen, Ci-C₄ alkyl or a group of formula CH₂COR⁸ wherein R⁸ is hydroxy or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl , heteroaryl, cycloalkyl, alkylcycloalkyl , heteroalkylcycloalkyl, heterocycloalkyl , aralkyl or heteroaralkyl radical; especially preferably, R⁸ is hydroxy or NH (CH₂) _PR⁹, wherein p is 0, 1, 2, 3 or 4 and R⁹ is a heterocycloalkyl radical (preferably containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from 0, S and N) .

Further preferred are compounds of formula (I) wherein R⁵ is hydrogen .

Especially preferably, the compounds of formula (I) are selected from the following compounds:

• 3, 4-Diphenyl-2, 8-dihydro-4H-pyrazolo [3,4- e] [1, 4] thiazepin-7-one

• 5, 5-Dioxo-3 , 4-diphenyl-2, 5,6, 8-tetrahydro-4H-5lambda*6*- pyrazolo [3,4-e] [1,4] thiazepin-7-one • (7-Oxo-3,4-diphenyl-2 ,6,7, 8-tetrahydro-4H-pyrazolo [3,4- e] [1, 4] thiazepin-6-yl) -acetic acid

• 3- (3-Morpholin-4-yl-phenyl) -4-phenyl-2 , 8-dihydro-4H- pyrazolo [3,4-e] [1,4] thiazepin-7-one

• 3- (3 -Morpholin-4-yl-phenyl) -5 , 5-dioxo-4-phenyl-2 ,5,6,8- tetrahydro-4H-5lambda*6*-pyrazolo [3 , 4-e] [1, 4] thiazepin-7- one

• [3- (3 -Morpholin-4-yl-phenyl) -7-oxo-4-phenyl-2 , 6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -acetic acid

• 4- (4 -Morpholin-4-ylmethyl -phenyl) -3-phenyl-2 , 8-dihydro- 4H-pyrazolo [3,4-e] [1,4] thiazepin-7-one

• [4- (4 -Morpholin-4-ylmethyl -phenyl) -7-oxo-3-phenyl- 2,6,7, 8-tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6- yl] -acetic acid

• 4- [4- (4 -Methyl -piperazin-1-ylmethyl) -phenyl] -3-phenyl- 2, 8-dihydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-7-one

• {4- [4- (4 -Methyl -piperazin-1-ylmethyl) -phenyl] -7-oxo-3- phenyl-2, 6,7, 8-tetrahydro-4H-pyrazolo [3,4- e] [1,4] thiazepin-6-yl} -acetic acid

• 6-Methyl-4- [4- (4-methyl-piperazin-l-ylmethyl) -phenyl] -3- phenyl-2 , 8-dihydro-4H-pyrazolo [3 , 4-e] [1,4] thiazepin-7-one

• 4- (4-Chloro-phenyl) -3-phenyl-2 , 8-dihydro-4H-pyrazolo [3,4- e] [1 , 4] thiazepin-7-one

• 4- (3 , 4 -Dimethoxy-phenyl) -3 -phenyl -2 , 8-dihydro-4H- pyrazolo [3,4-e] [1,4] thiazepin-7-one

• 4- (4 -Morpholin-4-yl-phenyl) -3-phenyl-2 , 8-dihydro-4H- pyrazolo [3,4-e] [1,4] thiazepin-7-one

• 4- (7-0x0-3 -phenyl -2 ,6,7, 8-tetrahydro-4H-pyrazolo [3,4- e] [1, 4] thiazepin-4-yl) -benzoic acid methyl ester • 4- (lH-Indol-3-yl) -3-phenyl-2 , 8-dihydro-4H-pγrazolo [3,4- e] [1, 4] thiazepin-7-one

• [3- (4-Fluoro-phenyl) -4- (4 -morpholin-4-ylmethyl -phenyl) -7- oxo-2 ,6,7, 8-tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin- 6-yl] -acetic acid

• [3- (4-Chloro-phenyl) -4- (4 -morpholin-4-ylmethyl -phenyl) -7- oxo-2, 6,7, 8-tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin- 6-yl] -acetic acid

• N- (3-Morpholin-4-yl-propyl) -2- (7-oxo-3 , 4-diphenyl- 2,6,7, 8-tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6- yl) -acetamide

