Indazolyl-isoxazole derivatives for treatment of diseases such as cancer

Abstract

To provide compounds or pharmaceutically acceptable salts thereof which inhibit c- KIT kinase across a wide range of c-KIT mutations and secondary mutations (V654A secondary resistance mutation in Exon 13) that may arise in GIST (gastrointestinal stromal tumor) patients, and to provide preparation processes thereof.SOLUTION: There is provided a pharmaceutically acceptable salt of 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazin-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A45").SELECTED DRAWING: None

Description

Technical Field

[0001] Background of the Invention The present invention had the objective of finding novel compounds having valuable properties, in particular those that can be used for the preparation of medicaments. The present invention relates to indazolyl-isoxazole derivatives which inhibit c-KIT kinase over a wide range of c-KIT mutations and secondary mutations (V654A secondary resistance mutation in exon 13) that can occur in patients with GIST (gastrointestinal stromal tumor).

[0002] The compounds of the present invention are thus useful for treating diseases such as cancer. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, compounds for use in the treatment of diseases, and methods for treating diseases using pharmaceutical compositions containing these compounds.

Background Art

[0003] Mutated forms of the receptor tyrosine kinase c-KIT are drivers of several cancers and attractive targets for therapy. In particular, while benefits are obtained from the use of inhibitors of KIT kinase activity such as imatinib in GIST, primary resistance occurs with certain oncogenic mutations. Furthermore, resistance occurs frequently due to secondary mutations (L.K. Ashman & R. Griffith (2013) Expert Opinion on Investigational Drugs, 22:1, 103 - 115). L.L. Chen et al. describe “A Missense Mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors” in Cancer res. 2004; 64:5913 - 5919. K.G. Roberts et al. describe “Resistance to c-KIT kinase inhibitors conferred by V654A mutation” in Mol. Cancer Ther. 2007; 6:1159-1166.

[0004] Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. GISTs are defined as c-KIT (CD117, stem cell factor receptor)-positive mesenchymal spindle cells or epithelioid neoplasms. GISTs generally have primary activating mutations of the KIT gene (90%), which result in ligand-independent activation of the receptor tyrosine kinase c-KIT and render the tumors dependent on oncogenic KIT activity.

[0005] Imatinib treatment of GISTs with primary mutations has an initial response rate of approximately 70%, but acquired resistance develops in 40 - 50% of cases with a mean of 2 years. V654A, a secondary mutation in exon 13, is the most frequent resistance mutation after imatinib. There is a high unmet medical need for the development of safe and specific inhibitors against the KIT V654A resistance mutation. The compounds according to the invention and their salts have been found to have highly valuable pharmacological properties while being well tolerated.

[0006] Specifically, the present invention relates to compounds of formula I which inhibit c-KIT kinase, preferably the mutant V654A of c-KIT kinase. Moreover, the compounds of formula I inhibit PDGFRα (V651D). Gain-of-function mutations of PDGFRα appear to play an important role in the development of GISTs without KIT mutations (S. Hirota et al., Gastroenterology 2003;125:660-667).

[0007] The host or patient may belong to any mammalian species, such as a primate species, especially humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are the subject of experimental investigations and provide models for the treatment of human diseases.

[0008] The sensitivity of a particular cell to treatment with a compound according to the present invention can be determined by in vitro testing. Typically, a culture of cells is combined with a compound according to the present invention at various concentrations for a sufficient period of time, usually between about 1 hour and 1 week, to allow an active agent such as anti-IgM to induce a cellular response, such as the expression of surface markers. Conducting in vitro testing can be carried out using cells cultured from blood or from a biopsy sample. The amount of expressed surface marker is assessed by flow cytometry using a specific antibody that recognizes the marker.

[0009] Dosages vary depending on the particular compound used, the particular disease, the patient's condition, etc. A therapeutic dose is typically sufficient to reduce the unwanted cell population in the target tissue while maintaining the viability of the patient. Treatment is generally continued until a significant reduction has occurred (e.g., at least about a 50% reduction in cell burden), and may be continued until essentially the unwanted cells are no longer detectable in the body.

[0010] prior art WO2012 / 084704 discloses compounds of the formula: [ka] This invention discloses indazolyltriazole derivatives of the formula: The presently claimed isoxazole compounds exhibit enhanced activity compared to the corresponding triazole derivatives (Table 2). Hongchan An et al (Bioorganic and Medicinal Chemistry Letters 21 (2011)) 6297-6300 reported that indazolyl-isoxazole is a HIF-1 inhibitor:

Chem.

[0011] Nicoloe Vivona et al, Journal of Heterocyclic Chemistry 22 (1985) 29-32 reported the following:

Chem.

SUMMARY OF THE INVENTION

[0012] Summary of the Invention The present invention relates to formula I

Chem.

[0013] The present invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers, and hydrates and solvates of these compounds.

[0014] Furthermore, the present invention relates to pharmaceutically acceptable derivatives of the compounds represented by formula I. The term solvate of a compound is interpreted to mean adductions in which inert solvent molecules are added to the compound (which are formed by their mutual attraction). Solvates are, for example, monohydrates or dihydrates or alkoxides. It is understood that the present invention also relates to solvates of salts.

[0015] The term pharmaceutically acceptable derivative is also interpreted to mean, for example, salts of the compounds according to the present invention and so-called prodrug compounds.

[0016] As used herein, unless otherwise indicated, the term "prodrug" means a derivative of a compound represented by formula I that can provide an active compound, especially a compound represented by formula I, by undergoing hydrolysis, oxidation, or otherwise reacting under biological conditions (in vitro or in vivo). Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds represented by formula I that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureas, and biohydrolyzable phosphate analogs.

[0017] In one aspect, the prodrug of a compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is advantageously formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods such as those described by Burger's Medicinal Chemistry and Drug Discovery, 6th Edition (edited by Donald J. Abraham, 2001, Wiley) and Design and Application of Prodrugs (edited by H. Bundgaard, 1985, Harwood Academic Publishers Gmfh).

[0018] The expression "effective amount" refers to the amount of a pharmaceutical or pharmaceutically active ingredient that causes a desired biological or pharmaceutical response, for example, as determined or desired by a researcher or physician, in a tissue, system, animal, or human.

[0019] In addition, the expression "therapeutically effective amount" refers to the amount that, when administered to a subject, as compared to a corresponding subject not receiving this amount, results in: Improved treatment, cure, prevention, or alleviation of a disease, syndrome, condition, complaint, disorder, or side effect, or also results in a reduction in the progression of a disease, complaint, or disorder.

[0020] The expression "therapeutically effective amount" also encompasses an amount effective to increase normal physiological function. The present invention also relates to the use of a mixture of compounds of formula I, for example, a mixture of two diastereomers, for example, a mixture thereof in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100, or 1:1000. These are, among other things, preferably mixtures of stereoisomeric compounds.

[0021] "Tautomers" refer to the isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is found and may differ, for example, depending on whether the compound is solid or in an organic or aqueous solution.

[0022] The present invention relates to compounds of formula I and their salts, and to a process for the preparation of compounds of formula I and their pharmaceutically acceptable salts, solvates, tautomers and stereoisomers, a) Formula I wherein, X represents phenylene, Y represents CO, Z represents [C(R 3 ) 2 n Het 2 and, n represents 0, for the preparation of the compound represented by Formula II

Chemical formula

Chemical formula

[0023] b) Formula I wherein, R 1 represents Het 1 for the preparation of the compound represented by using a compound of formula IV Formula IV

Chemical formula

Chemical formula

[0024] c) For the preparation of the compound represented by formula Ia

Chemical formula

Chemical formula

Chemical formula

[0025] d) For the preparation of the compound represented by formula Ib

Chemical formula

Chemical formula

Chemical formula

[0026] For example, in the case of all radicals occurring more than once such as R 3 etc., their meanings are independent of each other. In the above and below, unless otherwise specified, the radicals R 1 , R 2 , X, Y and Z have the meanings indicated in Formula I.

[0027] Preferably, the compound represented by Formula Ia

Chemical formula

Chemical formula

[0028] A represents alkyl, which is unbranched (linear) or branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, and even more preferably represents trifluoromethyl. A very specifically preferably represents alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl. Cyc preferably represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Moreover, A preferably represents CH 2 OCH 3 , CH 2 CH 2 OH or CH 2 CH 2 OCH 3 .

[0029] R 1 is preferably Hal, CF 3 , OCH 3 , OCH 2CH 2 OCH 3 、OCH 2 CH 2 OH, 1-methyl-1H-pyrazol-4-yl, COOCH 3 、CONH 2 、CONHCH 3 or CONHCH 2 CH 2 OCH 3 represents, R 2 preferably represents H, Hal or CN. R 3 is H or A, preferably H or CH 3 represents.

[0030] X preferably represents 1,4-phenylene, 1,3-phenylene, 2-fluoro-1,4-phenylene, 2-methyl-1,4-phenylene, pyridine-3,6-diyl, 1,3-thiazole-3,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl or pyrazole-1,4-diyl, each of which is unsubstituted or mono-, di- or tri-substituted by Hal and / or A. Y preferably represents CO, SO 2 、NHCO、NCH 3 、CONH(CH 2 ) n 、CONHCH 2 C(CH 3 ) 2 、CON(CH 3 )(CH 2 ) n 、O、OCH 2 、OCH 2 CH 2 、S(=O)(=NH)、-N=、SO 2 N(CH 3 ) represents, or does not exist. Z preferably represents H, Hal, OA, Het 2 、A、N=S(=O)A 2 represents. The bicyclic compounds also include spiro compounds.

[0031] Regardless of further substitution, Het 2 represents, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, even more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, pyrrolopyridinyl, purinyl, even more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]-octyl or dibenzofuranyl. The complex cyclic radical may also be partially or fully hydrogenated.

[0032] Regardless of further substitution, Het 2Also, thus, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, even more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, even more preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,It may represent 3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.,

[0033] Regardless of further substitution, Het 3is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, pyrrolopyridinyl, purinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]-octyl or dibenzofuranyl. The complex cyclic radical may also be partially or fully hydrogenated.

[0034] Regardless of further substitution, Het 3Also, thus, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-,-5-,-6-,-7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, even more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, even more preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,It may represent 3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.,

[0035] Het 2is preferably pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, 1,4-diazepanyl, pyridinyl, 1H-pyridinyl, 2H-pyridazinyl, 2,3-dihydropyridazinyl, octahydro-1H-pyrrolo[3.2-b]pyridinyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonan-5-yl, 1H-1,3-benzodiazol-2-yl (benzimidazol-2-yl), 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 8-oxa-2-azaspiro[4.5]decane-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl (1,3-dihydropyrrolo[3,4-c]pyridin-2-yl), 2,7-diazaspiro[3.5]nonan-2-yl, hexahydro-1H-furo[3,4-c]pyrrol-5-yl, octahydropyrrolo[2,3-c]pyrrol-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl, 1H, 4H, 5H,6H-pyrrolo[3,4-c]pyrazol-5-yl, octahydropyrano[3,4-c]pyrrol-2-yl, octahydrofuro[3,4-c]pyridin-5-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydro-1H-2λ6-thieno[3,4-c]pyrrol-5-yl, tetrahydrofuro[3,4-c]pyrrol-5-yl, and each of these is unsubstituted or mono-, di-, or trisubstituted by A, Hal, CN, OR, [C(R)][N(R)], [C(R)][SOA], [C(R)][NRSOA], Het, =NR, and / or =O. Each of these is unsubstituted or mono-, di-, or trisubstituted by A, Hal, CN, OR, 3 , [C(R 3 ) 2 n N(R 3 ) 2 , [C(R 3 ) 2 n SO 2 A, [C(R 3 ) 2 n NR 3 SO 2 A, Het 3 , =NR 3 and / or =O.

[0036] Het 3 preferably represents morpholinyl, 1H-pyrazolyl, 1λ6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, oxan-4-yl, 1,2,3-triazolyl, 1,2,4-triazolyl, and each of these is unsubstituted or mono-, di-, or trisubstituted by A, Hal, OR, oxetanyl, and / or =O. Each of these is unsubstituted or mono-, di-, or trisubstituted by A, Hal, OR, 3 , oxetanyl, and / or =O.

[0037] ​​​Throughout the present invention, all radicals occurring more than once may be the same or different, i.e., independent of each other. The compounds represented by formula I may have one or more chiral centers and can thus occur in various stereoisomeric forms. The compounds represented by formula I encompass all these forms.

[0038] Consequently, the present invention relates, inter alia, to compounds of formula I in which at least one of the radicals has one of the preferred meanings indicated above. Some preferred groups of the compounds may be represented by the following sub-formulas Ia - If which correspond to formula I, where the radicals not designed in more detail have the meanings indicated in formula I, where In Ia, R 1 represents Hal, CF 3 , OCH 3 , OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, 1 - methyl - 1H - pyrazol - 4 - yl, COOCH 3 , CONH 2 , CONHCH 3 or CONHCH 2 CH 2 OCH 3 ; In Ib, R 3 represents H or CH 3 ; In Ic, X represents 1,4 - phenylene, 1,3 - phenylene, 2 - fluoro - 1,4 - phenylene, 2 - methyl - 1,4 - phenylene, pyridine - 3,6 - diyl, 1,3 - thiazole - 3,5 - diyl, 1,3 - thiazole - 2,4 - diyl, 1,3 - thiazole - 2,5 - diyl or pyrazole - 1,4 - diyl, each of which is unsubstituted or mono - substituted, di - substituted or tri - substituted by Hal and / or A; In Id, Y is absent or represents CO, SO 2 , NHCO, NCH 3 , CONH(CH 2 ) n, CONHCH 2 C(CH 3 ) 2 , CON(CH 3 )(CH 2 ) n , O, OCH 2 , OCH 2 CH 2 , S(=O)(=NH), -N= or SO 2 N(CH 3 ) represents; In Ie, Het 2is pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, 1,4-diazepanyl, pyridinyl, 1H-pyridinyl, 2H-pyridazinyl, 2,3-dihydropyridazinyl, octahydro-1H-pyrrolo[3.2-b]pyridinyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonan-5-yl, 1H-1,3-benzodiazol-2-yl (benzimidazol-2-yl), 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 8-oxa-2-azaspiro[4.5]decane-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl (1,3-dihydropyrrolo[3,4-c]pyridin-2-yl), 2,7-diazaspiro[3.5] nonan-2-yl, hexahydro-1H-furo[3,4-c]pyrrol-5-yl, octahydropyrrolo[2,3-c]pyrrol-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl, 1H, 4H, 5H,6H-pyrrolo[3,4-c]pyrazol-5-yl, octahydropyrano[3,4-c]pyrrol-2-yl, octahydrofuro[3,4-c]pyridin-5-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydro-1H-2λ6-thieno[3,4-c]pyrrol-5-yl, tetrahydrofuro[3,4-c]pyrrol-5-yl, each of which is unsubstituted or substituted by A, Hal, CN, OR. 3 , [C(R 3 ) 2 n N(R 3 ) 2 , [C(R 3 ) 2 n SO 2 A, [C(R 3 ) 2 n NR 3 SO 2 A, Het 3 , =NR 3 and / or =O, and may be monosubstituted, disubstituted or trisubstituted; In If, Het 3 represents morpholinyl, 1H-pyrazolyl, 1λ6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, oxan-4-yl, 1,2,3-triazolyl, 1,2,4-triazolyl, each of which is unsubstituted or substituted by A, Hal, OR 3 , oxetanyl and / or =O, and may be monosubstituted or disubstituted; as well as their pharmaceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio.

