Indazolyl-isoxazole derivatives for the treatment of diseases such as cancer

Abstract

Compounds of formula I, wherein R 1 , R 2 , X, Y and Z have the meanings indicated in claim 1, is an inhibitor of c-Kit kinase and can be used for the treatment of cancer.

Description

[Technical field]

[0001] 2. Background of the Invention The present invention had the object of finding new compounds having valuable properties, especially those which can be used for the preparation of medicines. The present invention relates to indazolyl-isoxazole derivatives that inhibit c-KIT kinase across a broad range of c-KIT mutations and secondary mutations (V654A secondary resistance mutation in exon 13) that can occur in GIST (gastrointestinal stromal tumor) patients.

[0002] The compounds of the invention are therefore useful in treating diseases such as cancer. The invention also provides methods of preparing these compounds, pharmaceutical compositions containing these compounds, compounds for use for the treatment of disease, and methods of treating disease utilizing pharmaceutical compositions containing these compounds. [Background technology]

[0003] Mutated forms of the receptor tyrosine kinase c-KIT are drivers of several cancers and are attractive targets for therapy. While GISTs in particular benefit from the use of inhibitors of KIT kinase activity, such as imatinib, primary resistance occurs with certain oncogenic mutations. Furthermore, resistance frequently occurs due to secondary mutations (LK Ashman & R.Griffith (2013) Expert Opinion on Investigational Drugs, 22:1, 103-115). LL 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. KG 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 cell or epithelioid neoplasms. GISTs commonly harbor primary activating mutations (90%) in the KIT gene, leading to ligand-independent activation of the receptor tyrosine kinase c-KIT and rendering 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 after a mean of 2 years. A secondary mutation in exon 13, V654A, 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. It has been found that the compounds according to the invention and their salts are well tolerated and yet possess extremely valuable pharmacological properties.

[0006] The present invention specifically relates to compounds of formula I that inhibit c-KIT kinase, preferably the mutant V654A of c-KIT kinase. Moreover, the compound of formula I inhibits PDGFRα(V651D). Gain-of-function mutations of PDGFRα appear to play an important role in the development of GIST 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). In Hongchan An et al (Bioorganic and Medicinal Chemistry Letters 21 (2011)) 6297-6300, indazolyl-isoxazoles are described as HIF-1 inhibitors: [ka] It is described as:

[0011] Nicoloe Vivona et al, Journal of Heterocyclic Chemistry 22 (1985) 29-32, states the following: [ka] Indazolyl-isoxazoles of the formula are described. Summary of the Invention

[0012] SUMMARY OF THE PRESENT APPLICATION The present invention relates to a compound of formula I [ka] 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 ,CONR 3 [C(R 3 ) 2 ] n ,CONHCH 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 CH 2 - groups may be replaced by O atoms, and where 1 to 7 H atoms are R 5 may be replaced by Or (CH 2 ) n Cyc stands for Cyc represents a cyclic alkyl having 3 to 7 C atoms; R 5 are F, Cl, OH, and 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 NR 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 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 NR 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 , optionally 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 , optionally 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 salts, solvates, tautomers and stereoisomers, and mixtures thereof in any ratio.

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

[0014] Furthermore, the present invention relates to pharma- ceutically acceptable derivatives of the compounds of formula I. The term solvates of the compounds is understood to mean adductions of inert solvent molecules onto the compounds, which form due to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alkoxides. It will be understood that the invention also relates to solvates of the salts.

[0015] The term pharma- ceutically acceptable derivatives is taken to mean, for example, also the salts of the compounds according to the invention, and so-called prodrug compounds.

[0016] As used herein, and unless otherwise indicated, the term "prodrug" refers to a derivative of a compound represented by Formula I that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound represented by Formula I. Examples of prodrugs include derivatives and metabolites of a compound represented by Formula I that include biohydrolyzable moieties, such as, but are not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs.

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

[0018] The expression "effective amount" refers to an amount of a pharmaceutical or pharma- ceutical active ingredient that elicits the biological or pharmacological response sought or desired, for example, by a researcher or physician, in a tissue, system, animal or human.

[0019] In addition, the expression "therapeutically effective amount" refers to a therapeutically effective amount that, when compared to a corresponding subject not receiving this amount, produces the following results: It refers to an amount that effects an improved treatment, cure, prevention or elimination of a disease, syndrome, condition, complaint, disorder or side effect, or also a reduction in the progression of a disease, complaint or disorder.

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

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

[0022] The present invention relates to compounds of formula I and their salts, and to processes for the preparation of compounds of formula I and their pharma- ceutically acceptable salts, solvates, tautomers and stereoisomers, comprising: 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 [ka] In the formula, R 1 and R 2 has the meaning given in claim 1, The compound represented by formula III [ka] In the formula, Het 2 has the meaning given in claim 1, reacting a compound represented by or

[0023] b) Formula I During the ceremony, R 1 Het 1 Represents, For the preparation of a compound represented by Formula IV [ka] During the ceremony, R 2 , X, Y and Z have the meanings indicated in claim 1; The compound represented by formula V [ka] In the formula, Het 1 has the meaning given in claim 1, reacting a compound represented by or

[0024] c) Formula Ia [ka] 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 Equation VI [ka] During the ceremony, R 1 and R 2 has the meaning given in claim 1, The compound represented by formula VII [ka] During the ceremony, X, Y and Z have the meanings indicated in claim 1. reacting a compound represented by or

[0025] d) Formula Ib [ka] 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 VIII [ka] During the ceremony, R 1 and R 2 has the meaning given in claim 1, The compound represented by formula IX [ka] 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; The process is characterized in that

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

[0027] Preferably, the compound of formula Ia [ka] In the formula, R 1 , R 2 , X, Y and Z have the meanings indicated in claim 1; Preferred is a compound represented by the following formula: Moreover, preferably, the compound of formula Ib [ka] During the ceremony, R 1 , R 2 , X, Y and Z have the meanings indicated in claim 1; Preferred is a compound represented by the following 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 preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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, even more preferably trifluoromethyl. A very particularly 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 is preferably CH 2 OCH 3 , C.H. 2 CH 2 OH or CH 2 CH 2 OCH 3 Represents.

[0029] R 1 is preferably Hal, CF 3 , O.C.H. 3 , O.C.H. 2CH 2 OCH 3 , O.C.H. 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 trisubstituted by Hal and / or A. Y is preferably CO, SO 2 , N.H.C.O., N.C.H. 3 , CONH(CH 2 ) n ,CONHCH 2 C(CH 3 ) 2 , CON(CH 3 )(CH 2 ) n , O, OCH 2 , O.C.H. 2 CH 2 , S(=O)(=NH), -N=, SO 2 N(CH 3 ) or does not exist. Z is preferably H, Hal, OA, Het 2 , A, N=S(=O)A 2 Represents. Bicyclic compounds also include spiro compounds.

[0031] Regardless of further substitutions, Het 2 is, 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-benzyl 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 heterocyclic radicals may also be partially or fully hydrogenated.

[0032] Regardless of further substitutions, Het 2is thus also, 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-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro b-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, and even more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, diphenyl, 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 substitutions, 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, 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-benzyl 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 heterocyclic radicals may also be partially or fully hydrogenated.

[0034] Regardless of further substitutions, Het 3is thus also, 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-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro b-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, and even more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, diphenyl, 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]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 (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-2lambda6-thieno[3,4-c]pyrrol-5-yl, tetrahydrofuro[3,4-c]pyrrol-5-yl. Each of these 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 NR 3 SO 2 A, Het 3 , =NR 3 and / or may be mono-, di-, or trisubstituted by =O.

[0036] Het 3 preferably 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, 1,2,4-triazolyl, Each of these is A, Hal, OR 3 , oxetanyl and / or ═O may be mono-, di-, or trisubstituted.

[0037] Throughout the present invention, all radicals occurring more than once can be identical or different, i.e., independent of each other. The compounds of formula I may have one or more chiral centers and therefore may occur in various stereoisomeric forms, and the compounds of formula I include all such 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 compounds can be represented by the following subformulae Ia to If, which correspond to formula I, in which the radicals not specified in more detail here have the meanings indicated in formula I, where: In Ia, 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 ,CONH 2 ,CONHCH 3 or CONHCH 2 CH 2 OCH 3 represents In Ib, R 3 is H or CH 3 represents; 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-, di- or trisubstituted by Hal and / or A; In Id, Y is absent or is CO, SO 2 , N.H.C.O., N.C.H. 3 , CONH(CH 2 ) n,CONHCH 2 C(CH 3 ) 2 , CON(CH 3 )(CH 2 ) n , O, OCH 2 , O.C.H. 2 CH 2 , S(=O)(=NH), -N= or SO 2 N(CH 3 ) ; In Ie, Het 2are 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]decan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, ...8-ox 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-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-2lambda6-thieno[3,4-c]pyrrol-5-yl, tetrahydrofuro[3,4-c]pyrrol-5-yl, each of which is unsubstituted or 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 may be mono-, di- or trisubstituted by =O; In If, 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, 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; and their pharma-ceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio.

[0039] Preferably, the compound of formula Ib according to claim 1 [ka] 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 ,CONH 2 ,CONHCH 3 or CONHCH 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.C.H. 3 , CONH(CH 2 ) n ,CONHCH 2 C(CH 3 ) 2 , CON(CH 3 )(CH 2 ) n , O, OCH 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 one or two non-adjacent CH- and / or CH 2 - groups may be replaced by O atoms, and where 1 to 7 H atoms are R 5 may be replaced by Or (CH 2 ) n Cyc stands for Cyc represents a cyclic alkyl having 3 to 7 C atoms; R 5 are F, Cl, OH, and SO 2 A or N(R 3 ) 2 represents Het 1 represents pyrazolyl which may be mono- or disubstituted by A, Het 2are 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]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-2lambda6-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 NR 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 A, Hal, OR 3 , optionally 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 salts, tautomers and stereoisomers, and mixtures thereof in any ratio are preferred.

[0040] Moreover, the present invention relates to a group 2-Bromo-5-fluoro-4-(2-methoxyethoxy)benzaldehyde [ka] N'-[(1E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylidene]-4-methylbenzene-1-sulfonohydrazide [ka] 5-Fluoro-6-(2-methoxyethoxy)-1-(4-methylbenzenesulfonyl)-1H-indazole [ka] 5-Fluoro-6-(2-methoxyethoxy)-1H-indazole [ka] 5-Fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole [ka] tert-Butyl 5-fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate [ka] tert-Butyl 5-fluoro-6-(2-methoxyethoxy)-3-[2-(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate [ka] 3-Ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole [ka] tert-Butyl 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate [ka] tert-Butyl 5-fluoro-3-{3-[4-(methoxycarbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate [ka] Methyl 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoate [ka] 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid [ka] The present invention relates to an intermediate selected from

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

[0042] 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, The compound of formula II may be preferably obtained by reacting a compound of formula III with a compound of formula II.

[0043] The starting compounds of 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-dimethyl-aminopropyl)-N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The reaction is generally carried out in the presence of an acid binding agent, 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 be preferred. Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about -30° to 140°, usually from -10° to 100°, in particular from about 30° to about 90°.

[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 dimethylsulfoxide (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 said solvents. Particularly preferred are acetonitrile, dichloromethane and / or DMF.

[0045] Formula I During the ceremony, R 1 Het 1 Represents, The compound of formula (IV) can be preferably obtained by reacting a compound of formula (V) with a compound of formula (V). The starting compounds of formula IV and V are generally known. However, if they are novel, they can be prepared by methods known per se. Alternatively, Formula Va [ka] may be used in place of the compound of formula V. This coupling is generally carried out at elevated temperatures using a palladium catalyst, a base and an inert solvent. Overviews of catalysts and reaction conditions can be found in the literature [see, for example, S. Kotha et al., Tetrahedron 2002, 58, 9633-9695; TE Barder et al., J. Am. Chem. Soc. 2005, 127, 4685-4696]. The preferred catalyst for this reaction is tetrakis(triphenylphosphine)-palladium(0) or PdCl 2 (PPh 3 ) 2 The preferred base is sodium carbonate used as an aqueous solution. The reaction is carried out in an organic solvent which is inert under the reaction conditions, such as 1,4-dioxane, acetonitrile, N,N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or in water or in a mixture of these solvents. Preferably, the reaction is carried out in a mixture of 1,4-dioxane and water, or acetonitrile and water. The reaction is generally carried out at temperatures between +100° C. and +250° C., preferably between +110° C. and +150° C. The heating is preferably affected by a single mode microwave device. The reaction is usually carried out under an inert gas atmosphere, preferably under argon.

[0046] Formula Ia [ka] During the ceremony, R 1 , R 2 , X, Y and Z have the meanings indicated in claim 1; The compound of formula (VI) can be preferably obtained by reacting a compound of formula (VII) with a compound of formula (VII). The starting compounds of formula VI and VII are generally known. However, if they are novel, they can be prepared by methods known per se.

[0047] Formula Ib [ka] During the ceremony, R 1 , R 2 , X, Y and Z have the meanings given in claim 1; Compounds of formula VIII can preferably be obtained by reacting a compound of formula IX. The starting compounds of formula VIII and IX are generally known. However, if they are novel, they can be prepared by methods known per se.

[0048] Pharmaceutical Salts and Other Forms The compounds according to the present invention can be used in their final non-salt form.On the other hand, the present invention also covers the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.The pharmaceutically acceptable salt forms of the compound represented by formula I are mostly 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 are, for example, alkali metal hydroxides, including 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 of formula I are also included.

[0050] In the case of certain compounds of formula I, acid addition salts may be formed by treating these compounds with pharma- ceutically 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), and alkyl- and monoaryl sulfonates (such as ethanesulfonates, toluenesulfonates, and benzenesulfonates), and other organic acids and their corresponding salts (such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates, and the like).

[0051] As a result, pharma- ceutically acceptable acid addition salts of the compounds of formula I include the following: 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, glycosyl ester, glycerol ... These salts include, but are not limited to, cerolate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, and phthalate.

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

[0053] Salts of the compounds of formula I derived from pharma- ceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as, for example, arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- Examples of suitable amines include, but are not intended to represent a limitation, 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 salts of tris(hydroxymethyl)methylamine (tromethamine).

[0054] The compounds of the invention that contain a basic nitrogen-containing group are (C 1 ~C 4 ) alkyl halides (e.g., methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides); di(C 1 ~C 4 ) alkyl sulfates (e.g., dimethyl, diethyl and diamyl sulfates); (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 other agents. Both water- and oil-soluble compounds according to the invention can be prepared using such salts.

[0055] Preferred such pharmaceutical salts include, but are not intended to represent a limitation, 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.

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

[0057] The acid addition salts of the basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid, causing the formation of the salt 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 forms differ in some respects from the corresponding salt forms with respect to certain physical properties, such as solubility in polar solvents; however, for purposes of this invention, the salts correspond in other respects to their respective free base forms.