• [3- (4-Fluoro-phenyl) -7-oxo-4-phenyl-2 , 6,7, 8-tetrahydro- 4H-pyrazolo [3 , 4-e] [1 , 4] thiazepin-6-yl] -acetic acid

• [3- (4-Chloro-phenyl) -7-oxo-4-phenyl-2 ,6,7, 8-tetrahydro- 4H-pyrazolo [3 , 4-e] [1, 4] thiazepin-6-yl] -acetic acid

• 2- [3- (4-Fluoro-phenyl) -7-oxo-4-phenyl-2 , 6,7, 8-tetrahydro- 4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (3 -morpholin-4- yl -propyl) -acetamide

• 2- [3- (4-Chloro-phenyl) -7-oxo-4-phenyl-2 , 6,7, 8-tetrahydro- 4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (3-morpholin-4- yl -propyl) -acetamide

• 4- (6-Carboxymethyl-7-oxo-3-phenyl-2, 6,7, 8-tetrahydro-4H- pyrazolo [3 , 4-e] [1 , 4] thiazepin-4-yl) -benzoic acid methyl ester

• [4- (4-Methoxy-phenyl) -7-oxo-3-phenyl-2 , 6,7, 8-tetrahydro- 4H-pyrazolo [3 , 4-e] [1 , 4] thiazepin-6-yl] -acetic acid

• N- (2-Morpholin-4-yl-ethyl) -2- (7-oxo-3 , 4-diphenyl-2 ,6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl) - acetamide

• N- (4-Morpholin-4-yl-butyl) -2- (7-oxo-3 , 4-diphenyl-2 ,6,7,8- tetrahydro-4H-pyrazolo [3 , 4-e] [1,4] thiazepin-6-yl) - acetamide • N- [2- (4-Methyl-piperazin-l-yl) -ethyl] -2- (7-oxo-3,4- diphenyl-2, 6,7, 8-tetrahydro-4H-pyrazolo [3,4- e] [1, 4] thiazepin-6-yl) -acetamide

• 2- [3- (4-Fluoro-phenyl) -7-oxo-4-phenyl-2 , 6,7, 8-tetrahydro- 4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N, N-dimethyl - acetamide

• 3 -Methyl -4 -phenyl -2 , 8-dihydro-4H-pyrazolo [3,4- e] [1, 4] thiazepin-7-one

• [4- (4 -Methanesulfonyl-phenyl) -7-oxo-3-phenyl-2 ,6,7,8- tetrahydro-4H-pyrazolo [3 , 4-e] [1,4] thiazepin-6-yl] -acetic acid

• [4- (4 -Acetylamino-phenyl) -7-oxo-3-phenyl-2 , 6,7,8- tetrahydro-4H-pyrazolo [3 , 4-e] [1,4] thiazepin-6-yl] -acetic acid

• [4- (4-Methoxycarbonylmethoxy-phenyl) -7-oxo-3-phenyl- 2,6,7, 8-tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6- yl] -acetic acid

• [4- (4-Benzyloxy-phenyl) -7-oxo-3-phenyl-2 , 6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -acetic acid

• 4- {6- [ (2-Morpholin-4-yl-ethylcarbamoyl) -methyl] -7-oxo-3- phenyl-2 ,6,7, 8-tetrahydro-4H-pyrazolo [3,4- e] [1 , 4] thiazepin-4-yl} -benzoic acid methyl ester

• 2- [4- (4-Methoxy-phenyl) -7-oxo-3-phenyl-2 , 6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (2- morpholin-4-yl -ethyl) -acetamide

• 2- [4- (4-Benzyloxy-phenyl) -7-oxo-3-phenyl-2 , 6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (2- morpholin-4-yl -ethyl) -acetamide

• (3-Furan-2-yl-7-oxo-4-phenyl-2, 6,7, 8-tetrahydro-4H- pyrazolo [3, 4-e] [1 , 4] thiazepin-6-yl) -acetic acid • 2- (3-Furan-2-yl-7-oxo-4-phenyl-2, 6,7, 8-tetrahydro-4H- pyrazolo [3, 4-e] [1, 4] thiazepin-6-yl) -N- (2-morpholin-4-yl- ethyl) -acetamide

• 6- [2- (4-Methyl-piperazin-l-yl) -2-oxo-ethyl] -3 , 4-diphenyl- 2, 8-dihydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-7-one