[0039] ​​​Preferably, the formula Ib according to claim 1 [Chemical formula] In the formula R 1 represents Hal, CF 3 , OCH 3 , OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, 1-methyl-1H-pyrazol-4-yl, COOCH 3 , CONH 2 , CONHCH 3 or CONHCH 2 CH 2 OCH 3 and R 2 represents H, Hal or CN, R 3 represents H or CH 3 and X represents 1,4-phenylene, 1,3-phenylene, 2-fluoro-1,4-phenylene, 2-methyl-1,4-phenylene, pyridine-3,6-diyl, 1,3-thiazole-3,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl or pyrazole-1,4-diyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal and / or A, Y is absent or is CO, SO 2 , NHCO, NCH 3 , CONH(CH 2 ) n , CONHCH 2 C(CH 3 ) 2 , CON(CH 3 )(CH 2 ) n , O, OCH 2 , OCH 2 CH 2 , S(=O)(=NH), -N= or SO 2 N(CH 3 ) and Z represents H, A, Hal, OA, [C(R 3 ) 2 n Het 2 or N=S(=O)A 2 and represents, A represents unbranched or branched alkyl having 1 to 10 C atoms, where one or two non-adjacent CH- and / or CH 2 -groups may be replaced by an O atom, and where 1 to 7 H atoms may be replaced by R 5 and represents, alternatively (CH 2 ) n represents Cyc, Cyc represents cyclic alkyl having 3 to 7 C atoms, R 5 represents F, Cl, OH, SO 2 A or N(R 3 ) 2 and represents, Het 1 represents pyrazolyl which may be mono- or disubstituted by A, Het 2 ​is pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, 1,4-diazepanyl, pyridinyl, 1H-pyridinyl, 2H-pyridazinyl, 2,3-dihydropyridazinyl, octahydro-1H-pyrrolo[3.2-b]pyridinyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonan-5-yl, 1H-1,3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 8-oxa-2-azaspiro[4.5]decane-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl, 2,7-diazaspiro[3.5] nonan-2-yl, hexahydro-1H-furo[3,4-c]pyrrol-5-yl, octahydropyrrolo[2,3-c]pyrrol-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl, 1H, 4H, 5H,6H-pyrrolo[3,4-c]pyrazol-5-yl, octahydropyrano[3,4-c]pyrrol-2-yl, octahydrofuro[3,4-c]pyridin-5-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydro-1H-2λ6-thieno[3,4-c]pyrrol-5-yl or tetrahydrofuro[3,4-c]pyrrol-5-yl, each of which is unsubstituted or mono-, di- or tri-substituted by A, Hal, CN, OR. 3 , [C(R 3 ) 2 n N(R 3 ) 2 , [C(R 3 ) 2 n SO 2 A, [C(R 3 ) 2 n NR 3 SO 2 A, Het 3 , =NR 3 and / or =O, and may be mono-, di- or tri-substituted, Het 3 represents morpholinyl, 1H-pyrazolyl, 1λ6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, oxan-4-yl, 1,2,3-triazolyl or 1,2,4-triazolyl, each of which is unsubstituted or mono- or di-substituted by A, Hal, OR 3 , oxetanyl and / or =O, and may be mono- or di-substituted, Hal represents F, Cl, Br or I, n represents 0, 1, 2 or 3, ​​​Compounds represented by the formula, as well as pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in any ratio are preferred.

[0040] Furthermore, the present invention relates to the group 2-Bromo-5-fluoro-4-(2-methoxyethoxy)benzaldehyde [Chemical formula] N’-[(1E)-[2-Bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylidene]-4-methylbenzene-1-sulfonohydrazide [Chemical formula] 5-Fluoro-6-(2-methoxyethoxy)-1-(4-methylbenzenesulfonyl)-1H-indazole [Chemical formula] 5-Fluoro-6-(2-methoxyethoxy)-1H-indazole [Chemical formula] 5-Fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole [Chemical formula] tert-Butyl 5-fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate [Chemical formula] tert-Butyl 5-fluoro-6-(2-methoxyethoxy)-3-[2-(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate [Chemical formula] 3-Ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole

Chem.

Chem.

Chem.

Chem.

Chem.

[0041] The compounds represented by formula I and also the starting materials for their preparation are, in addition, prepared by methods known per se, precisely under reaction conditions known and suitable for the reaction, as described in the literature (for example, standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Variants known per se not mentioned in detail here can also be used here.

[0042] Formula I In which X represents phenylene, Y represents CO, Z is [C(R 3 ) 2 n Het 2 represents, and n represents 0, The compounds represented by formula I can preferably be obtained by reacting a compound represented by formula II with a compound represented by formula III.

[0043] The starting compounds represented by formula II and III are generally known. If they are novel, however, they can be prepared by methods known per se. The reaction is generally carried out in the presence of compounds such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The reaction is generally carried out in the presence of an acid binder, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine, quinoline or 4-methylmorpholine. The addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, or another salt of a weak acid of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium, may also preferably be the case. ​Depending on the conditions used, the reaction time is from several minutes to 14 days, and the reaction temperature is from about -30°C to 140°C, usually from -10°C to 100°C, especially from about 30°C to about 90°C.

[0044] Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of these solvents. Particularly preferably, it is acetonitrile, dichloromethane and / or DMF.

[0045] Formula I In the formula, R 1 represents Het 1 and the compound represented by can preferably be obtained by reacting the compound represented by formula IV with the compound represented by formula V. The starting compounds represented by formulas IV and V are generally known. However, if they are novel, they can be prepared by methods known per se. Alternatively, formula Va

Chemical formula

[0046] Formula Ia

Chemical formula

[0047] Formula Ib

Chem.

[0048] Pharmaceutical salts and other forms The compounds according to the invention can be used in their final non-salt form. On the other hand, the invention also encompasses the use of these compounds in the form of pharmaceutically acceptable salts thereof, which can be derived from various organic and inorganic acids and bases by procedures known in the art. Most of the pharmaceutically acceptable salt forms of the compounds represented by formula I are prepared by conventional methods. When the compound represented by formula I contains a carboxyl group, one of its suitable salts can be produced by reacting the compound with a suitable base to give the corresponding base addition salt.

[0049] Such bases include, for example, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Aluminum salts of the compounds represented by formula I are also included.

[0050] In the case of a compound represented by formula I, pharmaceutically acceptable acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids such as hydrogen halides (such as hydrogen chloride, hydrogen bromide or hydrogen iodide), other mineral acids and their corresponding salts (such as sulfates, nitrates or phosphates), etc., and alkyl- and monoarylsulfonates (such as ethanesulfonate, toluenesulfonate and benzenesulfonate), and other organic acids and their corresponding salts (such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc.).

[0051] As a result, pharmaceutically acceptable acid addition salts of the compounds represented by formula I include, but are not limited to: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, formate, galactarate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate.

[0052] Furthermore, the basic salts of the compounds according to the invention include salts of aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium and zinc, but this is not intended to be limiting. Among the above salts, preferred are ammonium; alkali metal salts, sodium and potassium, and alkaline earth metal salts, calcium and magnesium.

[0053] Salts of the compounds of formula I derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including also naturally occurring substituted amines, salts of cyclic amines, and basic ion exchange resins, for example, salts of arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine (tromethamine), but this is not intended to be limiting.

[0054] Compounds of the invention containing a basic nitrogen-containing group are (C 1 ~C 4 ) alkyl halides (e.g., methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide); di(C 1 ~C 4 ) alkyl sulfates (e.g., dimethyl, diethyl and diamyl sulfate); (C 10 ~C 18) Alkyl halides (e.g., decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides); and aryl (C 1 ~C 4 ) alkyl halides (e.g., benzyl chloride and phenethyl bromide) and the like can be used for quaternization. Both the water-soluble and oil-soluble compounds according to the present invention can be prepared using such salts.

[0055] Preferred pharmaceutically salts described above include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate, and tromethamine, but this is not intended to be limiting.

[0056] Particularly preferred are hydrochloride, dihydrochloride, hydrobromide, maleate, mesylate, phosphate, sulfate, and succinate.

[0057] Acid addition salts of the basic compounds represented by Formula I are prepared by contacting the free base form with a sufficient amount of the desired acid and causing salt formation in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs in certain physical properties, such as solubility in polar solvents, in some respects from its corresponding salt form; however, for the purposes of the present invention, the salts are equivalent to their respective free base forms in other respects.

[0058] As described above, pharmaceutically acceptable base addition salts of the compounds represented by formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

[0059] The base addition salts of the acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base and causing salt formation in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs in certain physical properties, such as solubility in polar solvents, from the corresponding salt form in some respects; however, for the purposes of the present invention, the salts are, in other respects, equivalent to their respective free acid forms.

[0060] If the compounds according to the invention contain more than one group capable of forming this type of pharmaceutically acceptable salt, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrates, diacetates, difumarates, dimiglumine, diphosphates, disodium and trihydrochlorides, but this is not intended to be limiting.

[0061] With regard to what has been stated above, it is clear that the expression "pharmaceutically acceptable salt" in this context is to be interpreted as meaning an active ingredient containing the compound represented by formula I in one of its salt forms, and this salt form, even more so when it confers improved pharmacokinetic properties on the active ingredient compared to the free form of the active ingredient or any other previously used salt form of the active ingredient. The active ingredient in pharmaceutically acceptable salt form can also provide an active ingredient with desired pharmacokinetic properties not previously possessed, and can even have a positive effect on the pharmacodynamics of this active ingredient with respect to its therapeutic effectiveness in the body.

[0062] Isotopes Furthermore, it is also intended that the compounds represented by Formula I include their forms labeled with isotopes. Compounds represented by Formula I in isotopically labeled forms are identical to this compound, apart from the fact that one or more atoms of the compound are replaced by atoms having an atomic mass or mass number different from that of the atoms normally found in nature.

[0063] Examples of isotopes that are commercially readily available and can be incorporated into the compounds represented by Formula I by well-known methods are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds represented by Formula I, their prodrugs or pharmaceutically acceptable salts are intended to be part of the present invention even if any of them contain one or more of the above isotopes and / or other isotopes of other atoms. Isotopically labeled compounds represented by Formula I can be used in a number of ways to obtain benefits.

[0064] For example, isotopically labeled compounds represented by Formula I are suitable for pharmaceutical and / or tissue distribution assays of substrates, for example, when radioactive isotopes such as 3 H or 14 C are incorporated therein. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C), are particularly preferred because of their simple preparation and excellent detectability. Incorporation of heavier isotopes, such as deuterium ( 2 H) into compounds represented by Formula I has therapeutic advantages due to the higher metabolic stability of the compounds labeled with this isotope.

[0065] Higher metabolic stability translates directly into increased half-life or lower dosages in vivo, and these represent, in most situations, preferred embodiments of the invention. Compounds labeled with isotopes of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and related descriptions, the examples section and the preparations section in this text, and replacing the non-isotope-labeled reactants with readily available isotope-labeled reactants.

[0066] Deuterium ( 2 H) can also be incorporated into the compounds of formula I for the purpose of manipulating the oxidative metabolism of the compounds by primary kinetic isotope effects. The primary kinetic isotope effect is a change in the rate of a chemical reaction due to the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required for covalent bond formation after this isotope exchange.

[0067] The exchange of heavier isotopes usually results in a decrease in the ground state energy for chemical bonding, and thus causes a reduction in the rate in rate-determining bond breakage. When the bond breakage occurs at or near the saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be substantially modified.

[0068] For illustration: when deuterium is bonded to a carbon atom at a non-exchangeable position, a rate difference of k M / k D = 2 - 7 is typical. When this rate difference is successfully applied to compounds of formula I that are susceptible to oxidation, the in vivo profile of this compound can be significantly modified, resulting in improved pharmacokinetic properties.

[0069] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining the desired in vitro properties. It is reasonable to presume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsome assays provide useful information about the course of this type of oxidative metabolism, which in turn enables the rational design of deuterated compounds represented by Formula I with improved stability through resistance to such oxidative metabolism.

[0070] Significant improvements in the pharmacokinetic profile of the compounds represented by Formula I are thereby obtained, quantitatively expressed in terms of increases in in vivo half-life (t1 / 2), concentration at maximum therapeutic effect (C max ), area under the dose-response curve (AUC) and F; and in terms of reduced clearance, dose and material costs.

[0071] The following is intended to illustrate the above: Compounds represented by Formula I having multiple potential sites of attack for oxidative metabolism (e.g., benzyl hydrogen atoms and hydrogen atoms attached to nitrogen atoms) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms such that some, most or all of these hydrogen atoms can be replaced by deuterium atoms.

[0072] Determination of the half-life allows for a favorable and accurate determination of the degree to which improved resistance to oxidative metabolism is achieved. In this way, it is determined that the half-life of the parent compound can be extended up to 100% as a result of this type of deuterium-hydrogen exchange.

[0073] Deuterium-hydrogen exchange in the compounds represented by formula I can also be used to achieve a preferred modification of the metabolite profile of the starting compound in order to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite results through oxidative carbon-hydrogen (C-H) bond cleavage, it can be reasonably speculated that the deuterated analog will significantly reduce or eliminate the formation of unwanted metabolites, even if a particular oxidation is not the rate-limiting step.

[0074] Further information on the state of the art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

[0075] The present invention also further relates to a medicament comprising at least one compound represented by formula I and / or their pharmaceutically acceptable salts, solvates and stereoisomers, and mixtures thereof in any ratio, and optionally, excipients and / or adjuvants.

[0076] The pharmaceutical preparation can be administered in the form of dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units can contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 100 mg of the compound according to the invention, depending on the condition to be treated, the method of administration, and the age, weight and condition of the patient, or the pharmaceutical preparation can be administered in the form of dosage units containing a predetermined amount of the active ingredient per dosage unit. Preferred dosage unit formulations include, as indicated above, those containing a daily dose or part-dose, or a corresponding fraction thereof of the active ingredient. Furthermore, pharmaceutical preparations of this type can be prepared using processes generally known in the pharmaceutical art.

[0077] The pharmaceutical preparation can be adapted for administration by any desired suitable method, for example, oral (including buccal or sublingual), rectal, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Such preparations can be prepared using all processes known in the pharmaceutical art, for example, by combining the active ingredient with excipient(s) or adjuvant(s).

[0078] Pharmaceutical preparations adapted for oral administration can be administered as discrete units, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or water-in-oil or oil-in-water liquid emulsions.

[0079] Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient components can be combined with oral, non-toxic, and pharmaceutically acceptable inert excipients such as ethanol, glycerol, water, etc. The powder is prepared by grinding the compound to a suitable fine size and mixing it with pharmaceutically excipients ground in a similar manner (such as edible carbohydrates, such as starch or mannitol). Flavors, preservatives, dispersants, and dyes may be present simultaneously.

[0080] Capsules are prepared by preparing a powder mixture as described above and filling it into a formed gelatin shell. Flow promoters and lubricants such as highly dispersible silicic acid, talc, magnesium stearate, calcium stearate, or polyethylene glycol in solid form can be added to the powder mixture before the filling operation. Disintegrants or solubilizers such as agar-agar, calcium carbonate, or sodium carbonate may be added simultaneously to improve the availability of the medicine after the capsule is taken.

[0081] In addition, suitable binders, lubricants, and disintegrants as well as dyes can be incorporated into the mixture simultaneously, if desired or necessary. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), sweeteners made from corn, natural and synthetic rubbers (such as acacia, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.

[0082] Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Tablets are formulated, for example, by preparing a powder mixture, granulating or dry compressing the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture to obtain tablets. The powder mixture is prepared by mixing a compound pulverized in a suitable manner, as described above, together with a diluent or a base, and optionally, a binder (e.g., carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, etc.), a dissolution retardant (e.g., paraffin, etc.), an absorption promoter (e.g., quaternary salts, etc.), and / or an absorbent (e.g., bentonite, kaolin or dicalcium phosphate, etc.).

[0083] The powder mixture can be granulated by wetting it with a binder (e.g., syrup, starch paste, acacia mucilage or a solution of cellulose or a polymeric material, etc.) and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tableting machine to obtain a mass of non-uniform shape, which can be disintegrated to form granules. The granules can be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the tablet casting mold.