[0058] As mentioned, the pharma- ceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines, such as alkali 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 acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base, causing the formation of the salt 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 forms differ in some respects from the corresponding salt forms with respect to certain physical properties, such as solubility in polar solvents; however, for purposes of this invention, the salts correspond in other respects to their respective free acid forms.

[0060] When a compound according to the invention contains more than one group capable of forming pharma- ceutically acceptable salts of this type, the invention also encompasses multiple salts. Exemplary multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium, and trihydrochloride, but this is not intended to represent a limitation.

[0061] In view of what has been said above, it is clear that the expression "a pharma- ceutically acceptable salt" in the present context is to be understood as meaning an active ingredient comprising a compound of formula I in the form of one of its salts, especially if this salt form confers improved pharmacokinetic properties to the active ingredient compared to the active ingredient in free form or to any other previously used salt form of the active ingredient. A pharma- ceutically acceptable salt form of an active ingredient may also provide the active ingredient with desired pharmacokinetic properties for the first time that it did not have before, and may even have a positive effect on the pharmacodynamics of this active ingredient with regard to its therapeutic effectiveness on the body.

[0062] Isotopes It is also intended that the compounds of formula I encompass isotopically labeled forms thereof. Isotopically labeled forms of the compounds of formula I are identical to the compounds except for the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of the normally naturally occurring atom.

[0063] Examples of isotopes that are readily commercially available and can be incorporated into compounds of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compounds of formula I, their prodrugs or pharma- ceutically acceptable salts, any of which contain one or more of the isotopes mentioned above and / or other isotopes of other atoms, are contemplated as part of the present invention. The isotopically labeled compounds of formula I can be used in a number of ways to advantage.

[0064] For example, an isotopically labeled compound of formula I may be prepared by, for example, 3 H or 14 Incorporation of radioactive isotopes such as C is suitable for drug and / or substrate tissue distribution assays. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes, such as deuterium ( 2 The incorporation of isotopically labeled H) into compounds of formula I has therapeutic advantages due to the greater metabolic stability of this isotopically labeled compound.

[0065] Higher metabolic stability translates directly into increased half-life or lower dosages in vivo, which under most circumstances represent preferred embodiments of the present invention. Isotopically labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and related descriptions in the present text, the Examples section and the Preparation section, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0066] deuterium( 2 H) may also be incorporated into compounds of formula I for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect, which is the change in the rate of a chemical reaction due to the exchange of an isotopic nucleus, which in turn is caused by the change in the ground state energy required for covalent bond formation following this isotope exchange.

[0067] Exchange of heavier isotopes usually results in a lowering of the ground state energy for a chemical bond, thus causing a reduction in the rate at which the rate-limiting bond breakage occurs. If the bond breakage occurs in or near a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be substantially altered.

[0068] For illustration: if deuterium is attached to a carbon atom at a non-exchangeable position, k M / k D A rate difference of 2-7 is typical. If this rate difference is successfully applied to a compound of formula I that is susceptible to oxidation, the in vivo profile of this compound may 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 retaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information about the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds of formula I with improved stability through resistance to such oxidative metabolism.

[0070] Significant improvements in the pharmacokinetic profile of the compounds of formula I are thereby obtained, including shorter in vivo half-life (t1 / 2), concentration at maximum therapeutic effect (C max ), quantitatively in terms of increases in 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 of formula I that have multiple potential attack sites for oxidative metabolism (e.g., benzylic 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] The half-life determination allows a convenient and accurate determination of the extent to which the resistance to oxidative metabolism is improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0073] Deuterium-hydrogen exchange in compounds of formula I can also be used to achieve favorable modification of the metabolic spectrum of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (CH) bond cleavage, it can be reasonably expected that a deuterated analog would greatly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate-limiting step.

[0074] Further information on the state of the art regarding deuterium-hydrogen exchange may 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 relates to medicaments comprising at least one compound of formula I and / or its pharma- ceutically acceptable salts, solvates and stereoisomers, as well as mixtures thereof in any ratio, and, optionally, excipients and / or adjuvants.

[0076] The pharmaceutical preparations may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Such units may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 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 preparations may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical preparations of this type may be prepared using processes generally known in the pharmaceutical art.

[0077] Pharmaceutical formulations may be adapted for administration via any desired suitable method, for example, orally (including buccal or sublingual), rectally, nasally, topically (including buccal, sublingual or transdermal), vaginally or parenterally (including subcutaneous, intramuscular, intravenous or intradermal).Such formulations may be prepared using any process known in the pharmaceutical art, for example, by combining the active ingredient with the excipient(s) or auxiliary(s).

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

[0079] Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient components can be combined with an oral, non-toxic and pharma- ceutically acceptable inert excipient, such as ethanol, glycerol, water, etc. Powders are prepared by grinding the compound to a suitable fine size and mixing it with a pharmaceutical excipient com- minuted in a similar manner, such as an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersing agents and dyes may also be present.

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

[0081] In addition, if desired or necessary, suitable binders, lubricants and disintegrating agents and dyes can be incorporated into the mixture at the same time. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), sweeteners made from corn, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethylcellulose, 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, for example, formulated by preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture to obtain tablets. The powder mixture is prepared by mixing the compound, comminuted in a suitable manner, as described above, with a diluent or base, and optionally with a binder (such as, for example, carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone), a dissolution retarder (such as, for example, paraffin), an absorption promoter (such as, for example, a quaternary salt), and / or an absorbent (such as, for example, bentonite, kaolin, or dicalcium phosphate).

[0083] The powder mixture can be granulated by wetting it with a binder (such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymeric materials, and forcing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet machine, giving lumps of non-uniform shape which are broken down to form granules. The granules can be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet casting molds.

[0084] The lubricated mixture is then compressed to give tablets. The compounds according to the invention can also be combined with free-flowing inert excipients and then compressed directly to give tablets without carrying out any granulation or dry pressing 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 to be able to distinguish between different dosage units.

[0085] For example, oral liquids such as solution, syrup and elixir can be prepared in the form of dosage unit so that a fixed amount can contain a pre-specified amount of compound.Syrup can be prepared by dissolving compound in aqueous solution with suitable flavoring, while elixir is prepared using non-toxic alcoholic vehicle.Suspension can be formulated by dispersing compound in non-toxic vehicle.Solubilizer and emulsifier (e.g., ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, etc.), preservative, flavor additive (e.g., peppermint oil or natural sweetener or saccharin, etc.), or other artificial sweetener, etc. can be added at the same time.

[0086] Dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulations can also be prepared so as to provide extended or delayed release, for example, by coating or embedding particulate material in polymers, waxes, and the like.

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

[0088] The compounds of 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 copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidophenol or polyethyleneoxide polylysine substituted with palmitoyl radicals.

[0089] The compounds may also be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as crosslinked block copolymers or amphiphilic block copolymers of polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and hydrogels.

[0090] Pharmaceutical formulations adapted for transdermal administration may be applied as independent plasters for prolonged, close contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered from the plaster by iontophoresis, as generally described 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 eye 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 to give an ointment, the active ingredient can be employed with either a paraffinic or water-miscible cream base.Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.

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

[0094] Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes. Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.

[0095] Pharmaceutical formulations adapted for intranasal administration in which the carrier material is a solid include coarse powders having a particle size in the range, for example, 20 to 500 microns, which are administered in the manner in which snuff is taken, that is, by rapid inhalation through the nasal passage from a container containing the powder, held close to the nose. Formulations suitable for administration as an intranasal spray or nasal drops, having a liquid as the carrier material, encompass solutions of the active ingredient in water or oil.

[0096] Pharmaceutical formulations adapted for administration by inhalation encompass fine particulate dusts or mists, which may be generated by various types of pressurized dispensers with aerosols, nebulisers or insufflators. Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0097] Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, which contain antioxidants, buffers, bacteriostats and solutes, by which the preparation is made isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may contain suspension media and thickening agents.The preparations can be managed in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and stored in a freeze-dried (lyophilised) state, so that it is only necessary to add a sterile carrier liquid (e.g., water for injection purposes) immediately before use.The injection solutions and suspensions prepared according to recipes can be prepared from sterile powders, granules and tablets.

[0098] It will be understood that, in addition to the components particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the particular type of formulation; thus, for example, formulations suitable for oral administration may include flavoring agents.

[0099] The therapeutically effective amount of a compound of formula I will depend on a number of factors, including, for example, the age and weight of the animal, the exact condition requiring treatment and its severity, the nature of the formulation and the method of administration, and will ultimately be determined by the treating physician or veterinarian. However, an effective amount of a compound according to the present invention will generally be in the range of 0.1-100 mg / kg of recipient (mammal) body weight per day, and more typically in the range of 1-10 mg / 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 dose per day or in a series of partial doses, usually per day (e.g., 2, 3, 4, 5 or 6 doses, etc.), so that the total daily dose is the same. The effective amount of the salt or solvate thereof, or of a physiologically functional derivative thereof, can be determined as the fraction of the effective amount of the compound according to the invention itself. Similar doses can be assumed to be suitable for the treatment of the other conditions mentioned above.

[0101] This type of combination treatment may be accomplished by utilizing the simultaneous, sequential, or separate administration of the individual components of the treatment. This type of combination product employs a compound according to the present invention.

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

[0103] The present invention also provides (a) an effective amount of a compound of formula I and / or its pharma- ceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in any ratio; and (b) an effective amount of a further pharmacologic active ingredient; The present invention also relates to a set (kit) consisting of separate packs of the above.

[0104] The set includes suitable containers such as boxes, individual bottles, bags or ampoules. The set may, for example, include individual ampoules, each containing an effective amount of the compound of formula I and / or its pharma- ceutically acceptable salts, tautomers and stereoisomers, and mixtures thereof in all ratios. and an effective amount of a further medicament active ingredient in dissolved or lyophilized form.

[0105] "Treating" as used herein means the total or partial alleviation of symptoms associated with a disorder or disease, or the slowing or halting 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 reference to a compound of formula (I) may refer to an amount that is capable of alleviating, in whole or in part, the symptoms associated with a disorder or disease, or slowing or halting the further progression or worsening of those symptoms, or preventing or providing prophylaxis for a disease or disorder (such as an inflammatory condition, immunological condition, cancer or metabolic condition) in a subject having or at risk of developing a disease disclosed herein.

[0107] In one embodiment, the effective amount of the compound of formula I is an amount that inhibits c-KIT kinase in cells, for example, in vitro or in vivo. In some embodiments, the effective amount of the compound of 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. The effective amount of the compound of formula I may be, for example, in a pharmaceutical composition, at a level that will exert a desired effect; for example, in a unit dosage for both oral and parenteral administration, from about 0.005 mg / kg of subject's body weight to about 10 mg / kg of subject's body weight.

[0108] use The compounds are suitable as pharmaceutical active ingredients for mammals, particularly for humans, in the treatment of cancers such as gastrointestinal stromal tumors. The present invention encompasses the use of compounds of formula I and / or their pharma- ceutically acceptable salts, tautomers and stereoisomers 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 for treating a disease, wherein the disease is cancer, preferably a gastrointestinal stromal tumor. Especially 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 of formula I can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a patient with cancer for the purpose of treating the cancer.

[0110] The anti-cancer treatment defined above may be applied as a sole therapy or may be accompanied by conventional surgery or radiation therapy or drug therapy in addition to the compound of formula I disclosed herein. Such drug therapy, 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, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302 4 , VAL-083 4 etc;

[0112] platinum compound Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin, etc.;

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

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

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

[0116] Antimetabolites Asparaginase 3 , azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur2,3 , trimetrexate, etc.;

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

[0118] Hormones / antagonists Abarelix, abiraterone, bicalutamide, buserelin, calsterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, 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, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, rifapril Nifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifanib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib 4 , Cabozantinib S-malate 1,3 , ibrutinib 1,3 , Icotinib 4 , buparlisib 2 , cipatinib 4 , cobimetinib 1,3 , idelalisiv 1,3 , fedratinib 1 , XL-647 4 etc;

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

[0122] antibody Alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab 1,2,3 , Onartuzumab 1,3 , racotumomab 1 , tabalumab 1,3 , EMD-525797 4 , nivolumab 1,3 etc;

[0123] Cytokines Aldesleukin, interferon alpha 2 , interferon alpha 2a 3 , interferon alpha 2b 2,3 ; Celmoleukin, tasonermin, teseleukin, 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, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab 1,3 , Vintaforid 1,3 etc;

[0125] vaccine Sipuleucel 3; Bitespen 3 , emepepimut-S 3 , oncoVAX 4 , rindopepimut 3 , troVax 4 , MGN-1601 4 , MGN-1703 4 etc;

[0126] others Alitretinoin, bexarotene, bortezomib, everolimus, ibandronate, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronate, pegaspargase, pentostatin, sipuleucel 3 , sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinosta , peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, travedersen, ubenimex, valspodar, gendicine 4 , Picibanil 4 , reolysin 4 , Retaspimycin hydrochloride 1,3 , trebananib 2,3 , virulizin 4 , Carfilzomib 1,3 , endostatin 4 , Immucothel 4, belinstat 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: aq (aqueous), h (hours), g (grams), l (liters), mg (milligrams), MHz (megahertz), min. (minutes), mm (millimeters), mmol (millimolar), mM (millimolar), mp (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 (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d 6 (deuterated dimethylsulfoxide), 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 (high performance chromatography), UV (ultraviolet). Above and below, all temperatures are given in °C.

[0129] 1 H 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) were determined based on the residual solvent signal (DMSO-d 6 Inside, 1 Reported in ppm for 1 H NMR (δ=2.49 ppm). 1 H NMR data are reported as follows: chemical shift (multiplicity, coupling constants, 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 (quintet).