• (3-Methyl-7-oxo-4-phenyl-2, 6,7, 8-tetrahydro-4H- pyrazolo [3 , 4-e] [1 , 4] thiazepin-6-yl) -acetic acid

• 2- (3 -Methyl -7-oxo-4-phenyl-2, 6,7, 8-tetrahydro-4H- pyrazolo [3,4-e] [1,4] thiazepin-6-yl) -N- (2-morpholin-4-yl- ethyl) -acetamide

• [4- (lH-Indol-3-yl) -7-oxo-3-phenyl-2 , 6,7, 8-tetrahydro-4H- pyrazolo [3 , 4-e] [1 , 4] thiazepin-6-yl] -acetic acid

• 2- [4- (lH-Indol-3-yl) -7-oxo-3-phenyl-2 , 6 , 7, 8-tetrahydro- 4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (2-morpholin-4- yl -ethyl) -acetamide

• 2- [4- (4-Methanesulfonyl -phenyl) -7-oxo-3-phenyl-2 ,6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (2- morpholin-4-yl -ethyl) -acetamide

• 2- [4- (4-Acetylamino-phenyl) -7-oxo-3 -phenyl -2 , 6,7,8- tetrahydro-4H-pyrazolo [3,4-e] [1,4] thiazepin-6-yl] -N- (2- morpholin-4-yl -ethyl) -acetamide

• (4- {6- [ (2-Morpholin-4-yl-ethylcarbamoyl) -methyl] -7-oxo-3- phenyl-2 , 6,7, 8-tetrahydro-4H-pyrazolo [3,4- e] [1, 4] thiazepin-4-yl} -phenoxy) -acetic acid methyl ester

• 3 -Methyl -4- (4-morpholin-4-ylmethyl-phenyl) -2 , 8-dihydro- 4H-pyrazolo [3,4-e] [1,4] thiazepin-7-one

Further preferred, the compounds disclosed in the following documents are excluded from the present invention:

1. Abu Elmaati, Tarek M et al . "Routes to Pyrazolo [3 , 4- e] [1, 4] thiazepine, Pyrazolo [1 , 5 -a] pyrimidine and Pyrazole

Derivatives" Journal of the Chinese Chemical Society, 2003, vol. 50, no. 3A, 413-418. (especially compounds 3a and 3b)

US 3,891,630 (Swett) . (especially compounds of gerneral formula I of US 3,891,630 wherein W is NH and/or the compound of example 18)

Joshi Krishna C et al . "Possible psychopharmacological agents Part 3 : Synthesis and CNS Activity of Some New Fluorine-Containing Pyrazolo [3 , 4-e] [1 , 4] thiazepines" , PHARMAZIE, 1979, vol. 34, no. 11, 716-718. (especially compounds 4g and 4h)

Sofan, M A et al . "Reactions with heterocyclic amidines : Synthesis of pyrazolo [3 , 4-e] thiazepine, pyrazolo [1 , 5- c] 1 , 2 , 4-triazine and pyrazolo [1 , 5-a] pyrimidine derivatives", PHARMAZIE, 1994, vol. 49, no. 7, 482-486. (especially compounds 5a, 5b and 5d)

Further preferred, the following compounds are excluded from the present invention:

Further, the following compounds of formula (II) are excluded from the present invention:

(ID

wherein W is NH,

R is hydrogen, loweralkyl or phenyl,

R² is loweralkyl, cyclopropyl, 2-furyl or , wherein X is hydrogen, halogen, trifluoromethyl , hydroxy, loweralkoxy or dimethylamino and Y is hydrogen, chlorine or loweralkoxy, R³ is hydrogen or loweralkyl,

R⁴ is hydrogen, loweralkyl or carboxyloweralkyl , and R⁵ is hydrogen, loweralkyl or diloweralkylamino- loweralkyl ; wherein the term "loweralkyl" or "loweralkoxy" is intended to refer to saturated hydrocarbon chains of 1 - 7 carbon atoms .

In one aspect of the present invention, a compound of formula (I) is used to modulate kinase activity. Another aspect of the invention is a metabolite of a compound of formula (I) or a pharmaceutical composition thereof.

Another aspect of the invention is a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

The present invention further relates to a method of modulating the in vivo activity of a kinase, by administering to a mammal an effective amount of the compound of Formula (I) or the pharmaceutical composition containing a compound of Formula (I) .