[0084] The lubricated mixture is then compressed to give tablets. The compounds according to the present invention can also be combined with a free-flowing inert excipient and then directly compressed to obtain tablets without performing granulation or dry compression steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymeric material and a gloss layer of wax may be present. Dyes can be added to these coatings so as to be able to distinguish between different dosage units.

[0085] For example, oral liquids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a predetermined quantity contains a specific amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution together with a suitable flavoring agent, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizing and emulsifying agents (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, etc.), preservatives, flavoring additives (such as peppermint oil or natural sweeteners or saccharin, etc.), or other artificial sweeteners, etc. can be added simultaneously.

[0086] Dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulations can also be prepared so that release is prolonged or delayed, for example, by coating particulate materials with polymers, waxes, etc., or embedding them therein.

[0087] The compounds of formula I and their pharmaceutically acceptable salts, tautomers, and stereoisomers can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles, etc. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine, etc.

[0088] The compounds represented by formula I and their salts, tautomers and stereoisomers can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled to soluble polymers as targeted pharmaceutical carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine substituted by palmitoyl radicals.

[0089] The compounds may also be coupled to biodegradable polymers of the type suitable for achieving controlled release of pharmaceuticals, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylate, and crosslinked block copolymers of hydrogels or their amphiphilic block copolymers.

[0090] Pharmaceutical formulations adapted for transdermal administration can be administered as self-adhesive patches for long-term intimate contact with the recipient's epidermis. Thus, for example, the active ingredient can be delivered from the patch by iontophoresis as described generally in Pharmaceutical Research, 3(6), 318 (1986).

[0091] Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0092] For the treatment of the eyes or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream. In the case of a formulation for giving an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible cream base. Alternatively, the active ingredient can be formulated to give a cream having an oil-in-water cream base or a water-in-oil base.

[0093] Pharmaceutical formulations suitable for topical application to the eyes include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0094] Pharmaceutical formulations suitable for topical application in the mouth cover medicated candies, troches and mouthwashes. Pharmaceutical formulations suitable for rectal administration can be administered in the form of suppositories or enemas.

[0095] Pharmaceutical formulations suitable for nasal administration in which the carrier substance is solid include, for example, coarse powders having a particle size in the range of 20 to 500 microns, which are administered by sniffing in the manner in which snuff is taken, i.e., by rapidly inhaling the powder through the nasal passages from a container containing the powder while bringing it close to the nose. Formulations suitable for administration as nasal sprays or nasal drops having a liquid as the carrier substance cover solutions of the active ingredient in water or in oil.

[0096] Pharmaceutical formulations suitable for administration by inhalation cover fine particulate powders or mists, which can be generated by various types of pressurized dispensers equipped with aerosols, nebulisers or insufflators. Pharmaceutical formulations suitable for vaginal administration can be administered in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays.

[0097] Pharmaceutical formulations adapted for parenteral administration are aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes, by means of which the formulation is made isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending media and thickening agents. The formulations are dispensed in single-dose or multi-dose containers (e.g., sealed ampoules and vials) so that they require only the addition of a sterile carrier liquid (e.g., water for injection purposes) immediately before use and can be stored in a freeze-dried (lyophilised) state. Injection solutions and suspensions prepared according to a recipe can be prepared from sterile powders, granules and tablets.

[0098] In addition to the components specifically mentioned above, it goes without saying that the formulations may also contain other agents which are normal in the art for a specific type of formulation; thus, for example, formulations suitable for oral administration may contain flavoring agents.

[0099] The therapeutically effective amount of the compound represented by formula I depends on a number of factors including, for example, the age and weight of the animal, the exact condition and its severity which requires treatment, the nature of the formulation and the method of administration, and is ultimately determined by the physician or veterinarian treating the patient. However, the effective amount of the compounds according to the invention generally ranges from 0.1 to 100 mg per recipient (mammal) per day per kg of body weight, and particularly typically ranges from 1 to 10 mg per kg of body weight per day.

[0100] Thus, for an adult mammal weighing 70 kg, the actual amount per day is usually between 70 and 700 mg, where this amount can be administered as a single daily dose, or usually as a series of partial doses (e.g., 2, 3, 4, 5, or 6 times a day, etc.) per day, such that the total daily dose is the same. The effective amount of the salt or solvate thereof, or of its physiologically functional derivative, can be determined as a fraction of the effective amount of the compound itself according to the invention. Similar dosages can be presumed to be suitable for the treatment of other conditions mentioned above.

[0101] This type of combined treatment can be achieved by utilizing simultaneous, sequential, or separate administration of the individual components of the treatment. This type of combined product employs a compound according to the invention.

[0102] The invention further also relates to a medicament comprising at least one compound of formula I and / or their pharmaceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio, and at least one further pharmaceutically active ingredient.

[0103] The invention also relates to (a) an effective amount of a compound of formula I and / or their pharmaceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio, and (b) an effective amount of a further pharmaceutically active ingredient and relates also to a set (kit) consisting of separate packs.

[0104] The set includes a suitable container such as a box, individual vials, bags or ampoules. The set may, for example, include individual ampoules, each containing an effective amount of a compound of formula I and / or their pharmaceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio, and an effective amount of a further pharmaceutically active ingredient in dissolved or lyophilized form.

[0105] As used herein, "treating" means the overall or partial alleviation of symptoms associated with a disorder or disease, or the slowing or stopping of further progression or worsening of those symptoms, or the prevention or prophylaxis of a disease or disorder in a subject at risk of developing the disease or disorder.

[0106] The term "effective amount" in relation to a compound represented by formula (I) can mean an amount that wholly or partly alleviates symptoms associated with a disorder or disease, or slows or stops further progression or worsening of those symptoms, or prevents or provides prophylaxis against a disease or disorder (such as an inflammatory condition, an immunological condition, cancer or a metabolic condition) in a subject having or at risk of developing a disease disclosed herein.

[0107] In one aspect, an effective amount of the compound represented by formula I is an amount that inhibits c-KIT kinase in cells, for example in vitro or in vivo. In some aspects, an effective amount of the compound represented by formula I inhibits c-KIT in cells by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% compared to the activity of c-KIT kinase in untreated cells. An effective amount of the compound represented by formula I is, for example, at a level in a pharmaceutical composition that will produce the desired effect; for example, in unit dosages for both oral and parenteral administration, it may be from about 0.005 mg / kg of the subject's body weight to about 10 mg / kg of the subject's body weight.

[0108] Use The present compound is suitable as a pharmaceutically active ingredient for mammals, particularly for humans, in the treatment of cancers such as gastrointestinal stromal tumors. The present invention encompasses the use of a compound represented by formula I and / or a pharmaceutically acceptable salt, tautomer, and stereoisomer thereof, for the preparation of a medicament for the treatment or prevention of cancer, preferably for the treatment of gastrointestinal stromal tumors. Preferably, the present invention relates to a method of treating a disease, wherein the disease is cancer, preferably gastrointestinal stromal tumor, said method. Most preferably, the present invention relates to a method wherein the disease is cancer and the administration is simultaneous, sequential or alternating with the administration of at least one other active agent.

[0109] The disclosed compounds represented by formula I can be administered in combination with other known therapeutic agents including anti-cancer agents. As used herein, the term "anti-cancer agent" relates to any agent administered to a patient having cancer for the purpose of treating the cancer.

[0110] The anti-cancer treatment defined above may be applied as monotherapy, or added to the compounds represented by formula I disclosed herein, with or without conventional surgery or radiotherapy or pharmacotherapy. Such pharmacotherapy, for example chemotherapy or targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents:

[0111] Alkylating agents Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Chloromethine, Cyclophosphamide, Dacarbazine, Ifosfamide, Inprosulfan Tosylate, Lomustine, Melphalan, Mitobronitol, Mitolactol, Nimustine, Ranimustine, Temozolomide, Thiotepa, Treosulfan, Mechlorethamine, Carbocone; Apaziquone, Fotemustine, Glufosfamide, Palifosfamide, Pipobroman, Trofosfamide, Uramustine, TH-302 4 VAL-083 4 etc.;

[0112] Platinum compounds Carboplatin, cisplatin, eptaplatin, milphlatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; such as lobaplatin, nedaplatin, picoplatin, satraplatin;

[0113] DNA altering agents Amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine 1,3 such as;

[0114] Topoisomerase inhibitors Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; such as amonafide, belotecan, elliptinium acetate, borerroxin, etc.;

[0115] Microtubule modifiers Cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; such as fosbretabulin, tesetaxel, etc.;

[0116] Antimetabolites Asparaginase 3 , azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, larotrexed, sapacitabine, tegafur2,3 , such as trimethoprim;

[0117] Anticancer antibiotics Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, dinostatin, zorubicin, daunorubicin, pirarubicin; aclarubicin, peplomycin, pirarubicin, etc.;

[0118] Hormones / antagonists Abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fludrocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, tripterelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitostanol, orteronel, enzalutamide 1,3 etc.;

[0119] Aromatase inhibitors Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane, etc.;

[0120] Small molecule kinase inhibitors Crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, luxitinib, sorafenib, sunitinib, vandetanib, bemrafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tibatinib, tiboxanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib 4 , cabozantinib S-malate 1,3 , ibrutinib 1,3 , icotinib 4 , buparlisib 2 , cipatinib 4 , cobimetinib 1,3 , idelalisib 1,3 , fedratinib 1 , XL-647 4 etc.;

[0121] Photosensitizing agents Methoxsalen 3 ; porfimer sodium, talaporfin, temoporfin, etc.;

[0122] Antibodies Alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3; Catumaxomab, Erlotuzumab, Epratuzumab, Farletuzumab, Mogamulizumab, Necitumumab, Nimotuzumab, Ofatumumab, Ocaratuzumab, Oregovomab, Ramucirumab, Rilotumumab, Siltuximab, Tocilizumab, Zalutumumab, Zanomimumab, Matsumumab, Dalotuzumab 1,2,3 , Onartuzumab 1,3 , Racotumomab 1 , Tabalumab 1,3 , EMD - 525797 4 , Nivolumab 1,3 etc.;

[0123] Cytokines Aldesleukin, Interferon Alfa 2 , Interferon Alfa 2a 3 , Interferon Alfa 2b 2,3 ; Sermolukin, Tasonermin, Teseplukin, Oprelvekin 1,3 , Recombinant Interferon Beta - 1a 4 etc.;

[0124] Drug conjugates Denileukin Diftitox, Ibritumomab Tiuxetan, Iobenguane I123, Prednimustine, Trastuzumab Emtansine, Estramustine, Gemtuzumab Ozogamicin, Aflibercept; Cintredekin Besudotox, Edotreotide, Inotuzumab Ozogamicin, Napumomab Estafenatox, Oportuzumab Monatox, Technetium (99mTc) Arcitumomab 1,3 , Vintafolide 1,3 etc.;

[0125] Vaccines Ciprolet 3; Vitespen 3 , emepepimut-S 3 , oncoVAX 4 , rindopepimut 3 , troVax 4 , MGN-1601 4 , MGN-1703 4 etc.;

[0126] Others alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, methylosin, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel 3 , schizophyllan, tamibarotene, temsirolimus, thalidomide, tretinoin, visomodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridafolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabectedin, ubenimex, valspodar, gendicine 4 , picibanil 4 , reolysin 4 , retaspimycin hydrochloride 1,3 , trebananib 2,3 , virulizin 4 , carfilzomib 1,3 , endostatin 4 , immucothel 4, belinostat 3 , MGN-1703 4 ;

[0127] 1 Prop. INN (Proposed International Nonproprietary Name) 2 Rec. INN (Recommended International Nonproprietary names) 3 USAN (United States Adopted Name) 4 No INN.

[0128] The following abbreviations refer to the following definitions, respectively: aq (aqueous), h (hour), g (gram), l (liter), mg (milligram), MHz (megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), ml (milliliter), μl (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl 3 (deuterated chloroform), CD 3 OD (deuterated methanol), CH 3 CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIPEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d 6 (deuterated dimethyl sulfoxide), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et 2O (diethyl ether), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (high performance liquid chromatography), i-PrOH (2-propanol), K 2 CO 3 (potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO 4 (magnesium sulfate), MS (mass spectrometry), MTBE (methyl tert-butyl ether), NaHCO 3 (sodium bicarbonate), NaBH 4 (sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UPLC (ultra performance liquid chromatography), UV (ultraviolet). In the above and below, all temperatures are shown in °C.

[0129] 1 1H NMR was recorded on a Bruker DPX-300, DRX-400, AVII-400 or 500 MHz spectrometer using the residual signal of the deuterated solvent as an internal standard. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (DMSO-d 6 in 1 for 1H NMR at δ = 2.49 ppm). 1 1H NMR data are reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogens). Multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), bs (broad singlet), p (pentuplet).

[0130] HPLC / MS Condition A: HPLC / MS: Agilent 1200 / 6100 Mobile Phase A: Water + 0.05% Formic Acid Mobile Phase B: Acetonitrile + 0.04% Formic Acid Column: Chromolith HR RP-18e; 50 - 4.6 mm Flow Rate: 3.3 ml / min Gradient: 0% -> 100% B: 0.0 -> 2.0 min | 100% B: 2.0 -> 2.5 min UV Detection: 220 nm MS Detection: 65 - 800 amu Positive

[0131] HPLC / MS Condition B: HPLC / MS: Agilent 1200 / 6100 Mobile Phase A: Water + 0.05% Formic Acid Mobile Phase B: Acetonitrile + 0.04% Formic Acid Column: Kinetex XB-C18; 2.6 μm; 50 - 4.6 mm Flow Rate: 2.5 ml / min Gradient: 0% -> 100% B: 0.0 -> 1.4 min | 100% B: 1.4 -> 2.0 min UV Detection: 220 nm MS Detection: 65 - 800 amu Positive

[0132] UPLC / MS Condition: UPLC / MS: Waters Acquity / SQD Mobile Phase A: Water + 0.05% Formic Acid Mobile Phase B: Acetonitrile + 0.04% Formic Acid Column: Kinetex XB-C18; 1.7 μm; 50 - 2.1 mm Flow Rate: 0.9 ml / min Gradient: 2% -> 100% B: 0.0 -> 1.0 min | 100% B: 1.0 -> 1.3 min UV Detection: 220 nm / 254 nm / MaxPlot / TotalPlot MS Detection: 61 - 800 amu Positive

[0133] Assays c-Kit (V654A) assay: c-Kit (V654A) (amino acid 544 terminus containing the V654A mutation of recombinant human c-Kit tagged with an N-terminal GST tag) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYEFMGGKKK, 10 mM magnesium acetate and [gamma-33P-ATP] (specific activity approximately 500 cpm / pmol, concentration 200 μM). The reaction was initiated by the addition of MgATP mix. After incubation at room temperature for 40 minutes, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μL of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

[0134] Assay principle of cell tests for cKIT mutants inhibitors The GIST430 / 654 cell line expressing the constitutively active cKIT receptor tyrosine kinase with mutations (Δ560-576 and V654A) was employed to assay the cellular efficacy of compounds. The cellular activity of the mutant cKIT was determined by the extent of cKIT autophosphorylation at tyrosine 307 using a Luminex-based bead assay. GIST430 / 654 cells were plated at 25,000 cells per well in a 96-well plate in 100 μl of medium (85% IMDM / 15% FCS supplemented with 100 nM imatinib). The next day, compounds were added in serial dilutions for 45 minutes. The cells were then lysed in 90 μl of lysis buffer (20 mM Hepes pH 7.5, 200 mM NaCl, 1.5 mM MgCl2·6H2O, 0.4 mM EDTA, 1% Triton-X-100, 1% phosphatase-inhibitor II, 20 mM β-glycerophosphate, 0.1% protease-inhibitor cocktail III, 0.01% benzonase), and the lysate was clarified by centrifugation in a 96-well filter plate (0.65 μm). Samples were incubated overnight at 4 °C with gentle stirring with Luminex beads conjugated to an anti-total cKIT antibody. For the detection of phospho-Y307-cKIT, a phospho-specific antibody and a species-specific PE-labeled secondary antibody were added. The amount of phospho-Y307-cKIT was determined using a Luminex 200 instrument by measuring 100 events per well within 60 seconds.