[0130] HPLC / MS Condition A: HPLC / MS:Agilent 1200 / 6100 Eluent A: Water + 0.05% formic acid Eluent B: Acetonitrile + 0.04% formic acid Column: Chromolith HR RP-18e; 50-4.6mm Flow rate: 3.3ml / min Gradient: 0%->100%B: 0.0->2.0 min | 100%B: 2.0->2.5 min UV detection: 220 nm MS detection: 65-800amu positive

[0131] HPLC / MS condition B: HPLC / MS:Agilent 1200 / 6100 Eluent A: Water + 0.05% formic acid Eluent B: Acetonitrile + 0.04% formic acid Column: Kinetex XB-C18; 2.6 μm; 50-4.6 mm Flow rate: 2.5ml / min Gradient: 0%->100%B: 0.0->1.4 min | 100%B: 1.4->2.0 min UV detection: 220 nm MS detection: 65-800amu positive

[0132] UPLC / MS conditions: UPLC / MS: Waters Acquity / SQD Eluent A: Water + 0.05% formic acid Eluent B: Acetonitrile + 0.04% formic acid Column: Kinetex XB-C18; 1.7 μm; 50-2.1 mm Flow rate: 0.9ml / min Gradient: 2%->100%B: 0.0->1.0 min | 100%B: 1.0->1.3 min UV detection: 220nm / 254nm / MaxPlot / TotalPlot MS detection: 61-800amu positive

[0133] Assay c-Kit(V654A) Assay: c-Kit(V654A) (recombinant human c-Kit N-terminally GST tagged, amino acid 544 end containing the V654A mutation) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYEFMGGKKK, 10 mM Mg 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 for 40 minutes at room temperature, 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 cellular testing of cKIT mutant inhibitors GIST430 / 654 cell line expressing mutated constitutively active cKIT receptor tyrosine kinase (Δ560-576 and V654A) was employed to assess the cellular efficacy of compounds. The cellular activity of mutant cKIT was determined by the degree of cKIT autophosphorylation at tyrosine 307 using a Luminex-based bead assay. GIST430 / 654 cells were plated at 25,000 cells per well of a 96-well plate in 100 μl medium (85% IMDM / 15% FCS supplemented with 100 nM imatinib). The following day, compounds were added in serial dilutions for 45 minutes. Cells were then lysed in 90 μl lysis buffer (20 mM Hepes pH 7.5, 200 mM NaCl, 1.5 mM MgCl2x6H2O, 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 lysates were cleared by centrifugation in 96-well filter plates (0.65 μm). Samples were incubated overnight at 4 °C with Luminex beads coupled with anti-total cKIT antibody under gentle agitation. For detection of phospho-Y307-cKIT, phospho-specific and species-specific PE-labeled secondary antibodies were added. The amount of phospho-Y307-cKIT was determined on a Luminex 200 instrument measuring 100 events per well within 60 seconds.

[0135] Counts from compound treated samples were calculated as a percentage of control 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 (IC 50 ) [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Description: 1,4E-06 is 1.4 x 10 -6 means

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

[0138] Table 2. Inhibition of c-KIT(V654A) and GIST 430 / 654 (IC) of some representative compounds represented by formula I compared to the corresponding triazole derivatives. 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 [ka] To a solution of 2-fluoro-4-hydroxybenzaldehyde (2.80 g, 20.0 mmol) in DMF (50 ml) is added potassium carbonate (8.29 g, 60 mmol) and the resulting slurry is stirred at 60° C. for 18 h. The reaction mixture is allowed to reach room temperature and treated with water and dichloromethane. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The residue is dried under high vacuum to give 2-fluoro-4-(2-methoxy-ethoxy)-benzaldehyde as a colorless oil; HPLC / MS 1.36 min (A), [M+H] + 199. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 7.78 (t, J = 8.6 Hz, 1H), 7.02 (dd, J = 13.0, 2.4 Hz, 1H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 4.29 - 4.19 (m, 2H), 3.74 - 3.63 (m, 2H), 3.31 (s, 3H).

[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. under stirring and maintained at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and diluted with water. Concentrated hydrochloric acid and 2N hydrochloric acid are then 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 H 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 [ka] Under nitrogen, potassium tert-butylate (6.43 g, 57.3 mmol) is added in portions to a solution of 5,6-difluoro-1H-indazole (2.94 g, 19.1 mmol) in ethylene glycol monomethyl ether (40 ml). The mixture is heated to 150° C. and stirred at this temperature for 5 days. The reaction mixture is allowed to reach room temperature and diluted with water (150 ml) and 1N hydrochloric acid (39 ml) to reach a pH value of about 6. The mixture is extracted twice with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane / ethyl acetate as eluent to give 5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole as an off-white solid; HPLC / MS 1.31 min (B), [M+H] + 211. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 7.93 (t, J = 1.3 Hz, 1H), 7.53 (d, J = 11.0 Hz, 1H), 7.12 (dd, J = 7.1, 1.0 Hz, 1H), 4.54 - 4.06 (m, 2H), 4.06 - 3.58 (m, 2H), 3.34 (s, 3H).

[0142] Alternative synthesis of 5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole [ka] In a nitrogen-flushed 10 l reactor equipped with cooling and heating jacket, 2-bromo-4,5-difluorobenzaldehyde (500 g, 2.26 mol) is dissolved in 2-methoxyethanol (4.5 l). Potassium tert-butylate (381 g, 3.39 mol) is added portionwise over a period of 1 h at a temperature of 20-25 ° C. The resulting solution is stirred for 16 h at a temperature of 18 ° C. The reaction mixture is quenched with water (2 l) and a saturated solution of citric acid in water (2 l). The mixture is treated with tert-butyl-methyl-ether (5 l) and the organic phase is separated. The organic phase is washed once with water and twice with brine and dried over sodium sulfate. The sodium sulfate is filtered off and the filtrate is evaporated to give 2-bromo-5-fluoro-4-(2-methoxy-ethoxy)-benzaldehyde as a light yellow partially crystalline oil which is used directly in the next step. A pure sample is obtained by chromatography on a silica gel column using dichloromethane / ethyl acetate as eluent; white crystalline solid; HPLC / MS 1.60 min (A), [M+H] + 277 / 279. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.05 (d, J = 3.0 Hz, 1H), 7.66 (d, J = 11.3 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 4.40 - 4.31 (m, 2H), 3.75 - 3.68 (m, 2H), 3.32 (s, 3H).

[0143] 4-Toluenesulfonohydrazide (377 g, 2.02 mol) is slurried in methanol (4 l) and the slurry is stirred at 60° C. for 30 min. Then 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 min and the reaction mixture is stirred at 60° C. for 18 h. The reaction mixture is cooled to 0° C. The precipitate is filtered off with suction, washed with methanol and dried under vacuum at 40° C. to give N-[(E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methyleneamino]-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]methyleneamino]-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 h. 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 h. The suspension is filtered and the filtrate is evaporated. The solid residue is crystallized from heptane (2 l) to give 5-fluoro-6-(2-methoxy-ethoxy)-1-(toluene-4-sulfonyl)-1H-indazole as yellow crystals; HPLC / MS 1.66 min (B), [M+H] + 365. 1H 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 with 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 similarly: [ka] 5-Fluoro-6-methoxy-1H-indazole; White crystalline solid; UPLC / MS 0.56 min, [M+H] + 167. 1 H NMR (700 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 7.94 (s, 1H), 7.54 (d, J = 11.1 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 3.91 (s, 3H).

[0147] [ka] 6-Ethoxy-5-fluoro-1H-indazole; White solid; UPLC / MS 0.61 min, [M+H] + 181. 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.87 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 11.1 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 6.9 Hz, 3H).

[0148] Synthesis of 5-chloro-6-(2-methoxy-ethoxy)-1H-indazole The compounds were synthesized according to the following synthetic scheme. [ka] Pale yellow crystalline solid; HPLC / MS 1.39 min (A), [M+H] + 227. 1 H NMR (300 MHz, chloroform-d 1 ) δ 10.19 (s, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.76 (s, 1H), 6.91 (s, 1H), 4.36 - 4.16 (m, 2H), 3.99 - 3.66 (m, 2H), 3.53 (s, 3H).

[0149] Synthesis of 6-(2-methoxy-ethoxy)-1H-indazole-5-carbonitrile The compounds were synthesized according to the following synthetic scheme. [ka] White crystalline solid; HPLC / MS 1.22 min (A), [M+H] + 281. 1H NMR (400 MHz, chloroform-d 1 ) δ 8.10 (s, 1H), 8.06 (s, 1H), 7.28 (s, 2H), 7.00 (s, 1H), 4.32 - 4.26 (m, 2H), 3.95 - 3.82 (m, 2H).

[0150] 3-Ethynyl-indazole Synthesis of 3-ethynyl-6-trifluoromethyl-1H-indazole [ka] To a solution of 6-trifluoromethylindazole (990 mg, 5.32 mmol) in DMF (200 ml) is added iodine (2.00 g, 7.88 mmol), followed by portionwise addition of potassium hydroxide pellets (1.20 g, 21.4 mmol) and the reaction mixture is stirred at room temperature. After 18 hours, the reaction mixture is poured into saturated aqueous sodium thiosulfate solution and the resulting mixture is extracted twice with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulfate. The sodium sulfate is filtered off and the residue is evaporated to give 3-iodo-6-trifluoromethyl-1H-indazole as a beige solid; UPLC / MS 0.80 min, [M+H] + 313. 1 H 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] To a suspension of 3-iodo-6-trifluoromethyl-1H-indazole (1.69 g, 5.43 mmol) in acetonitrile (100 ml) is added 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 solution and once with brine. The organic phase is dried over sodium sulfate and evaporated to give 3-iodo-6-trifluoromethyl-indazole-1-carboxylic acid tert-butyl ester 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 3-iodo-6-trifluoromethyl-indazole-1-carboxylic acid tert-butyl ester (1.87 g, 4.53 mmol) in 1,4-dioxane (45 ml) is flushed with nitrogen. 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 then added under nitrogen and the reaction mixture is stirred at 80° C. for 1 h in a sealed reaction vial. The reaction mixture is allowed to reach room temperature, absorbed onto Celite, and chromatographed on a silica gel column using cyclohexane / ethyl acetate as eluent to give 6-trifluoromethyl-3-trimethylsilanylethynyl-indazole-1-carboxylic acid tert-butyl ester as an off-white solid; UPLC / MS 1.12 min, [M- t Bu] + 327. 1H 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 6-trifluoromethyl-3-trimethylsilanylethynyl-indazole-1-carboxylic acid tert-butyl ester (1.60 g, 4.18 mmol) in ethanol (5 ml) is added potassium carbonate (120 mg, 0.87 mmol) and the reaction mixture is stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and evaporated to give 3-ethynyl-6-trifluoromethyl-1H-indazole as a light brown solid; UPLC / MS 0.75 min, [M+H] + 211. 1 H 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: [ka] 3-Ethynyl-6-(2-methoxy-ethoxy)-1H-indazole, off-white solid; UPLC / MS 0.63 min, [M+H] + 217. 1 H NMR (500 MHz, DMSO-d 6) δ 13.15 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.8, 2.1 Hz, 1H), 4.43 (s, 1H), 4.20 - 4.13 (m, 2H), 3.76 - 3.66 (m, 2H), 3.33 (s, 3H).

[0155] [ka] 6-Bromo-3-ethynyl-1H-indazole, light brown powder; UPLC / MS 0.75 min, [M+H] + 221,223. [ka]

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

[0157] [ka]

[0158] 3-Ethynyl-6-(2-methoxy-ethoxy)-1H-indazole-5-carbonitrile, light brown solid; HPLC / MS 1.85 min (A), [M+H] + 242. [ka] 3-Ethynyl-1H-indazole-6-carboxylic acid methyl ester, off-white solid; UPLC / MS 0.95 min, [M+H] + 201. [ka]

[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). [ka]

[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 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester [ka]

[0162] To a solution of 5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole (173 g, 822 mmol) in DMF (2.0 l) is added iodine (228 g, 905 mmol), followed by powdered potassium hydroxide (115 g, 2.57 mol) in small portions, and the reaction mixture is stirred at room temperature. After 18 h, the reaction mixture is poured into a mixture of cold water (12 l) and ethyl acetate (6 l). The phases are separated and the aqueous layer is extracted with ethyl acetate (2 l). The combined organic phases are washed with water (3 l), with aqueous sodium thiosulfate solution (3 l), and three times with water (2 l). The organic layer is dried over sodium sulfate, filtered, and concentrated. The resulting slurry is treated with heptane (2 l). Filter off the solid and dry under vacuum to give 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-1H-indazole as a beige 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, 150 mmol). Di-tert-butyl dicarbonate (238 ml, 1.11 mol) is then 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 give 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester 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] To a suspension of 5-fluoro-3-iodo-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (297 g, 680 mmol) and bis(triphenylphosphine)palladium(II) chloride (14.2 g, 20.3 mmol) in triethylamine (2 l) under nitrogen, trimethylsilylacetylene (112 ml, 810 mmol) is added 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 five times with water (5 l each) and with brine (4 l). The organic layer is dried over sodium sulfate and evaporated to give 5-fluoro-6-(2-methoxy-ethoxy)-3-trimethylsilanylethynyl-indazole-1-carboxylic acid tert-butyl ester 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] To a solution of 5-fluoro-6-(2-methoxy-ethoxy)-3-trimethylsilanylethynyl-indazole-1-carboxylic acid tert-butyl ester (273 g, 671 mmol) in ethanol (1.5 l) is added potassium carbonate (18.6 g, 143 mmol) and the reaction mixture is stirred at 30° C. for 3 h. The reaction mixture is poured into cold water and the solid is filtered off and washed with water. The solid is dissolved in dichloromethane (3 l) and filtered through silica gel (3 kg) using dichloromethane and tert-butyl methyl ether as eluents. The eluate is concentrated under reduced pressure and crystallized from heptane (300 ml) to give 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester 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: [ka] tert-Butyl 6-ethoxy-3-ethynyl-5-fluoro-1H-indazole-1-carboxylate; Off-white solid; UPLC / MS 0.93 min, [M- t Bu] + 249. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.71 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 10.0 Hz, 1H), 4.81 (s, 1H), 4.23 (q, J = 7.0 Hz, 2H), 1.65 (s, 8H), 1.43 (t, J = 6.9 Hz, 3H).

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

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

[0169] Carboxylic Acid Synthesis of 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid methyl ester [ka] A suspension of 3-ethynyl-6-trifluoromethyl-1H-indazole (166 mg, 0.79 mmol) and methyl 4-[(Z)-C-chloro-N-hydroxy-carbonimidoyl]benzoate (187 mg, 0.88 mmol) in a mixture of tert-butanol (1.2 ml) and THF (0.4 ml) is flushed with nitrogen. Under nitrogen, copper(I) iodide (13 mg, 0.068 mmol) is added and the suspension is stirred at room temperature for 5 min. Potassium bicarbonate (80 mg, 0.80 mmol) is then added and the reaction mixture is stirred at room temperature for 3 days. The reaction mixture is treated with water. The resulting solid is filtered off, washed with water and air-dried. The residue is triturated with ethyl acetate and dried under vacuum to give 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid methyl ester as an off-white solid; UPLC / MS 0.93 min, [M+H] + 388. 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.30 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 1.9 Hz, 1H), 7.89 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H).

[0170] To a solution of 4-[5-(6-trifluoromethyl-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid methyl ester (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 h and at room temperature for 16 h. 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 H 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: [ka] 4-{5-[6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid, brown solid; HPLC / MS 1.52 min (A), [M+H] + 380.

[0172] [ka] 4-[5-(6-Bromo-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid, brown solid; UPLC / MS 0.82 min, [M+H] + 384 / 386. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.99 (s, 1H), 13.1 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 7.50 (dd, J = 8.7, 1.6 Hz, 1H).

[0173] [ka] 4-{5-[5-cyano-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-benzoic acid, off-white solid; HPLC / MS 2.04 min (A), [M+H] + 405.

[0174] [ka] 4-{5-[5-chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid, brown solid; HPLC / MS 1.05 min, [M+H] + 414.

[0175] [ka] 4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-benzoic acid, brown solid; UPLC / MS 0.75 min, [M+H] + 354.