Another aspect of the present invention relates to a method, wherein modulating the in vivo activity of a kinase comprises inhibition of said kinase.

Another aspect of the invention is a method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the compound or the pharmaceutical composition described herein, wherein preferentially modulating the in vivo activity of the kinase comprises inhibition of said kinase, more preferentially wherein the kinase is at least one of c-Met, KDR, c-Kit, flt- 3, and flt-4.

Another aspect of the invention is a method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of the compound or the pharmaceutical composition as described. The present invention further relates to a method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a compound of Formula (I) to a cell or a plurality of cells.

The present invention further relates to a method of treating mammalian diseases or disorders associated with abnormal and unwanted cellular activities, the method comprising administering to a mammal a therapeutically effective amount of one or more compounds of Formula (I) .

The present invention further relates to a process for preparing a compound of Formula (I) , wherein an aminopyrazole, an aldehyde and a thioacetic acid derivative are reacted together, optionally in the presence of a base, optionally with heating or microwave radiation, to form compounds of Formula (I) .

The present invention further relates to a process for preparing a compound of Formula (I), wherein a compound of

Formula (I) is reacted with further compounds to form derivatives of Formula (I) .

The term metabolite refers to a product of a compound of Formula (I) produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8 th Ed., Pergamon Press, Gilman et al . , (eds) , 1990) . As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. Such metabolites are also encompassed within the scope of the present invention.

Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula (I) are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of formula (I) may form alkali or earth alkaline metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris- (2 -hydroxyethyl) amine, lysine or arginine salts; all of which are also further examples of salts of formula (I) . Compounds of formula (I) may be solvated, especially hydrated. The hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula (I) . The solvates and/or hydrates may e.g. be present in solid or liquid form.

It should be appreciated that certain compounds of formula (I) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system) . All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of formula (I) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio .

E.g. compounds of formula (I) may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclic systems. For purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., as amino, imino, hydroxy or oxo, respectively.

The therapeutic use of compounds according to formula (I) , their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

The pharmaceutical compositions according to the present invention comprise at least one compound of formula (I) as an active ingredient and, optionally, carrier substances and/or adjuvants .

The present invention also relates to pro-drugs which are composed of a compound of formula (I) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy- , acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl) , an 2-alkyl-, 2-aryl- or 2-arylalkyl- oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of formula (I) , carrying a hydroxy group (-OH) : a sulfate, a phosphate (-OPO₃ or OCH₂OPO₃) or an ester of an amino acid. Especially preferred are pro-drugs of the hydroxy group of a compound of formula (I) .

As mentioned above, therapeutically useful agents that contain compounds of formula (I) , their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of formula (I) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.

For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal . For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4) . For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants .

Compounds of formula (I) of the present invention may be used for the treatment and/or prevention of the following diseases:

Diseases associated with kinase activities including tumor growth (cancer) , pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like) .

Furthermore, the present invention relates to the use of compounds of formula (I) for the preparation of medicaments for the treatment and/or prevention of the diseases described herein.

In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 1 mg to about 10,000 mg, preferably from about 20 mg to about 1,000 mg, may e.g. be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolongs the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.

The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art . Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated. The term cancer as used herein refers to cellular- proliferative disease states, benign and malignant tumours that are solid or cystic in nature, adenomas, cystadenomas, papilloimas, adenocarcinonmas, adenocarcinonmas of the cirrhotic typo, basal cell carcinomas, sarcomas, fibrosarcomas, liposarcomas, lymphosarcomas, rhabdomyosarcomas, myxosarcomas, chondrosarcomas, reticulum cell sarcomas, Hodgkin's disease, embryonal tumours, neuroblastomas, nephtoblastomas, teratomas, adamantinomas, retroblastomas , haemangiomas, chordomas, odontomas, craniophacyngomas, hamartomas, lymphoangiomas, exostoses, neurofibrantosis, melanomas, lymphomas, hepatoblastomas, mammary carcinomas, cervical carcinomas, choriocarcinomas, adenoacanthomas, androblastomas, leiomyomas, arrhenoblastomas, Sertoli's cell tumours, theca and granulosa cell tumours, germinomas and seminomas, ovarian and vulvar carcinomas, urinary bladder and prostate carcinomas, tumours caused by schistosomiasis, astrocytomas, ependymogliomas, glioblastomas, medulloblastoma, oligodendrogliomas, spongioblastomas, meningeomas, tumours of Schwann's sheath cells, pinealomas, haemangioblastomas, osteoclastomas, Ewing ' s tumours, multiple myelomas, mycosis fungoides, Burkitt ' s tumours, leukaemias, acute and chronic lymphatic leukaemias, acute and chronic granulocytic leukaemias, acute and chronic monocytic leukaemias, stem cell leukaemias, basaliomas, fibromas, myomas, and metastases of any form of tumour that are accessible by surgical intervention in the form of a local injection.

Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can e.g. further be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous) , topically, transdermalIy, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such, as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

The compositions will e.g. include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Compositions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include e.g. preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can e.g. be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol , phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene , etc.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol , polyethyleneglycol , glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agent, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes . The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients .

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol , 1 , 3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound (s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound (s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990) . The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can e.g. be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art .

Preparation of compounds of formula (I) :

Scheme 1 depicts a general synthetic route for the preparation of compounds of the present invention and is not intended to be limiting. The reaction may be carried out as a multi component reaction, using reaction conditions that are favorable for product formation:

Scheme 1 (X = S)

More specifically, Scheme 2 and 3 depict examples of the synthesis of further pyrazolo [3 , 4-e] [I₇4] thiazepine compounds:

Scheme 2

Scheme 3 Specific examples are described subsequently to these general synthetic descriptions so as to allow one skilled in the art to make and use either pyrazolo [3 , 4-e] [1 , 4] thiazepines of the invention.

The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes.

Example 1 :

General Pyrazolo [3 , 4-e] [1 , 4] thiazepines Synthesis Equimolar amounts of aldehyde (leq) and amine (leq) were mixed in toluene and refluxed for 2 hours. Subsequently, 1 equivalents of the corresponding mercapto acid was added and the mixture was refluxed for additional 3 hours. Afterwards the reaction was stirred for 16 hours at room temperature, whereby the crude product precipitated. The solid was filtered off and recrystallized in ethyl acetate. The resulting solid was washed with ethyl acetate, water and ether. The final product was dried under high vacuum.

Example 2 :

Synthesis of Pyrazolo [3 , 4-e] [1 , 4] thiazepine carboxylic acid pentafluorophenyl esters according to Scheme 2.

1,5 equivalents of EDCI and 3 equivalents of pentafluorphenol were stirred in absolute DMF for 10 minutes at 0⁰C. Accordingly, 1 equivalent of a carbonic acid of Formula I was added and stirring was continued at 0⁰C for 30 minutes and at room temperature for 16 hours. After the reaction was completed, the crude product was evaporated to dryness and the final purification was performed by column chromatography on silica with ethyl acetate / dichloromethane mixtures as eluent .

Example 3 :

Synthesis of pyrazolo [3 , 4-e] [1 , 4] thiazepine carboxylic acid amides according to Scheme 2.

The pentafluorphenyl esters from Example 2 were solved in THF and reacted with the corresponding amines during 1 hour at room temperature. The crude product was evaporated to dryness and the final purification was performed by column chromatography on silica with ethyl acetate / methanol mixtures as eluent .

Example 5 :

Synthesis of pyrazolo [3 , 4-e] [1 , 4] thiazepine sulfones or sulfoxides according to Scheme 3.

The pyrazolo [3 , 4-e] [1 , 4] thiazepines of Formula (I) were dissolved in acetic acid and treated with hydrogenperoxide during 1 hour at room temperature. The crude product was evaporated to dryness and the final purification was performed by column chromatography on silica with ethyl acetate / methanol mixtures as eluent .

Example 6 :

According to examples 1, 2 or 3 the following compounds were synthesized and isolated:

Structure Mass Mass found by calculated HPLC-MS

433,58 434,2

360,44 361, 1

Assays

All kinase assays were performed according to literature methods (e.g. as disclosed in Curtin, Cell Notes 2005, 13, 11- 15) known to an expert skilled in the art by using γ~ 33 P ATP. The ATP concentrations were selected to be close to the Michaelis-Menten constant for each specific kinase. Dose- response experiments to determine IC₅₀ inhibition constants are performed by using different inhibitor concentrations in a 96- well plate format. Thus, a radiometric protein kinase was used for measuring the kinase activity of c-Met kinase. All kinase assays were performed in 96 -well FlashPlates from Perkin Elmer (Boston, MA, USA) in a 50 μl reaction volume. The reaction cocktail was pipetted in 4 steps in the following order: 20 μl of assay buffer, 5 μl of ATP solution (in H₂O) , 5 μl of test compound (in 10 % DMSO) , 10 μl of substrate / 10 μl of enzyme solution (premixed) . The assay contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl₂, 3 mM MnCl₂, 3 μM Na-orthovanadate, 1.2 mM DTT, 50 μg/ml PEG20000, 1 μM [γ-33P] -ATP (approx. 1.5 x 1005 cpm per well) . For the kinase assays enzyme (100 ng/50μl per well) and substrate poly(Ala, GIu, Lys, Tyr) 6:2:5:1 125 ng/50μl were used per well. The reaction cocktails were incubated at 30° C for 80 minutes. The reaction was stopped with 50 μl of 2 % (v/v) H₃PO₄, plates were aspirated and washed two times with 200 μl of 0.9 % (w/v) NaCl. Incorporation of ³³Pi was determined with a microplate scintillation counter (Microbeta Trilux, WaIlac) . All assays were performed with a BeckmanCoulter/Sagian robotic system.

Compounds of the present invention show a kinase inhibitory activity of below 100 μM in the described assay.

Claims

1. Compound of formula (I)

(D wherein

X is S, SO or SO₂;

R¹ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl , heteroaryl , cycloalkyl, alkylcyclo- alkyl, heteroalkylcycloalkyl , heterocycloalkyl , aralkyl or heteroaralkyl radical;

R² is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclo- alkyl, heteroalkylcycloalkyl , heterocycloalkyl, aralkyl or heteroaralkyl radical;

R³ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclo- alkyl , heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;

R⁴ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclo- alkyl, heteroalkylcycloalkyl , heterocycloalkyl , aralkyl or heteroaralkyl radical; and

R⁵ is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl , heteroaryl, cycloalkyl, alkylcyclo- alkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;

wherein all of the above radicals may optionally be substituted;

or a pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate or a pharmaceutically acceptable formulation thereof.

2. Compound according to claim 1 wherein R¹ is an optionally substituted aryl or heteroaryl or an alkyl radical.

3. Compound according to claim 1, wherein R¹ is an optionally substituted phenyl radical or an optionally substituted heteroaryl radical containing 5 or 6 ring atoms and 1, 2, 3 or 4 ring-heteroatoms selected from 0, S and N.

4. Compound according to anyone of claims 1 to 3 wherein R² is an optionally substituted aryl or heteroaryl radical .

5. Compound according to anyone of claims 1 to 3 wherein R² is an optionally substituted phenyl or naphthyl radical or an optionally substituted heteroaryl radical containing 5 or 6 to 10 ring atoms and 1, 2, 3 or 4 ring-heteroatoms selected from 0, S and N.

6. Compound according to anyone of claims 1 to 5 wherein R³ is a hydrogen atom or a Ci-C₄ alkyl radical.

7. Compound according to anyone of claims 1 to 6 wherein R⁴ is a hydrogen atom or an alkyl, heteroalkyl or heteroalkylcycloalkyl radical .

8. Compound according to anyone of claims 1 to 6 wherein R⁴ is hydrogen, Ci-C₄ alkyl or a group of formula CH₂COR⁸ wherein R⁸ is hydroxy or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl , heteroaryl, cycloalkyl, alkylcyclo- alkyl, heteroalkylcycloalkyl, heterocycloalkyl , aralkyl or heteroaralkyl radical .

9. Compound according to claim 8 wherein R⁸ is hydroxy or NH (CH₂) _pR⁹, wherein p is 0, 1, 2, 3 or 4 and R⁹ is an optionally substituted cycloalkyl or heterocycloalkyl radical .

10. A pharmaceutical composition comprising a compound according to anyone of the preceding claims or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

11. Use of a compound or a pharmaceutical composition according to anyone of the preceding claims for the modulation of kinase activity.

12. Use of a compound or a pharmaceutical composition according to anyone of the preceding claims for the treatment and/or prevention of diseases mediated by kinase activity.

13. Use of a compound or a pharmaceutical composition according to anyone of the preceding claims for the treatment and/or prevention of cancer.