[0135] Counts from samples treated with compounds were calculated as a percentage of controls from vehicle-treated (0.3% DMSO) samples. Dose-response curves were fitted and IC 50 values were determined using Genedata Screener software.

[0136] Pharmacological data Table 1 Inhibition of c-KIT (V654A) and GIST 430 / 654 by the compounds of formula I (IC 50 )

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0137] The compounds shown in Table 1 are specifically preferred compounds according to the present invention.

[0138] Table 2 Inhibition of c-KIT (V654A) and GIST 430 / 654 of some representative compounds represented by Formula I compared with the corresponding triazole derivatives (IC 50 )

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

[0139] Synthesis of intermediates Indazole Synthesis of 6-(2-Methoxy-ethoxy)-1H-indazole

Chem.

[0140] A solution of 2-Fluoro-4-(2-methoxy-ethoxy)-benzaldehyde (6.16 g, 31.1 mmol) in hydrazinium hydroxide (30.2 ml, 31.1 g, 621 mmol) is heated to 140 °C with stirring and maintained at this temperature for 16 h. The reaction mixture is allowed to reach room temperature and is diluted with water. Then concentrated hydrochloric acid and 2N hydrochloric acid are carefully added until a pH value of 2 is reached. The mixture is extracted four times with dichloromethane. The combined organic phases are extracted with saturated sodium chloride solution and dried over sodium sulfate. The sodium sulfate is filtered off and the filtrate is evaporated and dried under vacuum to give 6-(2-Methoxy-ethoxy)-1H-indazole as a pale yellow crystalline solid; HPLC / MS 1.21 min (A), [M+H] + 193。 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s, 1H), 7.93 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.75 (dd, J = 8.8, 2.1 Hz, 1H), 4.20 - 4.11 (m, 2H), 3.88 - 3.65 (m, 2H), 3.33 (s, 3H).

[0141] Synthesis of 5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazole

Chemical formula

[0142] Alternative Synthesis of 5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazole

Chem.

[0143] 4-Toluenesulfonohydrazide (377 g, 2.02 mol) is slurried in methanol (4 l), and the slurry is stirred at 60 °C for 30 minutes. Next, a solution of crude 2-bromo-5-fluoro-4-(2-methoxy-ethoxy)-benzaldehyde (700 g, approximately 2.02 mol) in methanol (1 l) is added over a period of 30 minutes, and the reaction mixture is stirred at 60 °C for 18 hours. The reaction mixture is cooled to 0 °C. The precipitate is filtered off by suction, washed with methanol, and dried under vacuum at 40 °C to obtain N-[(E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylenamino]-4-methyl-benzenesulfonamide as white crystals; UPLC / MS 0.85 min, [M+H] + 445 / 447. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.65 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.49 - 7.36 (m, 4H), 4.28 - 4.21 (m, 2H), 3.70 - 3.57 (m, 2H), 3.30 (s, 3H), 2.38 (s, 3H).

[0144] A suspension of N-[(E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylenamino]-4-methyl-benzenesulfonamide (445 g, 1.00 mol) and copper(I) oxide (100 g, 700 mmol) in 1-butanol (5 l) is flushed with nitrogen. The mixture is heated to 117 °C and stirred at this temperature for 5 hours. The reaction mixture is allowed to reach room temperature and evaporated. The residue is taken up in toluene (5 l), the suspension is heated to 80 °C, treated with activated charcoal (100 g), and stirred at 50 °C for 1 hour. The suspension is filtered, and the filtrate is evaporated. The solid residue is crystallized from heptane (2 l) to obtain 5-fluoro-6-(2-methoxy-ethoxy)-1-(toluene-4-sulfonyl)-1H-indazole as yellow crystals; HPLC / MS 1.66 min (B), [M+H] + 365。 11H NMR (500 MHz, DMSO-d 6 ) δ 8.38 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 6.9 Hz, 1H), 7.69 (d, J = 10.4 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 4.43 - 4.34 (m, 2H), 3.86 - 3.71 (m, 2H), 3.36 (s, 3H), 2.34 (s, 3H).

[0145] A suspension of 5-fluoro-6-(2-methoxy-ethoxy)-1-(toluene-4-sulfonyl)-1H-indazole (360 g, 988 mmol) and cesium carbonate (644 g, 1.98 mol) in a mixture of THF (2.0 L) and 2,2,2-trifluoroethanol (2.0 L) is stirred at 40 °C for 18 h. The reaction mixture is diluted with ethyl acetate and filtered off by suction. The residue is washed with ethyl acetate. The filtrate is evaporated and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is recrystallized from ethyl acetate / heptane to give 5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole as an off-white crystalline solid; UPLC / MS 0.57 min, [M+H] + 211.

[0146] The following compounds are prepared in the same manner:

Chemical Structure

[0147]

Chemical Structure

[0148] Synthesis of 5-chloro-6-(2-methoxy-ethoxy)-1H-indazole The compound was synthesized according to the following synthetic scheme.

Chemical Structure

[0149] Synthesis of 6-(2-methoxy-ethoxy)-1H-indazole-5-carbonitrile The compound was synthesized according to the following synthetic scheme.

Chemical Structure

[0150] 3-Ethynyl-indazole Synthesis of 3-Ethynyl-6-(trifluoromethyl)-1H-indazole [Chemical formula] To a solution of 6-(trifluoromethyl)indazole (990 mg, 5.32 mmol) in DMF (200 ml) was added iodine (2.00 g, 7.88 mmol), followed by the addition of potassium hydroxide pellets (1.20 g, 21.4 mmol) in small portions, and the reaction mixture was stirred at room temperature. After 18 h, the reaction mixture was poured into a saturated aqueous sodium thiosulfate solution, and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off, and the residue was evaporated to give 3-iodo-6-(trifluoromethyl)-1H-indazole as a beige solid; UPLC / MS 0.80 min, [M+H] + 313. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 13.95 (s, 1H), 7.97 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 8.5, 1.5 Hz, 1H).

[0151] A suspension of 3-iodo-6-trifluoromethyl-1H-indazole (1.69 g, 5.43 mmol) in acetonitrile (100 mL) is added to N,N-dimethylpyridin-4-amine (133 mg, 1.09 mmol) and di-tert-butyl dicarbonate (1.78 g, 8.15 mmol), and the reaction mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed twice with saturated aqueous ammonium chloride and once with brine. The organic phase is dried over sodium sulfate, evaporated, and tert-butyl 3-iodo-6-trifluoromethyl-indazole-1-carboxylate is obtained as a pale yellow solid; UPLC / MS 1.00 min, [M- t Bu] + 357. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 1.67 (s, 9H).

[0152] A solution of tert-butyl 3-iodo-6-trifluoromethyl-indazole-1-carboxylate (1.87 g, 4.53 mmol) in 1,4-dioxane (45 mL) is flushed with nitrogen. Then, bis(triphenylphosphine)palladium(II) chloride (470 mg, 0.67 mmol), copper(I) iodide (127 mg, 0.67 mmol), N-ethyldiisopropylamine (1.57 mL, 9.07 mmol) and trimethylsilylacetylene (1.34 g, 13.6 mmol) are added under nitrogen, and the reaction mixture is stirred in a sealed reaction vial at 80 °C for 1 hour. The reaction mixture is allowed to reach room temperature, absorbed onto celite, and chromatographed on a silica gel column using cyclohexane / ethyl acetate as the eluent to give tert-butyl 6-trifluoromethyl-3-trimethylsilylethynyl-indazole-1-carboxylate as an off-white solid; UPLC / MS 1.12 min, [M- t Bu] + 327. 11H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.4, 1.5 Hz, 1H), 1.43 (s, 9H), 0.09 (s, 9H).

[0153] To a solution of tert-butyl 6-(trifluoromethyl)-3-(trimethylsilylethynyl)-1H-indazole-1-carboxylate (1.60 g, 4.18 mmol) in ethanol (5 ml) was added potassium carbonate (120 mg, 0.87 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed three times with water. The organic phase was dried over sodium sulfate, evaporated, and 3-ethynyl-6-(trifluoromethyl)-1H-indazole was obtained as a pale brown solid; UPLC / MS 0.75 min, [M+H] + 211. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 13.87 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.5, 1.5 Hz, 1H), 4.59 (s, 1H).

[0154] The following compounds are prepared similarly:

Chemical formula

[0155]

Chem.

Chem.

[0156] 5-Chloro-3-ethynyl-6-(2-methoxy-ethoxy)-1H-indazole, light brown solid; UPLC / MS 1.05 min, [M+H] + 251.

[0157]

Chem.

[0158] 3-Ethynyl-6-(2-methoxy-ethoxy)-1H-indazole-5-carbonitrile, light brown solid; HPLC / MS 1.85 min (A), [M+H] + 242.

Chem.

Chem.

[0159] 3-Ethynyl-5-fluoro-6-methoxy-1H-indazole, off-white solid; UPLC / MS 0.65 min, [M+H] + 191. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.34 (s, 1H), 7.47 (d, J = 10.6 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 4.48 (s, 1H), 3.92 (s, 3H).

Chem.

[0160] 3-Ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole, light brown solid; UPLC / MS 0.66 min, [M+H]+ 235. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.32 (s, 1H), 7.45 (d, J = 10.5 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 4.45 (s, 1H), 4.41 - 4.17 (m, 2H), 3.80 - 3.64 (m, 2H), 3.34 (s, 3H).

[0161] Synthesis of tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole-1-carboxylate

Chem.

[0162] To a solution of 5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole (173 g, 822 mmol) in DMF (2.0 l), iodine (228 g, 905 mmol) was added, followed by the addition of potassium hydroxide powder (115 g, 2.57 mol) in small portions, and the reaction mixture was stirred at room temperature. After 18 h, the reaction mixture was poured into a mixture of cold water (12 l) and ethyl acetate (6 l). The phases were separated and the aqueous layer was extracted with ethyl acetate (2 l). The combined organic phases were washed three times with water (3 l), with an aqueous sodium thiosulfate solution (3 l), and with water (2 l). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting slurry was treated with heptane (2 l). The solid was filtered off and dried under vacuum to give 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-1H-indazole as an off-white solid; UPLC / MS 0.71 min, [M+H] + 337。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.37 (s, 1H), 7.20 (d, J = 10.6 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 4.32 - 4.16 (m, 2H), 3.82 - 3.65 (m, 2H), 3.34 (s, 3H).

[0163] To a solution of 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-1H-indazole (249 g, 0.74 mmol) in acetonitrile (2.5 l) is added 4-(dimethylamino)-pyridine (133 mg, 1.50 mmol). Then di-tert-butyl dicarbonate (238 ml, 1.11 mol) is added slowly and the mixture is stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate (4 l) and washed with water (5 l), 10% aqueous citric acid solution (3 l), water (3 l) and brine (2 l). The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is crystallized from heptane to afford tert-butyl 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-indazole-1-carboxylate as a white crystalline solid; UPLC / MS 0.93 min, [M- t Bu] + 381. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.71 (d, J = 7.1 Hz, 1H), 7.40 (d, J = 10.0 Hz, 1H), 4.35 - 4.25 (m, 2H), 3.94 - 3.67 (m, 2H), 3.34 (s, 3H), 1.65 (s, 9H).

[0164] Under nitrogen, trimethylsilylacetylene (112 ml, 810 mmol) is added to a suspension of tert-butyl 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-indazole-1-carboxylate (297 g, 680 mmol) and bis(triphenylphosphine)palladium(II) chloride (14.2 g, 20.3 mmol) in triethylamine (2 l) and the mixture is stirred at 84 °C for 3 h. The reaction mixture is allowed to reach room temperature and diluted with tert-butyl methyl ether. The solution is washed 5 times with water (5 l each) and brine (4 l). The organic layer is dried over sodium sulfate, evaporated to afford tert-butyl 5-fluoro-6-(2-methoxy-ethoxy)-3-trimethylsilylethynyl-indazole-1-carboxylate as a pale brown solid; UPLC / MS 1.03 min, [M-t Bu] + 351。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.73 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 9.9 Hz, 1H), 4.31 - 4.24 (m, 2H), 3.78 - 3.70 (m, 2H), 3.33 (s, 3H), 1.64 (s, 9H), 0.30 (s, 9H).

[0165] A solution of tert-butyl 5-fluoro-6-(2-methoxy-ethoxy)-3-trimethylsilylethynyl-indazole-1-carboxylate (273 g, 671 mmol) in ethanol (1.5 l) was added with potassium carbonate (18.6 g, 143 mmol), and the reaction mixture was stirred at 30 °C for 3 h. The reaction mixture was poured into cold water, the solid was filtered off and washed with water. The solid was dissolved in dichloromethane (3 l) and filtered through silica gel (3 kg) using dichloromethane and tert-butyl methyl ether as eluents. The eluate was concentrated under reduced pressure and crystallized from heptane (300 ml) to give tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylate as a pale brown solid; HPLC / MS 2.54 min (A), [M - t Bu] + 279。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.73 (d, J = 7.1 Hz, 1H), 7.62 (d, J = 9.9 Hz, 1H), 4.82 (s, 1H), 4.42 - 4.26 (m, 2H), 3.94 - 3.72 (m, 2H), 3.35 (s, 3H), 1.66 (s, 9H).

[0166] The following compounds are prepared similarly:

Chemical formula

[0167] Alternative synthesis of tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylate:

Chem.

[0168] To a solution of tert-butyl 5-fluoro-6-(2-methoxy-ethoxy)-3-trimethylsilylethynyl-indazole-1-carboxylate (488 mg, 1.20 mmol) in ethanol (12 ml) was added potassium fluoride (3.5 mg, 0.06 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled in an ice bath. The solid was filtered off, washed with ice-cold ethanol, and dried under vacuum to give tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylate as an off-white solid; HPLC / MS 2.54 min (A), [M - t Bu] + 279.

[0169] Carboxylic acid Synthesis of methyl 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoate

Chem.

[0170] To a solution of methyl 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoate (124 mg, 0.32 mmol) in methanol, 2M aqueous sodium hydroxide solution (1.3 ml) is added and the reaction mixture is stirred at 80 °C for 1 hour and at room temperature for 16 hours. The resulting suspension is acidified with concentrated hydrochloric acid. The resulting solid is filtered off, washed with water and dried under vacuum to give 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid as an off-white solid; UPLC / MS 0.82 min, [M+H] + 374. 1 1H NMR (500 MHz, DMSO-d 6 ) δ 14.48 (s, 1H), 13.20 (s, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.15 - 8.08 (m, 3H), 7.88 (s, 1H), 7.65 (dd, J = 8.7, 1.5 Hz, 1H).

[0171] The following compounds are prepared similarly:

Chemical formula

[0172]

Chemical formula

[0173]

Chemical formula

[0174]

Chem.

[0175]

Chem.

[0176]

Chem.

[0177]

Chem.

[0178] [Chemical formula] 2-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-thiazole-4-carboxylic acid, brown solid; HPLC / MS 2.56 min (A), [M+H] + 405.