[0176] [ka] 6-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-nicotinic acid, brown solid; HPLC / MS 2.52 min (A), [M+H] + 399.

[0177] [ka] 2-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-thiazole-5-carboxylic acid, brown solid; HPLC / MS 2.57 min (A), [M+H] + 405.

[0178] [ka] 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 [ka] To a solution of 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (205 g, 614 mmol) and 4-(hydroxyimino-methyl)-benzoic acid methyl ester in dichloromethane (2.6 l) is added dropwise an aqueous solution of sodium hypochlorite (content ca. 12%, 944 ml, ca. 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 give 5-fluoro-3-[3-(4-methoxycarbonyl-phenyl)-isoxazol-5-yl]-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester 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 5-fluoro-3-[3-(4-methoxycarbonyl-phenyl)-isoxazol-5-yl]-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (339 g, 662 mmol) in THF (3.36 l) is slowly added 2 M aqueous sodium hydroxide solution (1.33 l, 2.65 mol) via a dropping funnel and the reaction mixture is stirred at 60° C. for 5 h. The reaction mixture is cooled to room temperature and the organic solvents are evaporated under vacuum. The resulting suspension is diluted with ice water (3 l). Under continuous stirring, the pH value of the suspension is adjusted from pH 11 to pH 2 using 2.5 N hydrochloric acid. The solid is filtered off and washed with water (3 times 600 ml) and tert-butyl methyl ether (300 ml). The solid is dried under reduced pressure at 45° C. for several days to give 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 similarly: [ka] 5-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridine-2-carboxylic acid, yellow solid; HPLC / MS 2.51 min (A), [M+H] + 399.

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

[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 1M solution of boron tribromide (1.2 ml). The reaction mixture is stirred at room temperature for 16 hours. 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") [ka] 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 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 similarly: 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") [ka] Off-white solid; HPLC / MS 1.60 min (A), [M+H] + 491. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.57 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H), 8.08 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.70 (s, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.9, 2.1 Hz, 1H), 4.88 (s, 1H), 4.31 (t, J = 7.2 Hz, 1H), 4.24 - 4.19 (m, 2H), 3.76 - 3.70 (m, 2H), 3.56 - 3.48 (m, 1H), 3.41 - 3.33 (m, 4H), 2.00 - 1.81 (m, 3H), 1.68 - 1.54 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H).

[0186] 3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ("A3") [ka] 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") [ka] 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") [ka] 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") [ka] 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") [ka] Off-white solid; UPLC / MS 0.54 min, [M+H] + 480 / 482. 1 H 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") [ka] 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") [ka] 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") [ka]

[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") [ka] Off-white solid; UPLC / MS 0.70 min, [M+H] + 481. 1 H NMR (400 MHz, DMSO-d 6 , rotamers) δ 13.72 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.80 (broad, 1H), 4.34 - 4.22 (m, 2H), 4.18 (broad, 1H), 3.80 - 3.69 (m, 2H), 3.69 - 3.41 (m, 4H), 3.36 (s, 3H), 2.03 -1.66 (m;6H).

[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") [ka] Off-white solid; UPLC / MS 0.70 min, [M+H] + 481. 1 H NMR (400 MHz, DMSO-d 6 , rotamers) δ 13.72 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.80 (broad, 1H), 4.34 - 4.22 (m, 2H), 4.18 (broad, 1H), 3.80 - 3.69 (m, 2H), 3.69 - 3.41 (m, 4H), 3.36 (s, 3H), 2.03 -1.66 (m;6H).

[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") [ka] White crystal; HPLC / MS 1.33 min (A), [M+H] + 522. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 11.0 Hz, 1H), 7.83 - 7.79 (m, 2H), 7.76 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.36 (t, J = 8.1 Hz, 1H), 4.32 - 4.28 (m, 2H), 4.19 (dd, J = 9.2, 4.9 Hz, 1H), 4.14 - 4.06 (m, 1H), 3.92 (dd, J = 10.9, 4.4 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.60 (t, J = 4.7 Hz, 4H), 3.36 (s, 3H), 3.18 (tt, J = 7.2, 5.0 Hz, 1H), 2.34 (broad, 4H).

[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") [ka] Light brown solid; HPLC / MS 1.22 min (A), [M+H] + 510. 1 H NMR (500 MHz, DMSO-d 6 , rotamer, signal selection) δ 13.72 (s, 1H), 8.08 (d, J = 7.9 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 4.83 (s, 1H), 4.31- 4.28 (m, 2H), 3.96 - 3.56 (m, 5H), 3.35 (s, 3H), 2.16 (s, 3H).

[0198] 5-Fluoro-3-(3-{4-[(2R)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole ("A55") [ka] White solid; UPLC / MS 0.73 min, [M+H] + 543. 1 H NMR (500 MHz, DMSO-d 6) δ 13.73 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 10.9 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.62 - 4.51 (m, 1H), 4.35 - 4.24 (m, 2H), 3.83 - 3.71 (m, 3H), 3.53 (dt, J = 10.1, 7.0 Hz, 1H), 3.42 - 3.29 (m, 5H), 3.11 (s, 3H), 2.20 (dq, J = 13.9, 7.1 Hz, 1H), 2.05 (dq, J = 12.5, 6.4 Hz, 1H), 1.96 (dp, J = 13.1, 6.6 Hz, 1H), 1.86 - 1.75 (m, 1H).

[0199] 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methylazetidin-3-amine ("A56") [ka] Trifluoroacetate; white solid; HPLC / MS 2.24 min (A), [M+H] + 465. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 8.28 (s, 3H), 8.15 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.80 (s, 1H), 7.29 (d, J = 7.1 Hz, 1H), 4.43 (d, J = 9.5 Hz, 1H), 4.36 - 4.26 (m, 3H), 4.17 (d, J = 10.8 Hz, 1H), 4.02 (d, J = 10.8 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.35 (s, 3H), 1.58 (s, 3H).

[0200] 4-[1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-3-yl]-1lambda 6-thiomorpholine-1,1-dione ("A57") [ka] White powder; UPLC / MS 0.68 min, [M+H] + 570. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.40 (t, J = 8.1 Hz, 1H), 4.32 - 4.25 (m, 2H), 4.20 (dd, J = 9.2, 5.0 Hz, 1H), 4.13 (dd, J = 10.3, 7.3 Hz, 1H), 3.92 (dd, J = 10.5, 5.0 Hz, 1H), 3.81 - 3.74 (m, 2H), 3.48 (tt, J = 7.2, 5.0 Hz, 1H), 3.35 (s, 3H), 3.13 (t, J = 5.2 Hz, 4H), 2.88 - 2.76 (m, 4H).

[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") [ka] White solid; HPLC / MS 1.59 min (A), [M+H] + 495. 1 H NMR (500 MHz, DMSO-d 6) δ 13.74 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.79 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 5.02 (s, 1H), 4.40 (dd, J = 9.2, 5.6 Hz, 1H), 4.35 - 4.22 (m, 3H), 3.99 (td, J = 8.9, 5.5 Hz, 1H), 3.83 - 3.71 (m, 2H), 3.36 (s, 3H), 2.30 (qd, J = 9.8, 6.3 Hz, 1H), 2.13 (ddt, J = 11.1, 9.0, 5.6 Hz, 1H), 1.16 (s, 3H), 1.15 (s, 3H).

[0202] 2-[(2S)-1-(4-{5-[5-フルオロ-6-(2-メトキシエトキシ)-1H-インダゾール-3-イル]-1,2-オキサゾール-3-イル}ベンゾイル)アゼチジン-2-イル]プロパン-2-オール(「A59」)

change

[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") [ka] Off-white solid; UPLC / MS 0.72 min, [M+H] + 507. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.36 (s, 4H), 4.33 - 4.28 (m, 2H), 3.80 - 3.72 (m, 2H), 3.55 (bs, 2H), 3.37 (s, 3H), 3.30 (bs, 2H), 1.84 (bs, 4H).

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

[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") [ka]

[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") [ka]

[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") [ka] White solid; mp 200~201℃, [M+H] + 538. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.78 (s, 1H), 8.32 (s, 1H), 8.16-8.09 (m, 2H), 7.88-7.79 (m, 3H), 7.26 (s, 1H), 4.41-4.34 (m, 1H), 4.33-4.27 (m, 2H), 4.24-4.16 (m, 1H), 4.15-4.05 (m, 1H), 3.96-3.88 (m, 1H), 3.82-3.70 (m, 2H), 3.66-3.52 (m, 4H), 3.38 (s, 3H), 3.23-3.13 (m, 1H), 2.43-2.25 (m, 4H).

[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") [ka]

[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") [ka] White solid; mp 115~116℃, [M+H] + 513. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O) δ 8.39-8.28 (m, 1H), 8.16 -8.01 (m, 2H), 7.95-7.78 (m, 1H), 7.66-7.55 (m, 2H), 7.28 (s, 1H), 4.35-4.25 (m, 2H), 4.22-3.86 (m, 2H), 3.86-3.79 (m, 2H), 3.76-3.45 (m, 6H), 3.39-3.32 (m, 3H), 3.31-2.72 (m, 1H).

[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") [ka]

[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") [ka]

[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") [ka]

[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") [ka]

[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") [ka]

[0215] 3-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-N,N-dimethyl-benzamide ("A135") [ka] White solid; mp160~165℃, [M+H] + 424. 1 H NMR (400 MHz, DMSO-d 6): δ 13.73 (s, 1H), 8.14- 8.05 (m, 3H), 7.83 (s, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.56 (dt, J = 7.7, 1.4 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.30 (dd, J = 5.6, 3.3 Hz, 2H), 3.79- 3.72 (m, 2H), 3.01 (d, J = 31.0 Hz, 6H).

[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") [ka] A microwave vial is charged with {4-[5-(6-bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-[(R)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone (74 mg, 0.15 mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (47 mg, 0.23 mmol), cesium fluoride (69 mg, 0.45 mmol), bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.016 mmol), dioxane (800 μl) and water (400 μl). The vial is flushed with nitrogen and heated to 120° C. for 1 h in a microwave reactor. Water is added to the reaction mixture. The solid is filtered off and washed with water. The residue is chromatographed on a silica gel column with ethyl acetate / methanol to give 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 as a white powder; UPLC / MS 0.75 min, [M+H] + 497. 1 H NMR (400 MHz, DMSO-d6 ) δ 13.76 (s, 1H), 8.31 (s, 1H), 8.20 (dd, J = 8.5, 0.8 Hz, 1H), 8.13 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 0.8 Hz, 1H), 7.78 (t, J = 1.1 Hz, 1H), 7.77 - 7.71 (m, 3H), 7.59 (dd, J = 8.5, 1.4 Hz, 1H), 4.89 (s, 1H), 4.32 (t, J = 7.2 Hz, 1H), 3.91 (s, 3H), 3.54 (q, J = 9.3, 8.7 Hz, 1H), 3.39 (t, J = 9.2 Hz, 1H), 2.02 - 1.81 (m, 3H), 1.69 - 1.57 (m, 1H), 1.18 (s, 3H), 1.15 (s, 3H).

[0217] The following compounds are prepared similarly: 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") [ka] Pale yellow solid; UPLC / MS 0.50 min (A), [M+H] + 482. 1 H NMR (500 MHz, DMSO-d 6) δ 13.76 (s, 1H), 8.31 (s, 1H), 8.19 (dd, J = 8.5, 0.8 Hz, 1H), 8.12 (d, J = 8.2 Hz, 2H), 8.02 (d, J = 0.8 Hz, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.59 (dd, J = 8.5, 1.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 3.91 (s, 3H), 3.30 (s, 3H), 3.3 - 3.1 (broad, 1H), 2.81 - 2.71 (broad, 1H), 2.68 - 2.58 (m, 0H), 2.18 (s, 1H), 2.07 (dd, J = 11.4, 4.0 Hz, 1H), 1.97 - 1.81 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H).

[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") [ka] Brown solid; UPLC / MS 0.91 min, [M+H] + 510. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.62 (s, 1H), 8.17 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.25 (s, 1H), 4.32 - 4.26 (m, 2H), 3.81 - 3.74 (m, 2H), 3.38 (s, 3H), 3.40 - 3.10 (m, 3H), 2.75 (broad, 1H), 2.64 (broad, 1H), 2.18 (s, 3H), 2.06 (d, J = 11.4 Hz, 1H), 1.92 - 1.82 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H).

[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") [ka] Brown solid; HPLC / MS 2.21 min (A), [M+H] + 501. 1 H 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, 3H), 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") [ka] To 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), bis(trifluoroacetoxy)-iodobenzene (224 mg, 0.52 mmol) is added in four portions every 2 hours 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") [ka] Light brown solid; UPLC / MS 0.99 min, [M+H] + 385. 1H NMR (700 MHz, DMSO-d6) δ 13.74 (s, 1H), 9.10 (d, J = 2.3 Hz, 1H), 8.30 -8.27 (m, 2H), 7.82 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 4.32 - 4.27 (m, 2H), 3.80 - 3.76 (m, 2H).

[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") [ka] Off-white solid; HPLC / MS 2.73 min (A), [M+H] + 437. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 9.44 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 7.84 (s, 1H), 7.25 (s, 1H), 4.30 (dd, J = 5.5, 3.5 Hz, 2H), 3.80 - 3.74 (m, 2H), 3.38 (s, 3H).

[0223] 5-Chloro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole ("A15") [ka] Off-white solid; HPLC / MS 2.61 min (A), [M+H] + 448. 1 H NMR (500 MHz, DMSO-d 6) δ 13.77 (s, 1H), 8.36 - 8.29 (m, 3H), 8.12 (d, J = 8.4 Hz, 2H), 7.91 (s, 1H), 7.26 (s, 1H), 4.34 - 4.28 (m, 2H), 3.81 - 3.75 (m, 2H), 3.38 (s, 3H), 3.30 (s, 3H).

[0224] 5-Fluoro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole ("A16") [ka] Off-white solid; HPLC / MS 2.52 min (A), [M+H] + 432. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.86 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.37 - 4.17 (m, 2H), 3.89 - 3.69 (m, 2H), 3.36 (s, 3H), 3.30 (s, 3H).

[0225] N-(4-{5-[5-chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)acetamide ("A17") [ka] Off-white solid; HPLC / MS 2.56 min (A), [M+H] + 427. 1 H NMR (500 MHz, DMSO-d 6) δ 13.70 (s, 1H), 10.17 (s, 1H), 8.28 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.68 (s, 1H), 7.24 (s, 1H), 4.32 - 4.23 (m, 2H), 3.83 - 3.74 (m, 2H), 3.38 (s, 3H), 2.09 (s, 3H).

[0226] N-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)acetamide ("A18") [ka] Off-white solid; HPLC / MS 2.43 min (A), [M+H] + 411. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.67 (s, 1H), 10.16 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 7.26 (d, J = 7.1 Hz, 1H), 4.33 - 4.18 (m, 2H), 3.80 - 3.70 (m, 2H), 3.35 (s, 3H), 2.09 (s, 3H).