[0179] Synthesis of 4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid [Chemical formula] To a solution of tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylate (205 g, 614 mmol) and methyl 4-(hydroxyimino-methyl)-benzoate in dichloromethane (2.6 l) is added dropwise an aqueous sodium hypochlorite solution (content approximately 12%, 944 ml, approximately 1.84 mol). During the addition, the temperature of the mixture is adjusted to 22 °C - 26 °C by external cooling. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered. The filter cake is washed twice with water (1 l) and acetonitrile (300 ml) and dried under vacuum to obtain tert-butyl 5-fluoro-3-[3-(4-methoxycarbonyl-phenyl)-isoxazol-5-yl]-6-(2-methoxy-ethoxy)-indazole-1-carboxylate as pale yellow crystals; HPLC / MS 2.16 min (A), [M - t Bu] + 456. 1 H NMR (500 MHz, DMSO-d 6) δ 8.26 - 8.20 (m, 3H), 8.15 (d, J = 8.4 Hz, 2H), 8.12 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 4.38 - 4.34 (m, 2H), 3.92 (s, 3H), 3.82 - 3.76 (m, 2H), 3.30 (s, 9H).

[0180] To a suspension of tert-butyl 5-fluoro-3-[3-(4-methoxycarbonyl-phenyl)-isoxazol-5-yl]-6-(2-methoxy-ethoxy)-indazole-1-carboxylate (339 g, 662 mmol) in THF (3.36 l) was slowly added 2 M aqueous sodium hydroxide solution (1.33 l, 2.65 mol) via a dropping funnel, and the reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was cooled to room temperature, and the organic solvent was evaporated under vacuum. The resulting suspension was diluted with ice water (3 l). Under continuous stirring, the pH value of the suspension was adjusted from pH 11 to pH 2 using 2.5 N hydrochloric acid. The solid was filtered off and washed with water (3 × 600 ml) and tert-butyl methyl ether (300 ml). The solid was dried at 45 °C under reduced pressure for several days to obtain 4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid as an off-white solid; HPLC / MS 1.55 min (A), [M+H] + 398。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 13.20 (s, 1H), 8.18 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 8.06 - 8.00 (m, 2H), 7.80 (s, 1H), 7.29 (d, J = 7.1 Hz, 1H), 4.34 - 4.26 (m, 2H), 3.84 - 3.72 (m, 2H), 3.36 (s, 3H).

[0181] The following compounds are prepared in the same manner

Chemical formula

[0182] Synthesis of 4-{5-[5-Fluoro-6-(2-hydroxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid

Chem.

[0183] To a solution of 4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid (234 mg, 0.59 mmol) in dichloromethane (8 ml) is added dropwise a 1 M solution of boron tribromide (1.2 ml). The reaction mixture is stirred at room temperature for 16 h. The solid is filtered off and washed with dichloromethane and water. The residue is dried under high vacuum to give 4-{5-[5-Fluoro-6-(2-hydroxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid as an off-white solid; UPLC / MS 0.63 min, [M+H] + 384。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.79 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.19 (t, J = 4.9 Hz, 1H), 3.82 (t, J = 4.8 Hz, 1H).

[0184] Example 1 2-[1-(4-{5-[6-(Trifluoromethyl)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]propan-2-ol (「A1」) [Chemical formula] To a suspension of 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid (52 mg, 0.14 mmol), 2-(pyrrolidin-2-yl)-propan-2-ol (23 mg, 0.18 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (41 mg, 0.21 mmol) and 1-hydroxybenzotriazole hydrate (25 mg, 153 mmol) in DMF (1.4 ml) is added 4-methylmorpholine (63 μl, 0.57 mmol). The reaction mixture is heated to 80 °C and stirred at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and saturated sodium bicarbonate solution is added. The solid is filtered off, washed with water and dried. The residue is chromatographed on a silica gel column using cyclohexane / ethyl acetate as the eluent to give 2-[1-(4-{5-[6-(trifluoromethyl)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]propan-2-ol as an off-white powder; UPLC / MS 0.87 min, [M+H] + 485。 1 H NMR (500 MHz, DMSO-d 6) δ 14.28 (s, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H), 8.10 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.64 (dd, J = 8.7, 1.6 Hz, 1H), 4.88 (s, 1H), 4.31 (t, J = 7.2 Hz, 1H), 3.62 - 3.47 (m, 1H), 3.44 - 3.33 (m, 1H), 1.98 - 1.82 (m, 3H), 1.68 - 1.55 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H).

[0185] The following compounds are prepared in the same manner: 2-[(2R)-1-(4-{5-[6-(2-Methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]propan-2-ol (「A2」)

Chemical Structure

[0186] 3-(3-{4-[(2S)-2,4-Dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A3」) [Chemical Structure] Off-white solid; HPLC / MS 1.27 min (A), [M+H] + 494. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.34 - 4.26 (m, 2H), 3.81 - 3.74 (m, 2H), 3.36 (s, 3H), 3.20 (broad, 1H), 2.75 (broad, 1H), 2.69 - 2.59 (m, 1H), 2.18 (s, 3H), 2.10 - 2.03 (m, 1H), 1.93 - 1.83 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).

[0187] {4-[5-(6-Bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-[(R)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone (「A3a」) [Chemical Structure] Off-white solid; UPLC / MS 0.86 min, [M+H] + 495 / 497.

[0188] {4-[5-(6-Bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-[(S)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone (「A4」) [Chemistry] UPLC / MS 0.86 min, [M+H] + 495 / 497. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.96 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 1.5 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 7.9 Hz, 2H), 7.50 (dd, J = 8.7, 1.7 Hz, 1H), 4.89 (s, 1H), 4.32 (t, J = 7.1 Hz, 1H), 3.53 (q, J = 9.1, 8.4 Hz, 1H), 3.38 (t, J = 9.0 Hz, 1H), 2.04 - 1.78 (m, 3H), 1.69 - 1.55 (, 1H), 1.18 (s, 3H), 1.14 (s, 3H).

[0189] 2-[(2S)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]propan-2-ol (「A5」) [Chemistry] White solid; HPLC / MS 1.27 min (A), [M+H] + 509. 1 H NMR (500 MHz, DMSO-d 6) δ 13.70 (s, 1H), 8.11 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 4.88 (s, 1H), 4.36 - 4.23 (m, 3H), 3.79 - 3.73 (m, 2H), 3.58 - 3.47 (m, 1H), 3.41 - 3.34 (m, 4H), 2.00 - 1.80 (m, 3H), 1.67 - 1.55 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H).

[0190] {4-[5-(6-Bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-((S)-2,4-dimethyl-piperazin-1-yl)-methanone (“A5a”) [Chemical Structure] Off-white solid; UPLC / MS 0.54 min, [M+H] + 480 / 482. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 13.96 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 1.5 Hz, 1H), 7.78 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.6, 1.6 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.64 (d, J = 10.7 Hz, 1H), 2.18 (s, 3H), 2.06 (dd, J = 11.3, 3.8 Hz, 1H), 1.91 - 1.83 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).

[0191] 4-{5-[5-Cyano-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (“A6”) [Chemical] Off-white powder; HPLC / MS 2.01 min (A), [M+H] + 432. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.99 (s, 1H), 8.76 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.29 (s, 1H), 4.43 - 4.32 (m, 2H), 3.95 - 3.73 (m, 2H), 3.38 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H).

[0192] 5-Fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (「A7」) [Chemical] White powder; HPLC / MS 1.55 min (A), [M+H] + 543. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.56 (broad, 1H), 4.34 - 4.25 (m, 2H), 3.81 - 3.67 (m, 3H), 3.52 (q, J = 7.9, 7.3 Hz, 1H), 3.42 - 3.29 (m, 6H), 3.10 (s, 3H), 2.24 - 2.14 (m, 1H), 2.10 - 1.90 (m, 2H), 1.85 - 1,75 (m, 1H).

[0193] 3-(3-{4-[(2S)-2,4-Dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(trifluoromethyl)-1H-indazole (「A50」)

Chemical Structure

[0194] [(2S)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methanol (「A51」)

Chemical Structure

[0195] [(2R)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methanol (「A52」)

Chemical Structure

[0196] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A53”)

Chemical Structure

[0197] [1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-4-methylpiperazin-2-yl]methanol (「A54」)

Chem.

[0198] 5-Fluoro-3-(3-{4-[(2R)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (「A55」)

Chem.

[0199] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methylazetidin-3-amine (「A56」)

Chemical Structure

[0200] 4-[1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-3-yl]-1λ6-thiomorpholine-1,1-dione (「A57」)

Chem.

[0201] 2-[(2R)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]propan-2-ol (「A58」)

Chem.

[0202] 2-[(2S)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]propan-2-ol (「A59」)

Chemical formula

[0203] 7-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-2-oxa-7-azaspiro[3.5]nonane (“A60”)

Chem.

[0204] 5-Fluoro-6-methoxy-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A61”)

Chem.

[0205] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone (“A62”)

Chem.

[0206] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone (「A63」)

Chem.

[0207] (4-{5-[5-Chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone (「A64」)

Chem.

[0208] (4-{5-[5-Chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-[3-(4-methyl-piperazin-1-yl)-azetidin-1-yl]-methanone (「A65」)

Chem.

[0209] (4-{5-[5-Chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-((S)-3-hydroxymethyl-morpholin-4-yl)-methanone ("A66")

Chem.

[0210] (4-{5-[5-Chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-((R)-3-hydroxymethyl-morpholin-4-yl)-methanone ("A67")

Chem.

[0211] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone ("A68")

Chem.

[0212] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone (「A69」)

Chem.

[0213] (4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-2-methyl-phenyl)-(cis)-tetrahydro-furo[3,4-c]pyrrol-5-yl-methanone (「A70」)

Chem.

[0214] (2-Fluoro-4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(cis)-tetrahydro-furo[3,4-c]pyrrol-5-yl-methanone (「A71」)

Chem.

[0215] 3-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-N,N-dimethyl-benzamide (「A135」)

Chem.

[0216] Example 2 2-[(2R)-1-(4-{5-[6-(1-Methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]propan-2-ol (「A8」)

Chemical formula

[0217] The following compounds are prepared in the same manner: 3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole (「A9」)

Chemical formula

[0218] Example 3 5-Chloro-3-(5-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-3-yl)-6-(2-methoxyethoxy)-1H-indazole (「A10」)

Chemical Structure

[0219] The following compounds are prepared similarly: 3-(5-{4-[(2S)-2,4-Dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-3-yl)-6-(2-methoxyethoxy)-1H-indazole-5-carbonitrile (“A11”) [Chemical formula] Brown solid; HPLC / MS 2.21 min (A), [M+H] + 501. 1 1H NMR (500 MHz, DMSO-d 6 ) δ 13.90 (s, 1H), 8.52 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 4.49 - 4.22 (m, 2H), 3.99 - 3.57 (m, 2H), 3.39 (s, 3H), 3.32 - 3.10 (broad, 3 H), 2.80 - 2.70 (broad, 1H), 2.68 - 2.56 (broad, 1H), 2.18 (s, 3H), 2.06 (d, J = 11.1 Hz, 1H), 1.92 - 1.82 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).

[0220] Example 4 4-{5-[5-Chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (“A12”) [Chemical formula] A stirred solution of 5-chloro-3-ethynyl-6-(2-methoxy-ethoxy)-1H-indazole (97.8 mg, 0.39 mmol) and 4-(hydroxyimino-methyl)-N,N-dimethyl-benzamide (50.0 mg, 0.26 mmol) in a mixture of methanol (4 ml) and water (800 μl) is added bis(trifluoroacetoxy)-iodobenzene (224 mg, 0.52 mmol) in 4 portions at 2-hour intervals, and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is filtered. The residue is washed with methanol and dried under vacuum to give 4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-N,N-dimethyl-benzamide as a brown solid; HPLC / MS 2.61 min (A), [M+H] + 441. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 8.30 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.81 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 4.37 - 4.26 (m, 2H), 3.83 - 3.73 (m, 2H), 3.38 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H).

[0221] The following compounds are prepared similarly: 5-chloro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol-5-yl]-1H-indazole (「A13」)

Chemical Structure

[0222] 5-Chloro-6-(2-methoxyethoxy)-3-{3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (「A14」)

Chemical Structure

[0223] 5-Chloro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole (「A15」)

Chemical Structure

[0224] 5-Fluoro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole (「A16」)

Chemical Structure

[0225] N-(4-{5-[5-Chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)acetamide (「A17」)

Chemical Structure

[0226] N-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)acetamide (「A18」)

Chemical formula

[0227] Methyl 3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole-6-carboxylate (「A19」)

Chemical formula

[0228] 4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (「A20」)

Chemical formula

[0229] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (「A21」)

Chemical formula

[0230] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol-5-yl]-1H-indazole (「A22」)

Chemical formula

[0231] (4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)(imino)methyl-lambda6-sulfanone (「A226」)

Chemical formula

[0232] Example 5 N-(2-Methoxyethyl)-3-(3-{4-[(2-methoxyethyl)carbamoyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole-6-carboxamide ("A23")

Chemical Structure

[0233] The following compounds are prepared similarly: Methyl 3-[3-(4-dimethylcarbamoyl-phenyl)-isoxazol-5-yl]-1H-indazole-6-carboxamide ("A24")

Chemical Structure

[0234] 3-{3-[4-(Dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-N-(2-methoxyethyl)-1H-indazole-6-carboxamide (“A25”)

Chemical formula

[0235] Example 6 5-Fluoro-3-{3-[4-(3-fluoroazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (“A26”)

Chemical formula

[0236] To a solution of 4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid (52 mg, 0.06 mmol) in DMF (2 ml), 3-fluoroazetidine hydrochloride (8.42 mg, 0.08 mmol) is added, followed by 4-methylmorpholine (28 μl, 0.25 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium-hexafluorophosphate (36 mg, 0.09 mmol). The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is concentrated under vacuum and the residue is chromatographed on a silica gel column using ethyl acetate / methanol as eluent to obtain (3-fluoro-azetidin-1-yl)-(4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-methanone as a white powder; HPLC / MS 2.51 min (A), [M+H] + 455。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.8 (broad, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 11.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 5.53 (tt, J = 6.1, 3.2 Hz, 0.5H), 5.39 (tt, J = 6.2, 3.2 Hz, 0.5H), 4.7 - 4.0 (m, 4H), 4.33 - 4.23 (m, 1H), 3.85 - 3.67 (m, 2H), 3.38 (s, 3H).

[0237] The following compounds are prepared similarly: 5-Fluoro-3-(3-{4-[(3R)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A27”)

Chemical Structure

[0238] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidine-3-carbonitrile (「A28」)

Chemical formula

[0239] 5-Fluoro-3-{3-[4-(3-methanesulfonylazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole ("A29")

Chem.

[0240] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1λ6-thiomorpholine-1,1-dione ("A30")

Chem.

[0241] N-Cyclopropyl-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-methylbenzamide (「A31」)

Chemical formula

[0242] 5-Fluoro-3-(3-{4-[(3S)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (「A32」)

Chemical formula

[0243] 5-Fluoro-3-{3-[4-(3-methoxyazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (「A33」)

Chemical formula

[0244] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methylazetidin-3-ol (「A34」)

Chemical formula

[0245] N-[Dimethyl(oxo)-lambda6-sulfanylidene]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide (“A35”)

Chem.

[0246] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (「A36」) trifluoroacetate

Chemical Structure

[0247] N-[2-(Dimethylamino)ethyl]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide (「A72」)

Chemical Structure

[0248] 4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-(1-methylazetidin-3-yl)benzamide (「A73」)

Chem.

[0249] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{2-oxa-6-azaspiro[3.3]heptane-6-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A74」)

Chem.

[0250] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(1H-pyrazol-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A75」)

Chem.

[0251] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-N,N-dimethylazetidin-3-amine (「A76」)

Chemical formula

[0252] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{6-oxa-2-azaspiro[3.4]octane-2-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A77」)

Chemical Structure

[0253] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1λ4-thiomorpholin-1-one (「A78」)

Chemical Structure

[0254] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{1-oxa-6-azaspiro[3.3]heptane-6-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A79」)

Chemical formula

[0255] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1-imino-1λ6-thiomorpholin-1-one (「A80」)

Chemical formula

[0256] 5-Fluoro-3-{3-[5-(3-fluoroazetidine-1-carbonyl)pyridin-2-yl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (“A81”)

Chem.

[0257] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{5-[3-(morpholin-4-yl)azetidine-1-carbonyl]pyridin-2-yl}-1,2-oxazol-5-yl)-1H-indazole (「A82」)

Chem.

[0258] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{5-[3-(morpholin-4-yl)azetidine-1-carbonyl]-1,3-thiazol-2-yl}-1,2-oxazol-5-yl)-1H-indazole (「A83」)

Chem.

[0259] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]-1,3-thiazol-2-yl}-1,2-oxazol-5-yl)-1H-indazole (「A84」)

Chemical formula

[0260] 5-Fluoro-3-(3-{4-[3-(1H-imidazol-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (「A85」)

Chemical formula

[0261] 5-Fluoro-3-{3-[5-(3-fluoroazetidine-1-carbonyl)-1,3-thiazol-2-yl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole ("A86")

Chemical Structure

[0262] 5-Fluoro-3-{3-[4-(3-fluoroazetidine-1-carbonyl)-1,3-thiazol-2-yl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (「A87」)

Chem.

[0263] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A88」)

Chem.

[0264] (cis)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-octahydropyrrolo[3,4-b]pyrrol-6-one (「A89」)

Chemical formula

[0265] N-{[(2S)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methyl}methanesulfonamide (「A90」)

Chemical formula

[0266] 6-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylpyridine-3-carboxamide (「A91」)

Chemical formula

[0267] 2-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethyl-1,3-thiazole-5-carboxamide (「A92」)

Chemical formula

[0268] 2-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethyl-1,3-thiazole-4-carboxamide (「A93」)

Chemical formula

[0269] N-{[(2R)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methyl}methanesulfonamide (「A94」)

Chem.

[0270] [(2S)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]methanol (「A95」)

Chem.

[0271] 1-(5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridine-2-carbonyl)-azetidine-3-carbonitrile (「A96」)

Chem.

[0272] [(2R)-1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]methanol ("A97")

Chem.

[0273] (3-Fluoro-azetidin-1-yl)-(5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-methanone ("A98")

Chem.

[0274] 5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridine-2-carboxylic acid dimethylamide ("A99")

Chem.

[0275] 5-Fluoro-3-(3-{6-[(3R)-3-fluoropyrrolidine-1-carbonyl]pyridin-3-yl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A100”)

Chem.

[0276] 5-Fluoro-3-[3-(4-{3-fluoro-[1,3’-bi(azetidine)]-1’-carbonyl}phenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole (“A101”)

Chem.

[0277] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A102”)

Chem.

[0278] 1-[1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-3-yl]piperidin-4-ol (“A103”)

Chem.

[0279] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A104”)

Chem.

[0280] [(3R)-4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)morpholin-3-yl]methanol (「A105」)

Chem.

[0281] [(3S)-4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)morpholin-3-yl]methanol (「A106」)

Chem.

[0282] 2-[(2S)-1-(5-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridine-2-carbonyl)pyrrolidin-2-yl]propan-2-ol (「A107」)

Chemical formula

[0283] 6-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3λ6-thia-6-azabicyclo[3.1.1]heptane-3,3-dione (「A108」)

Chemical formula

[0284] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-[(R)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone (「A109」)

Chem.

[0285] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-(methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A110」)

Chem.

[0286] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3R)-3-(methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A111」)

Chem.

[0287] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{6-oxa-1-azaspiro[3.3]heptane-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A112」)

Chem.

[0288] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3R)-3-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A114")

Chem.

[0289] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A115")

Chem.

[0290] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1-methylpiperazin-2-one (「A116」)

Chemical formula

[0291] 5-Fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-methoxy-1H-indazole (「A117」)

Chemical formula

[0292] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-[(S)-2-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-methanone (「A118」)

Chemical formula

[0293] (5-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-[(R)-2-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-methanone (「A119」)

Chem.

[0294] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A120」)

Chem.

[0295] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methyl-1λ6-thiomorpholine-1,1-dione (「A121」)

Chem.

[0296] Example 7 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A37”)

Chemical formula

[0297] The following compounds are prepared in the same manner: 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1λ6-thiomorpholine-1,1-dione ("A122")

Chem.

[0298] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole ("A123")

Chem.

[0299] 3-(3-{4-[-Octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A124」)

Chem.

[0300] 3-(3-{4-[(cis)-4-Methyl-octahydropyrrolo[3,2-b]pyrrol-1-yl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A125」)

Chem.

[0301] 3-(3-{4-[(trans)-4-Methyl-octahydropyrrolo[3,2-b]pyrrol-1-yl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A126」)

Chem.

[0302] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1λ⁴-thiomorpholin-1-one (「A127」)

Chem.

[0303] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)piperidin-4-ol (「A128」)

Chem.

[0304] 1-[(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)imino]-1λ⁶-thiomorpholin-1-one (「A129」)

Chem.

[0305] Example 8 3-[3-(6-Ethoxypyridin-3-yl)-1,2-oxazol-5-yl]-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A38」)

Chemical formula

[0306] The following compounds are prepared in the same manner: 5-Fluoro-6-(2-methoxy-ethoxy)-3-[3-(6-methoxy-pyridin-3-yl)-isoxazol-5-yl]-1H-indazole (「A130」)

Chemical formula

[0307] Example 9 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2-oxazol-5-yl}-1H-indazole (「A39」)

Chemical Structure

[0308] The following compounds are prepared in the same manner: 4-(5-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridin-2-yl)-1λ6-thiomorpholine-1,1-dione (「A131」)

Chem.

[0309] Example 10 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A40」)

Chem.

[0310] The following compounds are prepared similarly: 4-[2-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenoxy)ethyl]-1λ6-thiomorpholine-1,1-dione (「A132」)

Chemical formula

[0311] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A133」)

Chemical formula

[0312] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A134」)

Chemical formula

[0313] Example 11 1-(4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-1H-pyridin-2-one (「A41」) hydrochloride

Chemical formula

[0314] The following compounds are prepared in the same manner: 2-(4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-6-methyl-2H-pyridazin-3-one (「A136」) [Chemistry]

[0315] 5-Fluoro-6-(2-methoxy-ethoxy)-3-[3-(1-methyl-1H-pyrazol-4-yl)-isoxazol-5-yl]-1H-indazole (「A137」) [Chemistry]

[0316] 2-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1λ6,2-thiazolidine-1,1-dione (「A138」) [Chemistry]

[0317] 4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)morpholin-3-one (「A139」) [Chemistry] Off-white solid; HPLC / MS 0.71 min, [M+H] + 453. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 11.0 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 4.34 - 4.28 (m, 2H), 4.26 (s, 2H), 4.07 - 4.00 (m, 2H), 3.89 - 3.81 (m, 2H), 3.81 - 3.73 (m, 2H), 3.36 (s, 3H).

[0318] 4-(5-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridin-2-yl)-1λ4-thiomorpholin-1-one (「A140」)

Chem.

[0319] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[6-(morpholin-4-yl)pyridin-3-yl]-1,2-oxazol-5-yl}-1H-indazole (「A141」)

Chem.

[0320] 2-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-2,3-dihydropyridin-3-one (「A142」)

Chem.

[0321] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(pyridin-2-yloxy)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A143”)

Chem.

[0322] 4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzene-1-sulfonamide (“A144”)

Chem.

[0323] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{6-[3-(morpholin-4-yl)azetidin-1-yl]pyridin-3-yl}-1,2-oxazol-5-yl)-1H-indazole (“A145”)

Chem.

[0324] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-sulfonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (「A227」)

Chemical Structure

[0325] Example 12 3-{3-[4-(1,4-Diazepan-1-yl)phenyl]-1,2-oxazol-5-yl}-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A42」) hydrochloride

Chemical Structure

[0326] Example 13 (4-{3-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-morpholin-4-yl-methanone (「A43」)

Chemical Structure

[0327] The following compounds are prepared similarly: (4-{3-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (「A113」)

Chemical Structure

[0328] (4-{3-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone (「A146」) [Chemical formula] White solid; m.p. 229 - 230 °C, [M+H] + 522. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.63 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.84 (dd, J = 9.6, 4.6 Hz, 3H), 7.69 (s, 1H), 7.27 (d, J = 7.0 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.33 - 4.26 (m, 2H), 4.24 - 4.16 (m, 1H), 4.15 - 4.05 (m, 1H), 3.96 - 3.88 (m, 1H), 3.80 - 3.73 (m, 2H), 3.66 - 3.55 (m, 4H), 3.36 (s, 3H), 3.23 - 3.12 (m, 1H), 2.44 - 2.26 (m, 4H).

[0329] (4-{3-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-[(R)-2-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-methanone (「A147」) [Chemical formula] Greyish-white solid; m.p. 210 - 211 °C, [M+H] + 495. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.64 (s, 1H), 8.14 - 8.07 (m, 2H), 7.88 - 7.79 (m, 3H), 7.69 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 5.01 (s, 1H), 4.39 (dd, J = 9.0, 5.6 Hz, 1H), 4.34 - 4.22 (m, 3H), 4.01 - 3.92 (m, 1H), 3.80 - 3.73 (m, 2H), 3.36 (s, 3H), 2.34 - 2.27 (m, 1H), 2.18 - 2.10 (m, 1H), 1.15 (s, 6H).

[0330] (4-{3-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-[(S)-2-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-methanone (「A148」)

Chem.

[0331] Example 14 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(1,4-oxazepane-4-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (「A44」)

Chem.

[0332] To a suspension of 4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid (79.5 mg, 0.20 mmol) in DMF (1.0 ml), homomorpholine (24.3 mg, 0.24 mmol) is added, followed by 1-hydroxybenzotriazole hydrate (6.1 mg, 0.04 mmol) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol). The reaction mixture is stirred at room temperature for 16 h. Water is added to the reaction mixture. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column using methanol / dichloromethane to give (4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-[1,4]oxazepan-4-yl-methanone as a white solid; UPLC / MS 0.71 min, [M+H] + 481。 1 H NMR (500 MHz, DMSO-d 6) δ 13.70 (s, 1H), 8.10 (d, J = 6.7 Hz, 3H), 8.02 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J = 7.3 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 4.33 - 4.24 (m, 2H), 3.82 - 3.67 (m, 7H), 3.62 (t, J = 5.1 Hz, 1H), 3.49 - 3.46 (m, 2H), 3.36 (s, 3H), 1.94 - 1.87 (m, 1H), 1.81 - 1.69 (m, 1H).

[0333] The following compounds are prepared in the same manner: 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A45") [Chemical formula] White powder; HPLC / MS 1.26 min (A), [M+H] + 522. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 11.0 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 4.33 - 4.26 (m, 2H), 3.82 - 3.73 (m, 2H), 3.68 (broad, 2H), 3.51 - 3.37 (m, 3H), 2.35 (broad, 2H), 2.27 (broad, 2H).

[0334] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-2-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A149") [Chemical formula] White solid; UPLC / MS 0.67 min, [M+H] + 514. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.68 - 8.56 (m, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 11.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.84 - 7.76 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.36 - 7.24 (m, 2H), 4.75 (t, J = 8.6 Hz, 1H), 4.54 (t, J = 7.2 Hz, 1H), 4.47 (t, J = 9.3 Hz, 1H), 4.35 - 4.28 (m, 2H), 4.25 (t, J = 8.0 Hz, 1H), 4.10 (tt, J = 8.9, 6.1 Hz, 1H), 3.80 - 3.73 (m, 2H), 3.36 (s, 3H).

[0335] 4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-(2-methanesulfonylethyl)-N-methylbenzamide ("A150") [Chemical formula]

[0336] 6-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-2λ6-thia-6-azaspiro[3.3]heptane-2,2-dione ("A151") [Chemistry]

[0337] 5-Fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (「A152」) [Chemistry] White solid; UPLC / MS 0.71 min, [M+H] + 529. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.69 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 11.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.89 (bs, 1H), 4.46 (bs, 1H), 4.35 - 4.21 (m, 2H), 4.17 (bs, 1H), 3.85 (bs, 1H), 3.82 - 3.63 (m, 3H), 3.35 (s, 3H), 3.07 (s, 3H), 2.56 (bs, 1H), 2.44 - 2.26 (m, 1H).

[0338] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A153」) [Chemistry] White powder; HPLC / MS 1.25 min, [M+H] + 536. 1 H NMR (400 MHz, DMSO-d 6) δ 13.70 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 11.0 Hz, 0H), 7.76 (s, 0H), 7.73 - 7.66 (m, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.36 - 4.26 (m, 2H), 3.81 - 3.71 (m, 2H), 3.72 - 3.40 (m, 8H), 3.36 (s, 3H), 2.92 - 2.74 (m, 1H), 2.50 - 2.36 (m, 3H), 2.34 - 2.24 (m, 1H), 2.20 - 2.10 (m, 1H), 1.85 - 1.65 (m, 1H).

[0339] 5-Fluoro-3-(3-{4-[(2R)-2-(methanesulfonylmethyl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A154”)

Chemical formula

[0340] 5-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-2,8-dioxa-5-azaspiro[3.5]nonane (“A155”)

Chemical formula

[0341] N-[(1H-1,3-Benzodiazol-2-yl)methyl]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide (「A156」)

Chemical formula

[0342] 7-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-2-oxa-7-azaspiro[4.4]nonane (「A157」)

Chemical formula

[0343] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{2-oxa-6-azaspiro[3.4]octane-6-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A158」)

Chemical Structure

[0344] 2-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-8-oxa-2-azaspiro[4.5]decane (「A159」)

Chem.

[0345] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{2-methyl-2,6-diazaspiro[3.4]octane-6-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A160」)

Chem.

[0346] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A161」)

Chem.

[0347] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A162」)

Chem.

[0348] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A163」)

Chem.

[0349] 4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-[2-methyl-2-(morpholin-4-yl)propyl]benzamide (「A164」)

Chemical Structure

[0350] 2-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-7-oxa-2-azaspiro[3.5]nonane (「A165」)

Chemical Structure

[0351] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A166」)

Chemical Structure

[0352] (4-{5-[5-Chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (「A167」)

Chemical Structure

[0353] (2-Fluoro-4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone (「A168」)

Chem.

[0354] (4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-2-methyl-phenyl)-(6-oxa-1-azaspiro[3.3]hept-1-yl)-methanone (「A169」)

Chem.

[0355] (2-Fluoro-4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(6-oxa-1-azaspiro[3.3]hept-1-yl)-methanone (「A170」)

Chem.

[0356] (4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-2-methyl-phenyl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone (「A171」)

Chem.

[0357] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrimidin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A172”)

Chem.

[0358] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(2-methylpyrimidin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A173」)

Chemical formula

[0359] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-methyl-4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A174」) [Chemical formula]

[0360] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxolan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A175」) [Chemical formula]

[0361] 7-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-2-methyl-2,7-diazaspiro[3.5]nonane (「A176」) [Chemical formula]

[0362] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(piperidin-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A177”)

Chem.

[0363] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrrolidin-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A178”)

Chem.

[0364] 3-(3-{4-[4-(Cyclopropylmethyl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A179」) [Chemical formula] White solid; UPLC / MS 0.51 min, [M+H] + 520. 1 1H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.34 - 4.22 (m, 2H), 3.81 - 3.73 (m, 2H), 3.66 (bs, 2H), 3.38 (bs, 2H), 3.36 (s, 3H), 2.44 (bs, 4H), 2.23 (d, J = 6.6 Hz, 2H), 0.90 - 0.78 (m, 1H), 0.52 - 0.43 (m, 2H), 0.12 - 0.05 (m, 2H).

[0365] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2R)-2-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A180」)

Chem.

[0366] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-N,N,3-trimethylazetidine-3-amine (「A181」)

Chem.

[0367] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-oxa-6-azabicyclo[3.1.1]heptane-6-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A182」)

Chem.