[0227] Methyl 3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole-6-carboxylate ("A19") [ka] Off-white solid; UPLC / MS 1.01 min, [MH] - 389. 1 H NMR (700 MHz, DMSO-d 6) δ 14.20 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.90 (dd, J = 8.5, 1.3 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 3.94 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H).

[0228] 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide ("A20") [ka] Off-white solid; HPLC / MS 2.47 min (A), [M+H] + 425. 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), 7.58 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.40 - 4.17 (m, 2H), 3.85 - 3.68 (m, 2H), 3.36 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H).

[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") [ka] Off-white solid; UPLC / MS 1.04 min, [M+H] + 421. 1 H NMR (500 MHz, DMSO-d 6) δ 13.73 (s, 1H), 9.44 (s, 1H), 8.31 (s, 1H), 8.23 ​​(d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 10.9 Hz, 1H), 7.81 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.34 - 4.24 (m, 2H), 3.79 - 3.73 (m, 2H), 3.36 (s, 3H).

[0230] 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol-5-yl]-1H-indazole ("A22") [ka] White solid; HPLC / MS 2.08 min (A), [M+H] + 425. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 9.10 (d, J = 2.2 Hz, 1H), 8.29 (dd, J = 8.0, 2.3 Hz, 1H), 8.01 (d, J = 10.9 Hz, 1H), 7.78 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.31 - 4.25 (m, 2H), 3.80 - 3.69 (m, 2H), 3.35 (s, 3H).

[0231] (4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)(imino)methyl-lambda 6-sulfanone ("A226") [ka]

[0232] Example 5 N-(2-methoxyethyl)-3-(3-{4-[(2-methoxyethyl)carbamoyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole-6-carboxamide ("A23") [ka] White powder; UPLC / MS 0.85 min, [MH] - 374. 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.0 (broad, 1H) 8.27 (d, J = 8.6 Hz, 1H), 8.22 - 8.17 (m, 2H), 8.11 (d, J = 8.3 Hz, 2H), 7.84 (dd, J = 8.6, 1.3 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.50 (s, 1H), 3.02 (s, 3H), 2.96 (s, 3H).

[0233] The following compounds are prepared similarly: 3-[3-(4-Dimethylcarbamoyl-phenyl)-isoxazol-5-yl]-1H-indazole-6-carboxylic acid methylamide ("A24") [ka] White solid; HPLC / MS 2.16 min (A), [M+H] + 390. 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.1 (broad, 1H), 8.65 (q, J = 4.4 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.80 (dd, J = 8.6, 1.4 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 3.02 (s, 3H), 2.96 (s, 3H), 2.85 (d, J = 4.5 Hz, 3H).

[0234] 3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-N-(2-methoxyethyl)-1H-indazole-6-carboxamide ("A25") [ka] White solid; HPLC / MS 2.21 min (A), [M+H] + 434. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.9 (broad, 1H), 8.75 (t, J = 5.1 Hz, 1H), 8.29 (dd, J = 8.6, 0.9 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.82 (dd, J = 8.6, 1.4 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 3.56 - 3.44 (m, 4H), 3.30 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H).

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

[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) is added 3-fluoroazetidine hydrochloride (8.42 mg, 0.08 mmol), 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 hours. The reaction mixture is concentrated under vacuum and the residue is chromatographed on a silica gel column with ethyl acetate / methanol as eluent to give (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") [ka] White solid; HPLC / MS 2.52 min (A), [M+H] + 469. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.14 - 8.08 (m, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.77 (s, 1H), 7.78 - 7.67 (m, 2H), 7.28 (d, J = 7.0 Hz, 1H), 5.49 - 5.24 (m, 1H), 4.33 - 4.24 (m, 2H), 3.91 - 3.47 (m, 6H), 3.36 (s, 3H), 2.29 - 1.96 (m, 2H).

[0238] 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidine-3-carbonitrile ("A28") [ka] White solid; HPLC / MS 2.45 min (A), [M+H] + 462. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.12 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.80 (s, 1H), 7.28 (d, J = 6.9 Hz, 1H), 4.64 (broad, 1H), 4.57 (broad, 1H), 4.39 (broad, 1H), 4.33 - 4.26 (m, 2H), 4.22 (broad, 1H), 3.88 (tt, J = 9.3, 6.3 Hz, 1H), 3.78 - 3.71 (m, 2H), 3.35 (s, 3H).

[0239] 5-Fluoro-3-{3-[4-(3-methanesulfonylazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole ("A29") [ka] Off-white solid; HPLC / MS 2.38 min (A), [M+H] + 515. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 10.9 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.80 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 4.75 - 4.64 (m, 1H), 4.54 - 4.49 (m, 1H), 4.40 - 4.35 (m, 2H), 4.32 - 4.25 (m, 3H), 3.79 - 3.72 (m, 2H), 3.35 (s, 3H), 3.08 (s, 3H).

[0240] 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1 lambda 6-thiomorpholine-1,1-dione ("A30") [ka] White solid; HPLC / MS 2.55 min (A), [M+H] + 515. 1 H NMR (500 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.33 - 4.24 (m, 2H), 4.04 (broad, 2H), 3.80 - 3.74 (m, 2H), 3.73 (broad, 2H), 3.36 (s, 3H), 3.29 (broad, 4H).

[0241] N-Cyclopropyl-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-methylbenzamide ("A31") [ka] White solid; HPLC / MS 2.61 min (A), [M+H] + 451. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 11.0 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.35 - 4.25 (m, 2H), 3.85 - 3.69 (m, 2H), 3.36 (s, 3H), 3.05 -2.93 (m, 4H), 0.63 - 0.40 (m, 4H).

[0242] 5-Fluoro-3-(3-{4-[(3S)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole ("A32") [ka] White solid; HPLC / MS 2.53 min (A), [M+H] +469. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.14 - 8.08 (m, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.77 (s, 1H), 7.78 - 7.67 (m, 2H), 7.28 (d, J = 7.0 Hz, 1H), 5.49 - 5.24 (m, 1H), 4.33 - 4.24 (m, 2H), 3.91 - 3.47 (m, 6H), 3.36 (s, 3H), 2.29 - 1.96 (m, 2H).

[0243] 5-Fluoro-3-{3-[4-(3-methoxyazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole ("A33") [ka] White solid; HPLC / MS 2.51 min (A), [M+H] + 467. 1H NMR (500 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 11.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.29 (d, J = 7.1 Hz, 1H), 4.55 - 4.45 (m, 0.5), 4.41 - 4.24 (m, 3.5H), 4.23 - 4.18 (m, 0.5H), 3.92 - 3.85 (m, 0.5H), 3.83 - 3.61 (m, 2H), 3.36 (s, 3H), 3.25 (s, 3H).

[0244] 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methylazetidin-3-ol ("A34") [ka] White solid; HPLC / MS 2.38 min (A), [M+H] + 467. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 8.12 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 10.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.79 (s, 1H), 5.71 (s, 1H), 4.30 (dd, J = 5.5, 3.4 Hz, 2H), 4.21 (d, J = 8.7 Hz, 1H), 4.16 (d, J = 8.8 Hz, 1H), 3.95 (d, J = 10.0 Hz, 1H), 3.92 (d, J = 10.1 Hz, 1H), 3.78 - 3.74 (m, 2H), 3.36 (s, 3H), 1.42 (s, 3H).

[0245] N-[Dimethyl(oxo)-lambda 6-sulfanylidene]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide ("A35") [ka] White solid; HPLC / MS 2.49 min (A), [M+H] + 473. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 10.9 Hz, 1H), 7.80 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 4.35 - 4.28 (m, 2H), 3.88 - 3.72 (m, 2H), 3.51 (s, 6H), 3.36 (s, 3H).

[0246] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole ("A36") trifluoroacetate [ka] White solid; HPLC / MS 2.19 min (A), [M+H] + 480. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 9.76 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.30 (s, 1H), 4.58 (broad, 1H), 4.33 - 4.29 (m, 2H), 3.80 (broad, 1H), 3.81 - 3.70 (m, 2H), 3,43 (broad, 4H) 3.36 (s, 3H), 3.13 (broad, 2H), 2.85 (s, 3H).

[0247] N-[2-(dimethylamino)ethyl]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide ("A72") [ka] Trifluoroacetate; white solid; HPLC / MS 2.24 min (A), [M+H] + 468. 1 H NMR (500 MHz, DMSO-d 6) δ 13.75 (s, 1H), 9.30 (s, 1H), 8.84 (t, J = 5.7 Hz, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.08 - 8.00 (m, 3H), 7.81 (s, 1H), 7.29 (d, J = 7.1 Hz, 1H), 4.33 - 4.16 (m, 2H), 3.80 - 3.74 (m, 2H), 3.65 (q, J = 5.9 Hz, 2H), 3.31 (q, J = 5.9 Hz, 2H), 2.88 (d, J = 4.7 Hz, 6H).

[0248] 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-(1-methylazetidin-3-yl)benzamide ("A73") [ka] Trifluoroacetate; White solid; UPLC / MS 0.86 min; [M+H] + 466. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 9.67 (s, 1H), 9.20 (d, J = 6.8 Hz, 1H), 8.23 ​​- 8.13 (m, 2H), 8.11 - 8.00 (m, 3H), 7.80 (s, 1H), 7.30 (d, J = 7.1 Hz, 1H), 4.92 - 4.72 (m, 1H), 4.59 -4.39 (m, 2H), 4.35 - 4.26 (m, 2H), 4.25 - 4.04 (m, H), 3.82 - 3.72 (m, 2H), 3.36 (s, 3H), 2.93 (s, 3H).

[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") [ka] White solid; HPLC / MS 2.55 min (A), [M+H] + 479. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 10.8 Hz, 1H), 7.81 - 7.78 (m, 3H), 7.29 (d, J = 7.0 Hz, 1H), 4.73 - 4.68 (m, 4H), 4.54 (s, 2H), 4.37 - 4.28 (m, 2H), 4.26 (s, 2H), 3.82 - 3.69 (m, 2H), 3.36 (s, 3H).

[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") [ka] White solid; HPLC / MS 2.62 min (A), [M+H] + 503. 1 H NMR (400 MHz, DMSO-d 6) δ 13.7 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.60 (d, J = 1.8 Hz, 0H), 7.29 (d, J = 7.1 Hz, 1H), 6.33 (t, J = 2.1 Hz, 1H), 5.38 (tt, J = 8.2, 5.4 Hz, 1H), 4.82 (t, J = 7.9 Hz, 1H), 4.70 - 4.63 (m, 1H), 4.58 (t, J = 9.1 Hz, 1H), 4.40 - 4.32 (m, 1H), 4.33 - 4.22 (m, 2H), 3.81 - 3.69 (m, 2H), 3.37 (s, 3H).

[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") [ka] Trifluoroacetate; white solid; UPLC / MS 0.84 min, [M+H] + 480. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.75 (s, 1H), 10.28 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.8 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.80 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 4.65 (t, J = 9.4 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.37 - 4.23 (m, 4H), 4.17 - 4.05 (m, 1H), 3.79 - 3.73 (m, 2H), 3.35 (s, 3H), 2.88 - 2.73 (m, 6H).

[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") [ka] Colorless resin; HPLC / MS 2.63 min (A), [M+H] + 493. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 4.38 - 4.32 (m, 2H), 4.32 - 4.27 (m, 2H), 4.09 - 4.03 (m, 2H), 3.86 - 3.66 (m, 6H), 3.36 (s, 3H), 2.15 (td, J = 7.0, 2.5 Hz, 2H).

[0253] 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1 lambda 4-thiomorpholin-1-one ("A78") [ka] Colorless resin; HPLC / MS 2.38 min (A), [M+H] + 499. 1 H NMR (500 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.77 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.37 (broad, 1H), 4.33 - 4.27 (m, 2H), 3.87 (broad, 1H), 3.79 - 3.73 (m, 3H), 3.58 (broad, 1H), 3.36 (s, 3H), 3.00 (td, J = 12.8, 11.6, 3.5 Hz, 2H), 2.94 - 2.67 (m, 2H).

[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") [ka] Colorless resin; HPLC / MS 2.61 min (A), [M+H] + 479. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.62 - 4.23 (m, 7H), 4.22 - 4.04 (m, 1H), 3.80 - 3.73 (m, 2H), 3.36 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H).

[0255] 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1-imino-1 lambda 6-thiomorpholin-1-one ("A80") [ka] White solid; HPLC / MS 2.32 min (A), [M+H] + 514. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.13 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 4.39 (s, 1H), 4.31 - 4.24 (m, 2H), 4.12 - 3.12 (broad, 8H), 3.79 - 3.75 (m, 2H), 3.36 (s, 3H).

[0256] 5-Fluoro-3-{3-[5-(3-fluoroazetidine-1-carbonyl)pyridin-2-yl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole ("A81") [ka] White foam; HPLC / MS 2.56 min (A), [M+H] + 456. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.76 (s, 1H), 9.00 (dd, J = 2.2, 0.9 Hz, 1H), 8.26 (dd, J = 8.2, 2.2 Hz, 1H), 8.21 (dd, J = 8.2, 0.9 Hz, 1H), 7.99 (d, J = 10.8 Hz, 1H), 7.61 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 5.48 (dtt, J = 57.5, 6.3, 3.2 Hz, 1H), 4.80 - 4.38 (m, 3H), 4.33 - 4.27 (m, 2H), 4.16 (dd, J = 24.6, 12.1 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.36 (s, 3H).

[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") [ka] Trifluoroacetate, pale yellow foam; HPLC / MS 2.19 min (A), [M+H] + 523. 1 H NMR (700 MHz, DMSO-d 6 , partially very broad signals, selection of signals) δ 13.78 (s, 1H), 10.57 (s, 1H), 9.01 (s, 1H), 8.30 - 8.22 (m, 2H), 7.98 (d, J = 10.7 Hz, 1H), 7.61 (s, 1H), 7.30 (d, J = 7.0 Hz, 1H), 4.72 - 4.46 (m, 2H), 4.37 - 4.19 (m, 2H), 3.94 - 3.69 (m, 2H), 3.36 (s, 3H).

[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") [ka] Trifluoroacetate, white foam; HPLC / MS 2.23 min (A), [M+H] + 529. 1 H NMR (700 MHz, DMSO-d 6, partially very broad signals, selection of signals) δ 13.84 (s, 1H), 10.8 (s, 1H), 8.47 (s, 1H), 8.01 (d, J = 10.8 Hz, 1H), 7.65 (s, 1H), 7.29 (d, J = 6.9 Hz, 1H), 4.91 - 4.5 (m, 2H), 4.32 - 4.28 (m, 2H), 3.88 - 3.66 (m, 2H).