[0368] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (“A183”)

Chem.

[0369] (4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-((R)-3-methanesulfonylmethyl-morpholin-4-yl)-methanone (「A184」)

Chemical formula

[0370] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{4-[(3R)-oxolan-3-yl]piperazine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A185」)

Chemical formula

[0371] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{4-[(3S)-oxolan-3-yl]piperazine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A186」)

Chemical formula

[0372] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(3-{2-oxa-6-azaspiro[3.3]heptan-6-yl}azetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (「A187」)

Chemical Structure

[0373] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxan-4-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A188」)

Chemical Structure

[0374] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2S)-2-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A189」)

Chemical formula

[0375] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2R)-2-methyl-4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A190")

Chem.

[0376] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A191")

Chem.

[0377] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-3-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A192」)

Chem.

[0378] (4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-2-methyl-phenyl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone (「A193」)

Chem.

[0379] (4-{5-[5-Chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone (「A194」)

Chemical formula

[0380] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-[4-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl]azetidine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A195」)

Chem.

[0381] (2-Fluoro-4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone (「A196」)

Chem.

[0382] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-[4-(oxetan-3-yl)piperazin-1-yl]azetidine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A197」) [Chemistry]

[0383] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)-1,4-diazepane-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A198」) [Chemistry] White solid; HPLC / MS 1.24 min (A), [M+H] + 536. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.62 - 7.52 (m, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.55 (t, J = 6.5 Hz, 1H), 4.50 (t, J = 6.4 Hz, 1H), 4.40 (t, J = 6.1 Hz, 1H), 4.34 (t, J = 6.1 Hz, 1H), 4.31 - 4.28 (m, 2H), 3.79 - 3.74 (m, 1H), 3.72 - 3.59 (m, 3H), 3.47 - 3.38 (m, 3H), 3.35 (s, 2H), 2.60 - 2.52 (m, 1H), 2.50 - 2.36 (m, 3H), 1.90 - 1.81 (m, 1H), 1.79 - 1.67 (m, 1H).

[0384] 2-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-7-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonane (「A199」) [Chemistry] White solid; HPLC / MS 1.23 min (A), [M+H] + 562. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.51 (t, J = 6.5 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.33 - 4.27 (m, 2H), 4.05 (s, 2H), 3.81 - 3.73 (m, 4H), 3.36 (s, 3H), 3.36 - 3.30 (m, 1H), 2.29 - 1.98 (m, 4H), 1.79 - 1.71 (m, 4H).

[0385] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-[(3S)-3-methylmorpholin-4-yl]azetidine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A200」)

Chem.

[0386] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-[(3R)-3-methylmorpholin-4-yl]azetidine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (“A201”)

Chem.

[0387] 3-(3-{4-[(cis)-Hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (“A202”)

Chem.

[0388] (cis)-5-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-octahydropyrrolo[2,3-c]pyrrol-2-one (“A203”)

Chem.

[0389] 4-[1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-3-yl]morpholin-3-one (「A204」)

Chem.

[0390] 2-{[5-Fluoro-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazol-6-yl]oxy}ethan-1-ol (「A205」)

Chem.

[0391] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-(pyridin-4-yl)azetidin-3-ol (「A206」)

Chemical formula

[0392] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A207」) [Chemical formula] Off-white solid; UPLC / MS 0.66 min (A), [M+H] + 501. 1 H NMR (500 MHz, DMSO-d 6 , mixture of rotamers) δ 13.71 (s, 1H), 9.11 (d, J = 13.4 Hz, 1H), 8.88 (s, 0.5H), 8.73 (s, 0.5H), 8.19 - 8.12 (m, 2H), 8.06 - 8.01 (m, 1H), 7.86 - 7.73 (m, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.98 (s, 1H), 4.92 (s, 1H), 4.90 (s, 2H), 4.33 - 4.28 (m, 2H), 3.79 - 3.72 (m, 2H), 3.36 (s, 3H).

[0393] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole ("A208") [Chemical formula] Off-white solid; UPLC / MS 0.65 min (A), [M+H] + 489. 1 H NMR (500 MHz, DMSO-d 6, mixture of rotamers) δ 13.71 (bs, 1H), 12.72 (s, 1H), 8.19 - 8.10 (m, 2H), 8.06 - 7.96 (m, 1H), 7.86 - 7.72 (m, 3H), 7.59 (s, 0.5H), 7.49 (s, 0.5H), 7.28 (d, J = 7.1 Hz, 1H), 4.65 (s, 2H), 4.59 (s, 1H), 4.54 (s, 1H), 4.38 - 4.26 (m, 2H), 3.93 - 3.72 (m, 2H), 3.36 (s, 3H).

[0394] 2-{[5-Fluoro-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazol-6-yl]oxy}ethan-1-ol (「A209」)

Chem.

[0395] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-[(2S)-2-methylmorpholin-4-yl]azetidine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A210」)

Chem.

[0396] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{3-[(2R)-2-methylmorpholin-4-yl]azetidine-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A211」)

Chemical formula

[0397] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrimidin-5-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A212」)

Chemical formula

[0398] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole (「A213」) [Chemical Structure] Off-white solid; UPLC / MS 0.69 min, [M+H] + 503. 1 H NMR (500 MHz, DMSO-d 6 , mixture of rotamers) δ 13.69 (s, 1H), 8.19 - 8.09 (m, 2H), 8.08 - 7.98 (m, 1H), 7.82 - 7.70 (m, 3H), 7.32 - 7.26 (m, 1.5H), 7.18 (s, 0.5H), 4.76 (s, 0.5H), 4.68 (m, 0.5H), 4.61 (s, 0.5H), 4.51 (s, 0.5H), 4.35 - 4.26 (m, 2H), 3.81 (s, 1.5H), 3.80 - 3.74 (m, 2H), 3.69 (s, 1.5H), 3.36 (s, 3H).

[0399] 3-(3-{4-[(cis)-Octahydropyrano[3,4-c]pyrrole-2-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ("A214")

Chem.

[0400] 3-(3-{4-[(cis)-Octahydropyrrolo[3,4-c]pyridine-5-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ("A215")

Chem.

[0401] 3-(3-{4-[(cis)-5-(oxetan-3-yl)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A216」)

Chem.

[0402] (cis)-5-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-hexahydro-1H-2λ6-thieno[3,4-c]pyrrole-2,2-dione (「A217」) [Chemical formula] White solid; UPLC / MS 0.66 min, [M+H] + 541. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.69 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.36 - 4.15 (m, 2H), 3.93 (bs, 1H), 3.80 - 3.69 (m, 2H), 3.52 (bs, 2H), 3.36 (s, 3H), 3.43 - 3.19 (broad signal), 3.12 (bs, 3H).

[0403] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(1-methyl-1H-pyrazol-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A218」) [Chemical formula] White solid; UPLC / MS 0.70 min, [M+H] + 517. 1 H NMR (400 MHz, DMSO-d 6) δ 13.91 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.75 (s, 1H), 7.48 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.67 (t, J = 8.6 Hz, 1H), 4.44 (t, J = 9.3 Hz, 1H), 4.38 - 4.22 (m, 3H), 4.01 - 3.91 (m, 1H), 3.89 - 3.76 (m, 4H), 3.78 - 3.74 (m, 1H), 3.35 (s, 3H).

[0404] {4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-(4-oxetan-3-yl-piperazin-1-yl)-methanone (「A219」)

Chem.

[0405] {4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-(cis)-tetrahydro-furo[3,4-c]pyrrol-5-yl-methanone (「A220」)

Chem.

[0406] 1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-(pyridin-3-yl)azetidin-3-ol (「A221」)

Chem.

[0407] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)(2,2,3,3,5,5,6,6-2 H 8 )Piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A233")

Chem.

[0408] 2-{[5-Fluoro-3-(3-{4-[4-(oxetan-3-yl)(2,2,3,3,5,5,6,6- 2 H8)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazol-6-yl]oxy}ethan-1-ol ("A234")

Chem.

[0409] Example 15 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(piperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole ("A46") hydrochloride

Chem.

[0410] A suspension of 4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid (79.5 mg, 0.20 mmol) in DMF (1.0 ml) is added to 1-Boc-piperazine (45.2 mg, 0.24 mmol), followed by 1-hydroxybenzotriazole hydrate (6.1 mg, 0.04 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol). The reaction mixture is stirred at room temperature for 16 h. Saturated sodium bicarbonate solution is added to the reaction mixture. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on silica gel column using cyclohexane / ethyl acetate as eluent to afford tert-butyl 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)piperazine-1-carboxylate as a white solid; HPLC / MS 1.75 min, [M+H] + 566。

[0411] tert-Butyl 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)piperazine-1-carboxylate (90 mg, 0.16 mmol) is dissolved in 4N HCl in dioxane and the reaction mixture is stirred at room temperature for 2.5 h. The solvent is removed under reduced pressure to afford 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(piperazine-1-carbonyl)-phenyl]-1,2-oxazol-5-yl}-1H-indazole hydrochloride as a white solid; HPLC / MS 1.21 min (A), [M+H] + 466。 1 H NMR (500 MHz, DMSO-d 6) δ 13.75 (s, 1H), 9.22 (s, 2H), 8.13 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 10.9 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 4.33 - 4.26 (m, 2H), 3.79 - 3.74 (m, 2H), 3.72 (broad, 4H), 3.36 (s, 3H), 3.18 (broad, 4H).

[0412] The following compounds are prepared similarly: {[1-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methyl}(methyl)amine (“A222”) [Chemical formula] Pale yellow solid; HPLC / MS 1.31 min (A), [M + H] + 494. 1 H NMR (500 MHz, DMSO-d 6 , rotamers, peak selection) δ 8.09 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 11.0 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.35 - 4.28 (m, 2H), 4.27 - 4.20 (m, 1H), 3.81 - 3.72 (m, 2H), 3.52 - 3.44 (m, 1H), 3.36 (s, 3H), 2.81 (dd, J = 11.6, 3.9 Hz, 1H), 2.69 - 2.56 (m, 1H), 2.34 (s, 3H), 2.05 - 1.83 (m, 4H), 1.71 (broad, 1H).

[0413] 3-(3-{4-[(cis)-Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (「A223」) hydrochloride

Chem.

[0414] 2-[(5-Fluoro-3-{3-[4-(piperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazol-6-yl)oxy]ethane-1-ol (「A224」)

Chem.

[0415] {4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-piperazin-1-yl-methanone (「A225」)

Chem.

[0416] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2,2,3,3,5,5,6,6- 2 H 8 )piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole hydrochloride (「A232」)

Chem.

[0417] Example 16 [(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)imino]dimethyl-lambda6-sulfanone (「A47」)

Chem.

[0418] Example 17 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(1,3-thiazol-5-yl)-1,2-oxazol-5-yl]-1H-indazole (「A48」)

Chemical formula

[0419] Example 18 4-{5-[5-Fluoro-6-(3-hydroxy-2-methoxypropoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (「A49」)

Chemical formula

[0420] Example 19 3-{3-[4-(3,3-dimethyl-piperidin-4-yl)-phenyl]-isoxazol-5-yl}-5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole (“A230”)

Chem.

Chem.

[0421] Synthesis scheme:

Chem.

[0422] Example 20 2-[4-(4-{5-[5-Fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)piperazin-1-yl]propane-1,3-diol (「A228」)

Chemical formula

[0423] Example 21 Alternative synthesis of "A45":

Chemical Structure

[0424] To a solution of terephthalaldehydic acid (300 mg, 2.00 mmol) in DMF (10 ml), 1-(oxetan-3-yl)piperazine (313 mg, 2.20 mmol) is added, followed by 1-hydroxybenzotriazole hydrate (15.3 mg, 0.10 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (403 mg, 2.10 mmol). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is evaporated and dried. The residue is treated with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, evaporated, and 4-[4-(oxetan-3-yl)piperazine-1-carbonyl]benzaldehyde is obtained as a yellow oil; HPLC / MS 0.82 min (A), [M+H] + 275. 1 H NMR (500 MHz, DMSO-d 6) δ 10.05 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 4.53 (t, J = 6.5 Hz, 2H), 4.44 (t, J = 6.1 Hz, 2H), 3.67 (broad, 2H), 3.49 - 3.43 (m, 1H), 3.30 (broad, 2H), 2.42 - 2.19 (m, 4H).

[0425] A slurry of 4-[4-(oxetan-3-yl)piperazine-1-carbonyl]benzaldehyde (403 mg, 1.47 mmol) in ethanol (3 ml) is heated to 80 °C. The resulting clear solution is allowed to reach room temperature, a solution of hydroxylammonium chloride (204 mg, 2.93 mmol) in water (500 μl) is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is neutralized with 1 N sodium hydroxide solution (2 ml). The resulting precipitate is filtered off, washed with water, and dried under vacuum to give N-({4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}methylidene)hydroxylamine as a white powder; UPLC / MS 0.30 min, [M+H] + 290。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.37 (s, 1H), 8.18 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.53 (t, J = 6.5 Hz, 3H), 4.44 (t, J = 6.1 Hz, 3H), 3.62 (bs, 2H), 3.45 (p, J = 6.3 Hz, 1H), 3.37 (bs, 2H), 2.28 (bs, 4H).

[0426] To a solution of tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole-1-carboxylate (41.6 mg, 0.11 mmol) and N-({4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}methylidene)hydroxylamine in dichloromethane (500 μl) was added dropwise an aqueous sodium hypochlorite solution (content approximately 14%, 143 μl, approximately 0.33 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was treated with water and dichloromethane. The aqueous phase was separated and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel column using dichloromethane / methanol as eluent to give tert-butyl 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole-1-carboxylate as a colorless resin; UPLC / MS 0.69 min, [M+H] + 622.

[0427] To a suspension of tert-butyl 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole-1-carboxylate (62 mg, 0.12 mmol) in methanol (1 ml) was added sodium hydroxide (9.26 mg, 0.23 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was treated with saturated ammonium chloride solution. The resulting precipitate was filtered off, washed with water and dried under vacuum to give 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole as an off-white solid; UPLC / MS 0.53 min, [M+H] + 522。

[0428] The following compounds are prepared similarly: 6-Ethoxy-5-fluoro-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A229」)

Chemical Structure

[0429] Example 22 - Salt Formation

Chemical Structure

[0430] The following salts of (4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone (「A45」) were prepared in a similar manner: - hydrochloride - maleate - hemi-ethanedisulfonate - hemi-phosphate - sulfate - benzenesulfonate - para-toluenesulfonate

[0431] The following salts of 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (「A53」) were similarly prepared: - Methanesulfonate - Trifluoroacetate.

[0432] The following examples relate to pharmaceuticals: Example A: Injection vial A solution prepared by dissolving 100 g of the active ingredient represented by formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterilized by filtration, transferred into injection vials, lyophilized under sterile conditions, and sealed under sterile conditions. Each injection vial contains 5 mg of the active ingredient. Example B: Suppository A mixture of 20 g of the active ingredient represented by formula I, 100 g of soy lecithin, and 1400 g of cocoa butter was melted, poured into molds, and allowed to cool. Each suppository contains 20 mg of the active ingredient.

[0433] Example C: Solution In 940 ml of double-distilled water, 1 g of the active ingredient represented by formula I, 9.38 g of NaH 2 PO 4 ·2H 2 O, 28.48 g of Na 2 HPO 4 ·12H 2 O and 0.1 g of benzalkonium chloride were used to prepare a solution. The pH was adjusted to 6.8, the solution was made up to a maximum of 1 l, and sterilized by irradiation. This solution can be used in the form of an eye drop. Example D: Ointment 500 mg of the active ingredient represented by formula I was mixed with 99.5 g of petrolatum under sterile conditions.