[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") [ka] Trifluoroacetate, white foam; HPLC / MS 2.33 min (A), [M+H] + 529. 1 H NMR (700 MHz, DMSO-d 6 , partially very broad signals, selection of signals) δ 13.86 (s, 1H), 10.53 (s, 1H), 8.63 (s, 1H), 7.96 (d, J = 10.7 Hz, 1H), 7.66 (s, 1H), 7.30 (d, J = 6.9 Hz, 1H), 5.07 - 4.66 (m, 2H), 4.36 - 4.23 (m, 2H), 3.85 - 3.73 (m, 2H).

[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") [ka] Trifluoroacetate, white foam; HPLC / MS 2.26 min (A), [M+H] + 503. 1 H NMR (700 MHz, DMSO-d 6 ) δ 14.53 (s, 1H), 13.75 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.12 (s, 1H), 8.04 (d, J = 10.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 5.44 (tt, J = 8.2, 5.3 Hz, 1H), 4.84 (t, J = 8.8 Hz, 1H), 4.76 (dd, J = 10.1, 5.3 Hz, 1H), 4.63 (t, J = 9.7 Hz, 1H), 4.36 (dd, J = 11.3, 5.2 Hz, 1H), 4.32 - 4.28 (m, 2H), 3.79 - 3.75 (m, 2H), 3.36 (s, 3H).

[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") [ka] White foam; HPLC / MS 2.66 min (A), [M+H] + 462. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.83 (s, 1H), 8.48 (s, 1H), 8.02 (d, J = 10.8 Hz, 1H), 7.65 (s, 1H), 7.30 (d, J = 7.0 Hz, 1H), 5.52 (dtt, J = 57.5, 6.2, 3.1 Hz, 1H), 4.87 (d, J = 20.1 Hz, 1H), 4.78 - 4.67 (m, 1H), 4.51 - 4.32 (m, 1H), 4.36 - 4.27 (m, 2H), 4.16 (dd, J = 24.5, 12.5 Hz, 1H), 3.82 - 3.69 (m, 2H), 3.36 (s, 3H).

[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") [ka] White foam; HPLC / MS 2.74 min (A), [M+H] + 462. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.85 (s, 1H), 8.59 (s, 1H), 8.03 (d, J = 10.7 Hz, 1H), 7.68 (s, 1H), 7.30 (d, J = 7.0 Hz, 1H), 5.51 (dtt, J = 57.8, 6.0, 3.1 Hz, 1H), 5.04 (dddd, J = 22.5, 12.0, 5.9, 1.9 Hz, 1H), 4.82 (ddt, J = 25.3, 12.4, 2.6 Hz, 1H), 4.45 (dddd, J = 21.6, 11.8, 6.0, 1.9 Hz, 1H), 4.34 - 4.26 (m, 2H), 4.15 (ddt, J = 24.8, 11.8, 2.3 Hz, 1H), 3.82 - 3.72 (m, 2H), 3.36 (s, 3H).

[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") [ka] Trifluoroacetate, white foam; HPLC / MS 2.24 min (A), [M+H] + 492. 1 H NMR (500 MHz, DMSO-d 6) δ 13.74 (s, 1H), 9.56 - 9.43 (m, 1H), 8.19 - 8.10 (m, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.81 - 7.76 (m, 3H), 7.29 (d, J = 7.1 Hz, 1H), 4.58 (s, 1H), 4.52 (s, 1H), 4.45 - 4.35 (m, 2H), 4.34 - 4.28 (m, 3H), 4.24 (s, 1H), 4.20 - 4.07 (m, 2H), 3.85 - 3.71 (m, 2H), 3.36 (s, 3H), 2.84 - 2.78 (m, 3H).

[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") [ka] UPLC / MS 0.65 min, [M+H] + 506.

[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") [ka] Off-white solid; HPLC / MS 1.53 min (A), [M+H] + 558. 1 H NMR (500 MHz, DMSO-d 6) δ 13.73 (s, 1H), 8.14 - 8.08 (m, 2H), 8.04 (d, J = 11.0 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 7.25 (t, J = 6.5 Hz, 1H), 4.34 - 4.28 (m, 2H), 4.27 - 4.21 (m, 1H), 3.80 - 3.74 (m, 2H), 3.50 (dt, J = 10.2, 6.9 Hz, 1H), 3.39 - 3.28 (m, 4H), 3.23 (dt, J = 12.9, 6.5 Hz, 1H), 2.94 (s, 3H), 2.81 - 2.69 (m, 3H), 2.07 - 1.84 (m, 3H), 1.81 - 1.66 (m, 1H).

[0266] 6-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylpyridine-3-carboxamide ("A91") [ka]

[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") [ka]

[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") [ka]

[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") [ka]

[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") [ka] Off-white solid; HPLC / MS 1.94 min (A), [M+H] + 467. 1 H NMR (700 MHz, DMSO-d 6 , rotamer, signal selection) δ 13.73 (s, 1H), 8.11 (d, J = 7.9 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.83 - 7.71 (m, 3H), 7.28 (d, J = 7.0 Hz, 1H), 5.02 - 4.84 (m, 1H), 4.57 - 4.46 (m, 1H), 4.37 - 4.25 (m, 3H), 4.10 (q, J = 8.1 Hz, 1H), 3.78 - 3.74 (m, 2H), 3.68 - 3.58 (m, 1H), 3.36 (s, 3H), 2.45 - 2.07 (m, 3H).

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

[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") [ka] Off-white solid; HPLC / MS 1.45 min (A), [M+H] + 467. 1 H NMR (700 MHz, DMSO-d 6 , rotamer, signal selection) δ 13.73 (s, 1H), 8.11 (d, J = 7.9 Hz, 2H), 8.03 (d, J = 10.9 Hz, 1H), 7.83 - 7.71 (m, 3H), 7.28 (d, J = 7.0 Hz, 1H), 5.02 - 4.84 (m, 1H), 4.57 - 4.46 (m, 1H), 4.37 - 4.25 (m, 3H), 4.10 (q, J = 8.1 Hz, 1H), 3.78 - 3.74 (m, 2H), 3.68 - 3.58 (m, 1H), 3.36 (s, 3H), 2.45 - 2.07 (m, 3H).

[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") [ka]

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

[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") [ka]

[0276] 5-Fluoro-3-[3-(4-{3-fluoro-[1,3'-biazetidine]-1'-carbonyl}phenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole ("A101") [ka]

[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") [ka]

[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") [ka]

[0279] 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole ("A104") [ka] White solid; UPLC / MS 0.72 min, [M+H] + 467. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.35 - 4.24 (m, 2H), 3.80 - 3.74 (m, 2H), 3.75 - 3.30 (broad, 8H), 3.36 (s, 3H).

[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") [ka]

[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") [ka] Off-white solid; HPLC / MS 1.42 min (A), [M+H] + 497. 1 H NMR (500 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.16 - 8.07 (m, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 4.93 (bs, 1H), 4.37 - 4.24 (m, 2H), 4.08 - 3.01 (broad, 11H), 3.36 (s, 3H).

[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") [ka] Off-white solid; mp 119~121℃, [M+H] + 510. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.78 (s, 1H), 9.26 (dd, J = 2.2, 0.9 Hz, 1H), 8.54 (dd, J = 8.2, 2.2 Hz, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.91-7.84 (m, 2H), 7.30 (d, J = 7.1 Hz, 1H), 5.05 (s, 1H), 4.34-4.27 (m, 3H), 3.80-3.74 (m, 2H), 3.63-3.48 (m, 2H), 3.36 (s, 3H), 1.98-1.87 (m, 3H), 1.69-1.62 (m, 1H), 1.17 (d, J = 5.8 Hz, 6H).

[0283] 6-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3 lambda 6-thia-6-azabicyclo[3.1.1]heptane-3,3-dione ("A108") [ka] Off-white solid; UPLC / MS 0.70 min, [M+H] + 527. 1H NMR (500 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.79 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 4.96 (bs, 1H), 4.73 (bs, 1H), 4.34 - 4.25 (m, 2H), 4.10 (bs, 1H), 3.83 - 3.71 (m, 3H), 3.36 (s, 3H), 3.02 (dt, J = 10.1, 7.0 Hz, 1H), 2.10 (d, J = 10.4 Hz, 1H), 1.24 (s, 1H).

[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") [ka]

[0285] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-(methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A110") [ka] Off-white solid; HPLC / MS 1.56 min (A), [M+H] + 511. 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), 7.59 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.35 - 4.23 (m, 2H), 4.18 - 3.05 (broad, 12H), 3.80 - 3.73 (m, 2H), 3.36 (s, 3H).

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

[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") [ka] White crystal; HPLC / MS 1.54 min (A), [M+H] + 479. 1 H NMR (700 MHz, DMSO-d 6) δ 13.72 (s, 1H), 8.12 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 10.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.79 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 5.39 (d, J = 6.6 Hz, 2H), 4.59 (d, J = 6.6 Hz, 2H), 4.37 - 4.27 (m, 2H), 4.17 (t, J = 7.5 Hz, 2H), 3.76 (dd, J = 3.9, 2.3 Hz, 2H), 3.35 (s, 3H), 2.57 (t, J = 7.5 Hz, 2H).

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

[0289] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A115") [ka] White solid; UPLC / MS 0.74 min, [M+H] + 481. 1 H NMR (400 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.12 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.49 - 4.19 (m, 2H), 3.90 - 3.74 (m, 3H), 3.69 - 3.56 (m, 2H), 3.51 - 3.38 (m, 1H), 3.37 (s, 3H), 1.29 (d, J = 6.9 Hz, 3H).

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

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

[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") [ka]

[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") [ka]

[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") [ka] White solid; UPLC / MS 0.54 min, [M+H] + 514. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.77 (s, 1H), 8.70 - 8.59 (m, 2H), 8.18 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 11.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.54 - 7.46 (m, 2H), 7.34 (d, J = 7.0 Hz, 1H), 4.80 (t, J = 8.9 Hz, 1H), 4.65 - 4.48 (m, 2H), 4.41 - 4.30 (m, 2H), 4.16 (t, J = 8.0 Hz, 2H), 4.12 - 4.01 (m, 1H), 3.84 - 3.76 (m, 2H), 3.41 (s, 3H).

[0295] 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methyl-1 lambda 6-thiomorpholine-1,1-dione ("A121") [ka] White solid; UPLC / MS 0.72 min, [M+H] + 529. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.38 - 4.22 (m, 2H), 3.85 - 3.71 (m, 2H), 3.65 - 3.08 (m, 7H), 3.36 (s, 3H), 1.44 (d, J = 7.1 Hz, 3H).

[0296] Example 7 5-Fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole ("A37") [ka] Off-white powder; HPLC / MS 1.68 min (A), [M+H] + 452. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.64 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.57 (s, 1H), 7.26 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.31 - 4.27 (m, 2H), 4.03 - 3.60 (m, 2H), 3.35 (s, 3H), 3.32 - 3.23 (broad, 4H), 2.50 - 2.44 (broad, 4H) 2.24 (s, 3H).

[0297] The following compounds are prepared similarly: 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1 lambda 6-thiomorpholine-1,1-dione ("A122") [ka] Pale yellow solid; HPLC / MS 2.06 min (A), [M+H] + 487. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.65 (s, 1H), 8.01 (d, J = 11.0 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.62 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.36 - 4.23 (m, 2H), 3.92 (t, J = 5.1 Hz, 4H), 3.82 - 3.69 (m, 2H), 3.36 (s, 3H), 3.25 - 3.11 (m, 4H).

[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") [ka] Off-white solid; HPLC / MS 1.31 min (A), [M+H] + 487. 1 H NMR (400 MHz, DMSO-d 6) δ 13.63 (s, 1H), 7.99 (d, J = 11.0 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.52 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 6.83 (d, J = 9.0 Hz, 2H), 4.36 - 4.26 (m, 2H), 3.81 - 3.73 (m, 2H), 3.64 - 3.57 (m, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.36 (s, 3H), 2.68 - 2.62 (m, 2H), 2.50 - 2.44 (m, 2H), 2.28 (s, 3H), 1.92 (p, J = 5.9 Hz, 2H).

[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") [ka]

[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") [ka]

[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") [ka]

[0302] 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1 lambda 4-thiomorpholin-1-one ("A127") [ka] Pale yellow solid; HPLC / MS 1.95 min (A), [M+H] + 471. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.64 (s, 1H), 8.01 (d, J = 11.0 Hz, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.60 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.23 - 7.03 (m, 2H), 4.36 - 4.15 (m, 2H), 3.92 (ddd, J = 12.9, 11.0, 2.1 Hz, 2H), 3.85 - 3.71 (m, 4H), 3.36 (s, 3H), 2.96 (ddd, J = 13.7, 10.7, 3.2 Hz, 2H), 2.78 - 2.65 (m, 2H).

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

[0304] 1-[(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)imino]-1lambda 6-thiomorpholin-1-one ("A129") [ka] Hydrochloride salt, off-white solid; HPLC / MS 1.29 min (A), [M+H]+ 486. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.68 (s, 1H), 9.38 (s, 2H), 8.00 (d, J = 11.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 4.40 - 4.28 (m, 2H), 3.96 - 3.40 (m, 10H), 3.36 (s, 3H).

[0305] Example 8 3-[3-(6-ethoxypyridin-3-yl)-1,2-oxazol-5-yl]-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ("A38") [ka] Off-white solid; UPLC / MS 0.68 min, [M+H] + 399. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 8.7, 2.5 Hz, 1H), 7.99 (d, J = 11.0 Hz, 1H), 7.71 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 4.36 - 4.27 (m, 2H), 3.83 - 3.73 (m, 2H), 3.36 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).

[0306] The following compounds are prepared similarly: 5-Fluoro-6-(2-methoxy-ethoxy)-3-[3-(6-methoxy-pyridin-3-yl)-isoxazol-5-yl]-1H-indazole ("A130") [ka] White solid;mp210 - 213℃;[M+H] + 385. 1 H NMR (400 MHz, DMSO-d 6 ) 13.73 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.73 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 4.30 (dd, J = 5.6, 3.4 Hz, 2H), 3.95 (s, 3H), 3.80-3.73 (m, 2H), 3.36 (s, 3H).

[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") [ka] Off-white powder; UPLC / MS 0.49 min, [M+H] + 453. 1 H NMR (500 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.75 (dd, J = 2.4, 0.7 Hz, 1H), 8.10 (dd, J = 9.0, 2.4 Hz, 1H), 7.64 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.36 - 4.02 (m, 2H), 3.84 - 3.69 (m, 2H), 3.71 - 3.52 (m, 4H), 3.36 (s, 3H), 2.44 - 2.39 (m, 4H), 2.24 (s, 3H).

[0308] The following compounds are prepared similarly: 4-(5-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridin-2-yl)-1 lambda 6-thiomorpholine-1,1-dione ("A131") [ka] Off-white solid; UPLC / MS 0.73 min, [M+H] + 488. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 8.9, 2.4 Hz, 1H), 7.99 (d, J = 10.9 Hz, 1H), 7.68 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 4.39 - 4.26 (m, 2H), 4.17 (t, J = 5.2 Hz, 4H), 3.89 - 3.65 (m, 2H), 3.36 (s, 3H), 3.18 (t, J = 5.2 Hz, 4H).