[0434] Example E: Tablet A mixture of 1 kg of the active ingredient represented by formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner to give tablets each containing 10 mg of the active ingredient. Example F: Sugar-coated tablets Tablets are compressed similar to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

[0435] Example G: Capsules 2 kg of the active ingredient represented by formula I is introduced into hard gelatin capsules in a conventional manner such that each capsule contains 20 mg of the active ingredient. Example H: Ampoules A solution of 1 kg of the active ingredient represented by formula I in 60 l of double-distilled water is sterile filtered, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of the active ingredient.

Claims

1. Formula I 【Chemistry 1】 During the ceremony, R １ Hal, C.F. ３ ,O.A.,Het. １ , COOR ３ or CON(R ３ ) ２ represents R ２ represents H, Hal or CN, R ３ represents H or A, X represents phenylene, pyridine-diyl, 1,3-thiazole-diyl or pyrazole-diyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal and / or A; Y is absent or is CO, O[C(R ３ ) ２ ] ｎ , N.R. ３ CO, CONR ３ , C.O.R. ３ [C(R ３ ) ２ ] ｎ , CONHC ２ C (CH ３ ) ２ , S.O. ２ , S.O. ２ N (R ３ ), -N= or S(=O, =NR ３ ) Z is H, A, Hal, OA, [C(R ３ ) ２ ] ｎ Het ２ Or N=S(=O)A ２ represents A represents an unbranched or branched alkyl group having 1 to 10 C atoms, in which there are 1 or 2 non-adjacent CH- groups and / or ２ The - group may be replaced by an O atom, and where 1 to 7 H atoms are R ５ may be replaced by Or (CH ２ ) ｎ Cyc, Cyc represents a cyclic alkyl having 3 to 7 C atoms, R ５ is F, Cl, OH, SO ２ A or N (R ３ ) ２ represents Het １ represents pyrazolyl which may be mono- or disubstituted by A, Het ２ represents a 4-7 membered monocyclic aromatic, unsaturated or saturated heterocycle having 1-4 N, O and / or S atoms, which is unsubstituted or is selected from the group consisting of A, Hal, CN, OR ３ , [C(R ３ ) ２ ] ｎ N (R ３ ) ２ , [C(R ３ ) ２ ] ｎ SO ２ A, [C(R ３ ) ２ ] ｎ N.R. ３ SO ２ A, Het ３ , =NR ３ and / or may be mono-, di- or trisubstituted by =O, or represents a 7-10 membered bicyclic aromatic, unsaturated or saturated heterocycle having 1-4 N, O and / or S atoms, which is unsubstituted or is substituted with A, Hal, CN, OR ３ , [C(R ３ ) ２ ] ｎ N (R ３ ) ２ , [C(R ３ ) ２ ] ｎ SO ２ A, [C(R ３ ) ２ ] ｎ N.R. ３ SO ２ A, Het ３ , =NR ３ and / or may be mono-, di- or trisubstituted by =O, Het ３ represents a 4-7 membered monocyclic aromatic, unsaturated or saturated heterocycle having 1-4 N, O and / or S atoms, which is unsubstituted or is selected from the group consisting of A, Hal, OR ３ , which may be mono- or disubstituted by oxetanyl and / or ═O, or represents a 7-10 membered bicyclic aromatic, unsaturated or saturated heterocycle having 1-4 N, O and / or S atoms, which is unsubstituted or is selected from the group consisting of A, Hal, OR ３ , which may be mono- or disubstituted by oxetanyl and / or ═O, Hal represents F, Cl, Br or I, n represents 0, 1, 2 or 3; and their pharma- ceutically acceptable solvates, salts, tautomers and stereoisomers, and mixtures thereof in any ratio.

2. Het ２ pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, 1,4-diazepanyl, pyridinyl, 1H-pyridinyl, 2H-pyridazinyl, 2,3-diphenylphosphine, 1H ... Hydropyridazinyl, octahydro-1H-pyrrolo[3.2-b]pyridinyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonan-5-yl, 1H-1,3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonane- 7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 3-oxa-6-azabicyclo[3.

1. 1]heptan-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, hexahydro-1H-furo[3,4-c]pyrrol-5-yl, octahydropyrrolo[2,3-c]pyrrol-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl, 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl, octahydropyrano[3,4-c]pyrrol-2-yl, octahydrofuro[3,4-c]pyridin-5-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydro-1H-2lambda 6-thieno[3,4-c]pyrrol-5-yl or tetrahydrofuro[3,4-c]pyrrol-5-yl, each of which is unsubstituted or is selected from the group consisting of A, Hal, CN, OR, ３ , [C(R ３ ) ２ ] ｎ N (R ３ ) ２ , [C(R ３ ) ２ ] ｎ SO ２ A, [C(R ３ ) ２ ] ｎ N.R. ３ SO ２ A, Het ３ , =NR ３ and / or may be mono-, di- or trisubstituted by =O, 13. The compound of claim 1, and its pharma- ceutically acceptable solvates, salts, tautomers and stereoisomers, and mixtures thereof in any ratio.

3. Het ３ represents morpholinyl, 1H-pyrazolyl, 1 lambda 6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, oxan-4-yl, 1,2,3-triazolyl or 1,2,4-triazolyl, each of which is unsubstituted or selected from A, Hal, OR ３ , optionally mono- or disubstituted by oxetanyl and / or ═O, 3. A compound according to claim 1 or 2, as well as its pharma- ceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio.

4. R １ But Hal, CF ３ , O.C.H. ３ , O.C.H. ２ CH ２ OCH ３ , O.C.H. ２ CH ２ OH, 1-methyl-1H-pyrazol-4-yl, COOCH ３ , C.O.N.H. ２ , CONHC ３ or CONHC ２ CH ２ OCH ３ represents R ２ represents H, Hal or CN, R ３ is H or CH ３ represents X represents 1,4-phenylene, 1,3-phenylene, 2-fluoro-1,4-phenylene, 2-methyl-1,4-phenylene, pyridine-3,6-diyl, 1,3-thiazole-3,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl or pyrazole-1,4-diyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal and / or A, Y is absent or is CO, SO ２ , N.H.C.O., N.H.C. ３ , CONH(CH ２ ) ｎ , CONHC ２ C (CH ３ ) ２ , CON(CH ３ ) (CH ２ ) ｎ , O, O.C.H. ２ , O.C.H. ２ CH ２ , S(=O)(=NH), -N= or SO ２ N (CH ３ ) Z is H, A, Hal, OA, [C(R ３ ) ２ ] ｎ Het ２ Or N=S(=O)A ２ represents A represents unbranched or branched alkyl having 1 to 10 C atoms, in which there are 1 or 2 non-adjacent CH- groups and / or CH ２ The - group may be replaced by an O atom, and where 1 to 7 H atoms are R ５ may be replaced by Or (CH ２ ) ｎ Cyc, Cyc represents a cyclic alkyl having 3 to 7 C atoms, R ５ F, Cl, OH, SO ２ A or N (R ３ ) ２ represents Het １ represents pyrazolyl which may be mono- or disubstituted by A, Het ２ pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, 1,4-diazepanyl, pyridinyl, 1H-pyridinyl, 2H-pyridazinyl, 2,3-diphenylphosphine, 1H ... Hydropyridazinyl, octahydro-1H-pyrrolo[3.2-b]pyridinyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonan-5-yl, 1H-1,3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonane- 7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 3-oxa-6-azabicyclo[3.

1. 1]heptan-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, hexahydro-1H-furo[3,4-c]pyrrol-5-yl, octahydropyrrolo[2,3-c]pyrrol-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl, 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl, octahydropyrano[3,4-c]pyrrol-2-yl, octahydrofuro[3,4-c]pyridin-5-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydro-1H-2lambda 6-thieno[3,4-c]pyrrol-5-yl or tetrahydrofuro[3,4-c]pyrrol-5-yl, each of which is unsubstituted or is selected from the group consisting of A, Hal, CN, OR, ３ , [C(R ３ ) ２ ] ｎ N (R ３ ) ２ , [C(R ３ ) ２ ] ｎ SO ２ A, [C(R ３ ) ２ ] ｎ N.R. ３ SO ２ A, Het ３ , =NR ３ and / or may be mono-, di- or trisubstituted by =O, Het ３ represents morpholinyl, 1H-pyrazolyl, 1 lambda 6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, oxan-4-yl, 1,2,3-triazolyl or 1,2,4-triazolyl, each of which is unsubstituted or selected from the group consisting of A, Hal, OR ３ , which may be mono- or disubstituted by oxetanyl and / or ═O, Hal represents F, Cl, Br or I, n represents 0, 1, 2 or 3; 2. The compound of claim 1, and its pharma- ceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in all ratios.

5. Formula Ib 【Chemistry 2】 During the ceremony, R １ Hal, C.F. ３ , O.C.H. ３ , O.C.H. ２ CH ２ OCH ３ , O.C.H. ２ CH ２ OH, 1-methyl-1H-pyrazol-4-yl, COOCH ３ , C.O.N.H. ２ , CONHC ３ or CONHC ２ CH ２ OCH ３ represents R ２ represents H, Hal or CN, R ３ is H or CH ３ represents X represents 1,4-phenylene, 1,3-phenylene, 2-fluoro-1,4-phenylene, 2-methyl-1,4-phenylene, pyridine-3,6-diyl, 1,3-thiazole-3,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl or pyrazole-1,4-diyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal and / or A; Y is absent or is CO, SO ２ , N.H.C.O., N.H.C. ３ , CONH(CH ２ ) ｎ , CONHC ２ C (CH ３ ) ２ , CON(CH ３ ) (CH ２ ) ｎ , O, O.C.H. ２ , O.C.H. ２ CH ２ , S(=O)(=NH), -N= or SO ２ N (CH ３ ) Z is H, A, Hal, OA, [C(R ３ ) ２ ] ｎ Het ２ Or N=S(=O)A ２ represents A represents an unbranched or branched alkyl group having 1 to 10 C atoms, in which there are 1 or 2 non-adjacent CH- groups and / or ２ The - group may be replaced by an O atom, and where 1 to 7 H atoms are R ５ may be replaced by Or (CH2) ｎ Cyc, Cyc represents a cyclic alkyl having 3 to 7 C atoms, R ５ is F, Cl, OH, SO ２ A or N (R ３ ) ２ represents Het １ represents pyrazolyl which may be mono- or disubstituted by A, Het ２ are pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, 1,4-diazepanyl, pyridinyl, 1H-pyridinyl, 2H-pyridazinyl, 2,3-di Hydropyridazinyl, octahydro-1H-pyrrolo[3.2-b]pyridinyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonan-5-yl, 1H-1,3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonane- 7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 3-oxa-6-azabicyclo[3.

1. 1]heptan-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, hexahydro-1H-furo[3,4-c]pyrrol-5-yl, octahydropyrrolo[2,3-c]pyrrol-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl, 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl, octahydropyrano[3,4-c]pyrrol-2-yl, octahydrofuro[3,4-c]pyridin-5-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydro-1H-2lambda 6-thieno[3,4-c]pyrrol-5-yl or tetrahydrofuro[3,4-c]pyrrol-5-yl, each of which is unsubstituted or is selected from the group consisting of A, Hal, CN, OR, ３ , [C(R ３ ) ２ ] ｎ N (R ３ ) ２ , [C(R ３ ) ２ ] ｎ SO ２ A, [C(R ３ ) ２ ] ｎ N.R. ３ SO ２ A, Het ３ , =NR ３ and / or may be mono-, di- or trisubstituted by =O, Het ３ represents morpholinyl, 1H-pyrazolyl, 1 lambda 6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, oxan-4-yl, 1,2,3-triazolyl or 1,2,4-triazolyl, each of which is unsubstituted or selected from the group consisting of A, Hal, OR ３ , which may be mono- or disubstituted by oxetanyl and / or ═O, Hal represents F, Cl, Br or I, n represents 0, 1, 2 or 3; 2. The compound according to claim 1, represented by the formula: and its pharma- ceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in all ratios.

6. group 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 2. The compound of claim 1 selected from: and their pharma- ceutically acceptable solvates, salts, tautomers and stereoisomers, and mixtures thereof in any ratio.

7. a) Formula I During the ceremony, X represents phenylene; Y represents CO; Z is [C(R ３ ) ２ ] ｎ Het ２ represents, and n represents 0; For the preparation of a compound represented by Formula II 【Chemistry 3】 In the formula, R １ and R ２ has the meaning given in claim 1, The compound represented by formula III 【Chemistry 4】 In the formula, Het ２ has the meaning given in claim 1, reacting a compound represented by or b) Formula I During the ceremony, R １ Het １ Represents, For the preparation of a compound represented by Formula IV 【Chemistry 5】 During the ceremony, R ２ , X, Y and Z have the meanings given in claim 1; The compound represented by formula V 【Chemistry 6】 In the formula, Het １ has the meaning given in claim 1, reacting a compound represented by or c) Formula Ia 【Chemistry 7】 During the ceremony, R １ , R ２ , X, Y and Z have the meanings indicated in claim 1; For the preparation of a compound represented by Formula VI 【Chemistry 8】 During the ceremony, R １ and R ２ has the meaning given in claim 1, The compound represented by formula VII 【Chemistry 9】 During the ceremony, X, Y and Z have the meanings indicated in claim 1. reacting a compound represented by or d) Formula Ib 【Chemistry 10】 During the ceremony, R １ , R ２ , X, Y and Z have the meanings given in claim 1; For the preparation of a compound represented by Formula VIII 【Chemistry 11】 During the ceremony, R １ and R ２ has the meaning given in claim 1, The compound represented by formula IX 【Chemistry 12】 During the ceremony, X, Y and Z have the meanings indicated in claim 1. reacting a compound represented by and / or Converting a base or acid of formula I into one of its salts; A process for the preparation of compounds of formula I according to claims 1 to 6, as well as their pharma- ceutically acceptable salts, solvates, tautomers and stereoisomers, characterized in that

8. A medicament comprising at least one compound of formula I as claimed in claim 1 and / or its pharma- ceutically acceptable salts, solvates, tautomers and stereoisomers, and mixtures thereof in any ratio, and optionally a pharma- ceutically acceptable carrier, excipient or vehicle.

9. 2. The compounds of formula I as claimed in claim 1 and their pharma- ceutically acceptable salts, solvates, tautomers and stereoisomers, and mixtures thereof in any ratio, for use in the treatment and / or prevention of cancer.

10. 11. The compound for use according to claim 10 for the treatment and / or prevention of cancer, wherein the cancer is a gastrointestinal stromal tumor.

11. 13. A medicament comprising at least one compound of formula I according to claim 1 and / or its pharma- ceutically acceptable salts, solvates, tautomers and stereoisomers, and mixtures thereof in all ratios, and at least one further pharma- ceutical active ingredient.

12. (a) an effective amount of a compound of formula I as defined in claim 1 and / or its pharma- ceutically acceptable salts, solvates, tautomers and stereoisomers, and mixtures thereof in any ratio; And (b) an effective amount of a further pharma- ceutical active ingredient; A set (kit) consisting of separate packs of:

13. group 2-Bromo-5-fluoro-4-(2-methoxyethoxy)benzaldehyde 【Chemistry 13】 N'-[(1E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylidene]-4-methylbenzene-1-sulfonohydrazide 【Chemistry 14】 5-Fluoro-6-(2-methoxyethoxy)-1-(4-methylbenzenesulfonyl)-1H-indazole 【Chemistry 15】 5-Fluoro-6-(2-methoxyethoxy)-1H-indazole 【Chemistry 16】 5-Fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole 【Chemistry 17】 tert-Butyl 5-fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate 【Chemistry 18】 tert-Butyl 5-fluoro-6-(2-methoxyethoxy)-3-[2-(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate 【Chemistry 19】 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole 【Chemistry 20】 tert-Butyl 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate 【Chemistry 21】 tert-Butyl 5-fluoro-3-{3-[4-(methoxycarbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate 【Chemistry 22】 Methyl 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoate 【Chemistry 23】 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid 【Chemistry 24】 An intermediate selected from:

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