[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") [ka] Off-white powder; HPLC / MS 1.29 min (A), [M+H] + 483. 1 H NMR (500 MHz, DMSO-d 6) δ 13.69 (s, 1H), 8.01 (d, J = 11.0 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 4.33 - 4.27 (m, 2H), 4.21 (broad, 2H), 3.80 - 3.71 (m, 2H), 3.62 (broad, 4H), 3.35 (s, 3H), 2.74 (broad, 2H).

[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]-1lambda 6-thiomorpholine-1,1-dione ("A132") [ka] White powder; HPLC / MS 2.06 min (A), [M+H] + 531. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.66 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.63 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.32 - 4.24 (m, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.85 - 3.67 (m, 2H), 3.35 (s, 3H), 3.14 - 3.04 (m, 8H), 2.97 (t, J = 5.6 Hz, 2H).

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

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

[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 [ka] Off-white solid; HPLC / MS 1.54 min (A), [M+H] + 447. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.17 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 6.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 6.52 (d, J = 9.3 Hz, 1H), 6.36 (t, J = 6.8 Hz, 1H), 4.33 - 4.28 (m, 2H), 3.79 - 3.74 (m, 2H), 3.36 (s, 3H).

[0314] The following compounds are prepared similarly: 2-(4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-6-methyl-2H-pyridazin-3-one ("A136") [ka]

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

[0316] 2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1 lambda 6,2-thiazolidine-1,1-dione ("A138") [ka]

[0317] 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)morpholin-3-one ("A139") [ka] 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)-1 lambda 4-thiomorpholin-1-one ("A140") [ka] Off-white powder; HPLC / MS 1.43 min (A), [M+H] + 472. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.66 (s, 1H), 8.79 (dd, J = 2.4, 0.7 Hz, 1H), 8.15 (dd, J = 8.9, 2.4 Hz, 1H), 7.98 (d, J = 10.9 Hz, 1H), 7.64 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.42 - 4.22 (m, 4H), 3.99 (ddd, J = 14.7, 11.1, 2.0 Hz, 2H), 3.82 - 3.62 (m, 2H), 3.35 (s, 3H), 2.92 (ddd, J = 14.1, 11.1, 3.3 Hz, 2H), 2.77 - 2.66 (m, 2H).

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

[0320] 2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-2,3-dihydropyridazin-3-one ("A142") [ka] White solid; HPLC / MS 1.55 min (A), [M+H] + 448. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.16 (d, J = 8.6 Hz, 2H), 8.12 (dd, J = 3.8, 1.6 Hz, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.53 (dd, J = 9.5, 3.8 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.12 (dd, J = 9.5, 1.6 Hz, 1H), 4.33 - 4.20 (m, 2H), 3.79 - 3.70 (m, 2H), 3.36 (s, 3H).

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

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

[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") [ka]

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

[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 [ka] Pale orange solid; HPLC / MS 1.32 min (A), [M+H] + 452. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.68 (s, 1H), 9.05 (s, 2H), 7.99 (d, J = 11.0 Hz, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.56 (s, 1H), 7.27 (d, J = 7.1 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 4.33 - 4.18 (m, 2H), 3.81 (t, J = 5.1 Hz, 2H), 3.79 - 3.73 (m, 2H), 3.61 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 3.27 (p, J = 4.8 Hz, 3H), 3.19 - 3.11 (m, 2H), 2.13 (p, J = 5.9 Hz, 2H).

[0326] Example 13 (4-{3-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-morpholin-4-yl-methanone ("A43") [ka] White solid; mp220 - 221℃, [M+H] + 467. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.65 (s, 1H), 8.15-8.05 (m, 2H), 7.82 (d, J = 10.8 Hz, 1H), 7.67-7.58 (m, 3H), 7.27 (d, J = 7.1 Hz, 1H), 4.33-4.26 (m, 2H), 3.80-3.73 (m, 2H), 3.73-3.53 (m, 6H), 3.48-3.43 (m, 5H).

[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") [ka] Off-white solid; mp210 - 211℃, [M+H] + 480. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.63 (s, 1H), 8.12-8.05 (m, 2H), 7.84 (d, J = 10.8 Hz, 1H), 7.65 (s, 1H), 7.62-7.55 (m, 2H), 7.27 (d, J = 7.0 Hz, 1H), 4.33-4.26 (m, 2H), 3.80-3.74 (m, 2H), 3.65 (s, 2H), 3.36 (s, 5H), 2.34 (d, J = 31.8 Hz, 4H), 2.21 (s, 3H).

[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") [ka] White solid; mp 229~230℃, [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") [ka] Off-white solid; mp210 - 211℃, [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") [ka]

[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") [ka]

[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) is added homomorpholine (24.3 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 hours. 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 with 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 similarly: 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A45") [ka] 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") [ka] 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") [ka]

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

[0337] 5-Fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole ("A152") [ka] 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") [ka] 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") [ka]

[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") [ka] White solid; UPLC / MS 0.73 min, [M+H] + 509. 1 H NMR (400 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.78 (d, J = 6.8 Hz, 2H), 4.41 (d, J = 6.9 Hz, 2H), 4.35 - 4.20 (m, 2H), 3.99 (s, 2H), 3.81 - 3.74 (m, 2H), 3.43 (t, J = 4.7 Hz, 2H), 3.39 - 3.34 (m, 5H).

[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") [ka]

[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") [ka] White solid; HPLC / MS 1.54 min (A), [M+H] + 507. 1 H NMR (400 MHz, DMSO-d 6; mixture of rotamers) δ 13.71 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.06 - 8.00 (m, 1H), 7.76 (d, J = 3.9 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.35 - 4.28 (m, 2H), 3.87 - 3.46 (m, 9H), 3.41 (s, 1H), 3.36 (s, 3H), 2.04 - 1.72 (m, 4H).

[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") [ka] White solid; HPLC / MS 1.48 min (A), [M+H] + 493. 1 H NMR (700 MHz, DMSO-d 6 ; mixture of rotamers) δ 13.72 (d, J = 2.6 Hz, 1H), 8.13 - 8.07 (m, 2H), 8.04 (d, J = 10.8 Hz, 1H), 7.79 - 7.77 (m, 1H), 7.73 - 7.67 (m, 2H), 7.29 - 7.26 (m, 1H), 4.64 (d, J = 5.9 Hz, 1H), 4.51 (d, J = 5.9 Hz, 1H), 4.49 (d, J = 6.3 Hz, 1H), 4.45 (d, J = 6.3 Hz, 1H), 4.32 - 4.28 (m, 2H), 3.78 - 3.65 (m, 2H), 3.74 (s, 1H), 3.69 (s, 1H), 3.52 (t, J = 7.2 Hz, 1H), 3.47 (t, J = 6.8 Hz, 1H), 3.36 (s, 3H), 2.20 (t, J = 7.2 Hz, 1H), 2.16 (t, J = 6.8 Hz, 1H).

[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") [ka] White solid; HPLC / MS 1.50 min (A), [M+H] + 521. 1 H NMR (700 MHz, DMSO-d 6 ; mixture of rotamers) δ 13.72 (s, 1H), 8.12 - 8.07 (m, 2H), 8.04 (d, J = 10.8 Hz, 1H), 7.79 - 7.77 (m, 1H), 7.76 - 7.66 (m, 2H), 7.30 - 7.27 (m, 1H), 4.31 - 4.28 (m, 2H), 3.84 - 3.73 (m, 2H), 3.68 - 3.50 (m, 5H), 3.49 - 3.44 (m, 1H), 3.43 (s, 1H), 3.36 (s, 3H), 3.33 (s, 1H), 1.86 (t, J = 7.3 Hz, 1H), 1.80 (t, J = 7.0 Hz, 1H), 1.63 - 1.53 (m, 2H), 1.50 - 1.42 (m, 2H).

[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") [ka]

[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") [ka] White solid; UPLC / MS 0.69 min, [M+H] + 479. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.67 (s, 1H), 4.50 (s, 1H), 4.38 - 4.23 (m, 2H), 3.99 (d, J = 13.9, 1H), 3.85 - 3.71 (m, 3H), 3.66 - 3.56 (m, 1H), 3.55 - 3.45 (m, 1H), 3.36 (s, 3H), 3.14 - 3.02 (m, 1H), 1.88 (d, J = 8.9 Hz, 1H).

[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") [ka]

[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") [ka] White solid; UPLC / MS 0.69 min, [M+H] + 479. 1 H NMR (500 MHz, DMSO-d6 , mixture of rotamers) δ 13.70 (s, 1H), 8.15 - 8.07 (m, 2H), 8.05 - 8.00 (m, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.67 (m, 1H), 7.28 (d, J = 7.0 Hz, 1H), 4.87 (s, 0.5H), 4.68 (s, 1H), 4.59 (s, 0.5H), 4.41 (s, 0.5H), 4.34 - 4.27 (m, 2H), 3.93 (d, J = 7.4 Hz, 0.5H), 3.85 (d, J = 7.5 Hz, 0.5H), 3.83 - 3.65 (m, 3H), 3.61 - 3.51 (m, 1H), 3.36 (s, 3H), 1.98 - 1.73 (m, 2H).

[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") [ka]

[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") [ka] White solid; HPLC / MS 1.57 min (A), [M+H] + 507. 1 H NMR (500 MHz, DMSO-d 6) δ 13.70 (s, 1H), 8.14 - 8.09 (m, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.34 - 4.23 (m, 2H), 4.11 (s, 2H), 3.82 (s, 2H), 3.79 - 3.74 (m, 2H), 3.63 - 3.43 (m, 4H), 3.36 (s, 3H), 1.79 - 1.69 (m, 4H).

[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") [ka] White solid; HPLC / MS 1.57 min, [M+H] + 519. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 11.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.78 (t, J = 7.7 Hz, 2H), 4.64 - 4.46 (m, 4H), 4.36 - 4.22 (m, 5H), 3.83 - 3.71 (m, 2H), 3.36 (s, 3H), 2.36 (s, 3H).

[0352] (4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone ("A167") [ka] White solid; mp 105~106℃, [M+H] + 496. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.73 (s, 1H), 8.32 (s, 1H), 8.16-8.09 (m, 2H), 7.83 (s, 1H), 7.61-7.53 (m, 2H), 7.27 (s, 1H), 4.34-4.27 (m, 2H), 3.82-3.75 (m, 2H), 3.71-3.59 (m, 2H), 3.41-.33 (m, 5H), 2.43-2.26 (m, 4H), 2.22 (s, 3H).

[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") [ka] White solid; mp 119~120℃, [M+H] + 540. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.76 - 13.68 (m, 1H), 8.09 - 7.91 (m, 3H), 7.82 (s, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 4.36 - 4.25 (m, 2H),4.15 - 4.04 (m, 2H), 3.94 - 3.85 (m, 2H), 3.81 - 3.73 (m, 2H), 3.68 - 3.47 (m, 4H), 3.36 (s, 3H), 3.24 - 3.14 (m, 1H), 2.43 - 2.19 (m, 4H).

[0354] (4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-2-methyl-phenyl)-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone ("A169") [ka] White solid; mp 129~130℃, [M+H] + 493. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.7 (s, 1H), 8.09-7.94 (m, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 5.37 (d, J = 6.7 Hz, 2H), 4.64 (d, J = 6.7 Hz, 2H), 4.34-4.27 (m, 2H), 3.80-3.69 (m, 4H), 3.37 (s, 3H), 2.55 (m, 2H), 2.42 (s, 3H).

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

[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") [ka] White solid; mp 125~126℃, [M+H] + 536. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.78 - 13.66 (m, 1H), 8.04 (d, J = 11.0 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.12 - 4.05 (m, 1H), 3.98 - 3.86 (m, 2H), 3.84 - 3.71 (m, 3H), 3.59 (t, J = 4.5 Hz, 4H), 3.41 - 3.26 (m, 3H), 3.21 - 3.13 (m, 1H), 2.41 (s, 3H), 2.37 - 2.21 (m, 4H).

[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") [ka] White solid; HPLC / MS 1.49 min (A), [M+H] + 515. 1 H NMR (400 MHz, DMSO-d 6) δ 13.75 (s, 1H), 9.22 (d, J = 1.3 Hz, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 11.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.57 (dd, J = 5.2, 1.4 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.75 (t, J = 8.7 Hz, 1H), 4.54 (dd, J = 8.5, 5.9 Hz, 1H), 4.47 (t, J = 9.4 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.24 (dd, J = 9.8, 6.0 Hz, 1H), 4.10 (tt, J = 8.8, 5.9 Hz, 1H), 3.85 - 3.70 (m, 2H), 3.35 (s, 3H).

[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") [ka] Trifluoroacetate, yellow powder; UPLC / MS 0.71 min, [M+H] + 529. 1 H NMR (500 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.36 (d, J = 5.2 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.72 (t, J = 8.7 Hz, 1H), 4.54 (t, J = 7.3 Hz, 1H), 4.46 (t, J = 9.4 Hz, 1H), 4.33 - 4.27 (m, 2H), 4.24 (t, J = 8.0 Hz, 1H), 4.06 (tt, J = 9.0, 6.1 Hz, 1H), 3.80 - 3.72 (m, 2H), 3.36 (s, 3H), 2.64 (s, 3H).

[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") [ka]

[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") [ka]

[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") [ka]

[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") [ka] White solid; HPLC / MS 1.28 min (A), [M+H] + 520. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.15 - 8.07 (m, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.34 (t, J = 8.1 Hz, 1H), 4.15 (dd, J = 8.7, 5.2 Hz, 1H), 4.12 - 4.05 (m, 1H), 3.87 (dd, J = 10.2, 5.2 Hz, 1H), 3.79 - 3.74 (m, 2H), 3.36 (s, 3H), 3.12 (tt, J = 7.2, 5.3 Hz, 1H), 2.25 (bs, 4H), 1.51 (dq, J = 11.0, 5.1 Hz, 4H), 1.45 - 1.38 (m, 2H).

[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") [ka] White solid; HPLC / MS 1.27 min (A), [M+H] + 506. 1 H NMR (500 MHz, DMSO-d 6) δ 13.71 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.39 (t, J = 8.0 Hz, 1H), 4.33 - 4.26 (m, 2H), 4.18 (dd, J = 8.8, 4.7 Hz, 1H), 4.16 - 4.09 (m, 2H), 3.92 (dd, J = 10.2, 4.7 Hz, 1H), 3.79 - 3.74 (m, 2H), 3.36 (s, 3H), 3.34 - 3.30 (m, 1H), 2.48 - 2.41 (m, 4H), 1.75 - 1.67 (m, 4H).

[0364] 3-(3-{4-[4-(cyclopropylmethyl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ("A179") [ka] White solid; UPLC / MS 0.51 min, [M+H] + 520. 1 H 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") [ka]

[0366] 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-N,N,3-trimethylazetidin-3-amine ("A181") [ka] Trifluoroacetate, white solid; UPLC / MS 0.79 min, [M+H] + 494. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 10.66 (bs, 1H), 8.15 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 10.9 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.29 (d, J = 7.1 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.38 - 4.25 (m, 4H), 3.98 (d, J = 11.2 Hz, 1H), 3.81 - 3.72 (m, 2H), 3.36 (s, 3H), 2.74 (bs, 6H), 1.62 (s, 3H).

[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") [ka] White solid; HPLC / MS 1.54 min (A), [M+H] + 479. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.76 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.64 (bs, 1H), 4.43 (bs, 1H), 4.35 - 4.22 (m, 2H), 3.87 - 3.73 (m, 3H), 3.69 (d, J = 10.7 Hz, 1H), 3.36 (s, 3H), 2.77 (q, J = 6.9 Hz, 1H), 1.82 (d, J = 8.2 Hz, 1H).

[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") [ka] White solid; HPLC / MS 1.34 min (A), [M+H] + 500. 1 H NMR (500 MHz, DMSO-d 6, mixture of rotamers), δ 13.71 (s, 1H), 8.72 (s, 0.5H), 8.60 - 8.51 (m, 1.5 H), 8.20 - 8.12 (m, 4H), 8.03 (d, J = 10.9 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.79 (s, 1H), 7.58 (d, J = 5.2 Hz, 0.5H), 7.45 (d, J = 5.1 Hz, 0.5H), 7.29 (d, J = 7.1 Hz, 1H), 5.02 - 4.95 (m, 2H), 4.91 (s, 2H), 4.36 - 4.17 (m, 2H), 3.87 - 3.72 (m, 2H), 3.36 (s, 3H).

[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") [ka]

[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") [ka]

[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") [ka] White solid; HPLC / MS 1.26 min (A), [M+H] + 536. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 8.11 (d, J = 7.9 Hz, 2H), 8.04 (d, J = 11.0 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.37 - 4.26 (m, 2H), 3.86 - 3.71 (m, 4H), 3.64 (q, J = 7.9 Hz, 2H), 3.55 - 3.48 (m, 1H), 3.35 (s, 3H), 2.96 (t, J = 7.1 Hz, 1H), 2.48 - 2.28 (m, 5H), 2.03 - 1.93 (m, 1H), 1.81 - 1.70 (m, 1H).

[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") [ka]

[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") [ka] Off-white solid; HPLC / MS 1.23 min (A), [M+H] + 550. 1 H NMR (500 MHz, DMSO-d 6) δ 13.70 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 10.9 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.52 - 4.20 (m, 2H), 4.03 - 3.82 (m, 2H), 3.82 - 3.68 (m, 2H), 3.64 (bs, 2H), 3.37 (bs, 2H), 3.36 (s, 3H), 3.30 - 3.24 (m, 2H), 2.62 - 2.40 (m, 5H), 1.74 - 1.65 (m, 2H), 1.41 (qd, J = 12.1, 4.3 Hz, 2H).

[0374] 5-Fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2S)-2-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole ("A189") [ka] White solid; UPLC / MS 0.73 min, [M+H] + 481. 1 H NMR (500 MHz, DMSO-d 6 , rotamers, peak selection) δ 13.70 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 11.0 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.33 - 4.25 (m, 2H), 3.79 - 3.73 (m, 2H), 3.58 - 3.40 (m, 2H), 3.36 (s, 3H), 2.94 (broad, 1H), 1.29 - 0.94 (m, 3H).

[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") [ka] White solid; HPLC / MS 1.34 min, [M+H] + 536. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.54 (td, J = 6.5, 4.4 Hz, 2H), 4.46 (t, J = 6.1 Hz, 1H), 4.39 (t, J = 6.0 Hz, 1H), 4.32 - 4.27 (m, 2H), 4.2 (broad, 2H), 3.80 - 3.73 (m, 2H), 3.41 (p, J = 6.3 Hz, 1H), 3.36 (s, 3H), 3.28 - 3.12 (m, 1H), 2.73 (bs, 1H), 2.61 - 2.53 (m, 1H), 2.03 (dd, J = 11.1, 3.8 Hz, 1H), 1.86 (td, J = 11.4, 3.4 Hz, 1H), 1.32 (d, J = 6.8 Hz, 3H).

[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") [ka]

[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") [ka] White powder; UPLC / MS 0.57 min, [M+H] + 514. 1 H NMR (700 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 10.9 Hz, 1H), 7.93 (dt, J = 7.9, 2.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.45 - 7.40 (m, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.75 (t, J = 8.8 Hz, 1H), 4.51 (dt, J = 31.8, 8.7 Hz, 2H), 4.31 - 4.27 (m, 2H), 4.14 - 4.08 (m, 1H), 4.03 (tt, J = 9.1, 6.3 Hz, 1H), 3.78 - 3.74 (m, 2H), 3.35 (s, 3H).

[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") [ka] White solid; mp 138~139℃, [M+H] + 536. 1 H NMR (400 MHz, DMSO-d 6) δ 13.74 (s, 1H), 8.04 (d, J = 11.0 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.90 (d, J = 7.8, 1.7 Hz, 1H), 7.75 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.33 - 4.26 (m, 2H), 3.81 - 3.75 (m, 2H), 3.72 - 3.60 (m, 2H), 3.49 - 3.42 (m, 1H), 3.35 (s, 3H), 3.24 - 3.17 (m, 2H), 2.40 - 2.30 (m, 5H), 2.26 - 2.13 (m, 2H).

[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") [ka] White solid; mp 123~124℃, [M+H] + 538. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.83 - 13.66 (m, 1H), 8.30 (s, 1H), 8.15 - 8.08 (m, 2H), 7.81 (s, 1H), 7.61 - 7.54 (m, 2H), 7.26 (s, 1H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 4.33 - 4.26 (m, 2H), 3.81 - 3.74 (m, 2H), 3.73 - 3.61 (m, 2H), 3.53 - 3.36 (m, 6H), 2.40 - 2.22 (m, 4H).

[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") [ka]

[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") [ka] Yellow solid; mp 161~162℃, [M+H] + 540. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.76 (s, 1H), 8.06 - 8.01 (m, 1H), 8.01 - 7.93 (m, 2H), 7.84 (s, 1H), 7.65 - 7.57 (m, 1H), 7.29 (d, J = 7.2 Hz, 1H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 4.34 - 4.27 (m, 2H), 3.80 - 3.73 (m, 2H), 3.73 - 3.69 (m, 2H), 3.50 - 3.43 (m, 1H), 3.36 (s, 3H), 3.33 - 3.30 (m, 2H), 2.38 - 2.34 (m, 2H), 2.28 - 2.24 (m, 2H).

[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") [ka]

[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") [ka] 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") [ka] 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") [ka] Trifluoroacetate, white solid; HPLC / MS 1.27 min (A), [M+H] + 536. 1 H NMR (500 MHz, DMSO-d 6 , partially very broad signal, selection of peaks) δ 13.72 (s, 1H), 10.55 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 10.9 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.79 - 4.4 (m, 2H), 4.35 - 4.23 (m, 2H), 3.80 - 3.73 (m, 2H), 3.36 (s, 3H), 1.30 - 1.30 (bs, 3H).

[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") [ka]

[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") [ka] White solid; UPLC / MS 0.69 min, [M+H] + 493. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 8.15 - 8.07 (m, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 4.35 - 4.20 (m, 2H), 3.90 - 3.64 (m, 5H), 3.65 - 3.44 (m, 3H), 3.36 (s, 3H), 3.34 - 3.31 (m, 1H), 2.93 (bs, 2H).

[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") [ka]

[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") [ka] White solid; HPLC / MS 1.41 min (A), [M+H] + 536. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.15 - 8.05 (m, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.77 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 4.64 - 4.45 (m, 2H), 4.35 - 4.18 (m, 4H), 4.07 (s, 2H), 3.96 - 3.84 (m, 2H), 3.79 - 3.73 (m, 2H), 3.71 - 3.52 (m, 2H), 3.36 (s, 3H).

[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") [ka] White solid; HPLC / MS 1.13 min (A), [M+H] + 508. 1 H NMR (500 MHz, DMSO-d 6) δ 13.67 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 10.9 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 4.19 (t, J = 4.9 Hz, 2H), 3.82 (q, J = 5.1 Hz, 2H), 3.68 (bs, 2H), 3.47 (p, J = 6.3 Hz, 1H), 3.40 (bs, 2H), 2.41 - 2.19 (m, 4H).

[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") [ka] Off-white solid; HPLC / MS 1.27 min (A), [M+H] + 530. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.96 - 8.51 (m, 2H), 8.18 - 8.11 (m, 2H), 8.02 (d, J = 11.0 Hz, 1H), 7.95 - 7.86 (m, 4H), 7.78 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 6.96 (bs, 1H), 4.81 - 4.65 (m, 1H), 4.58 - 4.44 (m, 1H), 4.39 - 4.26 (m, 4H), 3.81 - 3.70 (m, 2H).

[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") [ka] 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") [ka] 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") [ka]

[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") [ka] White solid; HPLC / MS 1.30 min (A), [M+H] + 536. 1 H NMR (500 MHz, DMSO-d 6, mixture of rotamers) δ 13.69 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 10.9 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 4.35 (t, J = 8.1 Hz, 1H), 4.32 - 4.25 (m, 2H), 4.23 - 4.16 (m, 1H), 4.09 (t, J = 8.8 Hz, 1H), 3.92 (dd, J = 10.5, 5.0 Hz, 1H), 3.81 - 3.71 (m, 3H), 3.56 - 3.46 (m, 2H), 3.36 (s, 3H), 3.20 - 3.13 (m, 1H), 2.78 (d, J = 11.0 Hz, 0.5H), 2.71 (d, J = 11.2 Hz, 1H), 2.67 - 2.60 (m, 0.5H), 1.92 (t, J = 11.4 Hz, 1H), 1.67 - 1.55 (m, 1H), 1.12 - 1.00 (m, 3H).

[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") [ka]

[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") [ka] White solid; HPLC / MS 1.40 min (A), [M+H] + 515. 1 H NMR (500 MHz, DMSO-d 6) δ 13.68 (s, 1H), 9.11 (s, 1H), 8.92 (s, 2H), 8.12 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 10.9 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.75 (s, 1H), 7.28 (d, J = 7.1 Hz, 1H), 4.72 (d, J = 8.9 Hz, 1H), 4.65 - 4.47 (m, 4H), 4.39 - 4.26 (m, 2H), 4.19 (s, 1H), 4.05 (tt, J = 9.1, 6.3 Hz, 1H), 3.83 - 3.70 (m, 2H), 3.36 (s, 3H).

[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") [ka] 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") [ka] White solid; HPLC / MS 1.54 min (A), [M+H] + 507. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.69 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 10.9 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 4.34 - 4.17 (m, 2H), 3.82 - 3.29 (m, 13H), 2.44 - 2.36 (m, 1H), 2.37 - 2.30 (m, 2H), 2.31 - 2.22 (m, 1H).

[0400] 3-(3-{4-[(cis)-octahydrofuro[3,4-c]pyridine-5-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ("A215") [ka] White solid; HPLC / MS 1.53 min (A), [M+H] + 507. 1 H NMR (500 MHz, DMSO-d 6) δ 13.69 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 10.9 Hz, 1H), 7.74 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 4.33 - 4.23 (m, 2H), 3.86 - 3.32 (m, 12H), 3.26 - 3.21 (m, 1H), 2.44 - 2.27 (m, 2H), 2.03 - 1.33 (m, 2H).

[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") [ka] Trifluoroacetate, white solid; UPLC / MS 0.48 min, [M+H] + 548. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 11.05 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 10.9 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 4.77 (t, J = 7.3 Hz, 2H), 4.64 (s, 2H), 4.48 (bs, 1H), 4.33 - 4.27 (m, 2H), 3.9 - 2.7 (broad signal, 8H), 3.80 - 3.70 (m, 2H), 3.36 (s, 3H).

[0402] (cis)-5-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-hexahydro-1H-2 lambda 6-thieno[3,4-c]pyrrole-2,2-dione ("A217") [ka] 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") [ka] 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") [ka]

[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") [ka]

[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") [ka]

[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") [ka]

[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") [ka]

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

[0410] 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) is added 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 hours. 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 a silica gel column using cyclohexane / ethyl acetate as eluent to give 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 give 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") [ka] 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 [ka]

[0414] 2-[(5-fluoro-3-{3-[4-(piperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazol-6-yl)oxy]ethan-1-ol ("A224") [ka]

[0415] {4-[5-(5-fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-piperazin-1-yl-methanone ("A225") [ka]

[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") [ka]

[0417] Example 16 [(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)imino]dimethyl-lambda 6-sulfanone ("A47") [ka] White solid; HPLC / MS 2.52 min (A), [M+H] + 445. 1 H NMR (500 MHz, DMSO-d6) δ 13.66 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 4.32 - 4.26 (m, 2H), 3.80 - 3.74 (m, 2H), 3.35 (s, 3H), 3.29 (s, 6H).

[0418] Example 17 5-Fluoro-6-(2-methoxyethoxy)-3-[3-(1,3-thiazol-5-yl)-1,2-oxazol-5-yl]-1H-indazole ("A48") [ka] Light brown solid; HPLC / MS 2.61 min (A), [M+H] + 361. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.77 (s, 1H), 9.31 (d, J = 0.7 Hz, 1H), 8.68 (d, J = 0.7 Hz, 1H), 7.96 (d, J = 10.8 Hz, 1H), 7.78 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 4.38 - 4.23 (m, 2H), 3.86 - 3.67 (m, 2H), 3.35 (s, 3H).

[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") [ka] Pale yellow solid; UPLC / MS 0.65 min (A), [M+H] + 455. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 10.8 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 4.81 (t, J = 5.3 Hz, 1H), 4.30 (dd, J = 10.4, 3.2 Hz, 1H), 4.17 (dd, J = 10.4, 5.3 Hz, 1H), 3.64 - 3.56 (p, J = 4.0 Hz, 3H), 3.42 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H).

[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") [ka] and 5-Fluoro-6-(2-methoxy-ethoxy)-3-{3-[4-(1,3,3-trimethyl-piperidin-4-yl)-phenyl]-isoxazol-5-yl}-1H-indazole ("A231") [ka]

[0421] Synthesis scheme: [ka] "A230": Yellow solid; [M+H] + 465;1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (d, J = 11.0 Hz, 1H), 7.96 - 7.91 (m, 2H), 7.67 (s, 1H), 7.35 - 7.31 (m, 2H), 7.27 (d, J = 7.1 Hz, 1H), 4.33 - 4.26 (m, 2H), 3.80 - 3.73 (m, 2H), 3.35 (s, 3H), 3.13 - 3.05 (m, 1H), 2.65 - 2.52 (m, 3H), 2.49 - 2.41 (m, 1H), 2.12 - 2.01 (m, 1H), 1.44 - 1.36 (m, 1H), 0.85 (s, 3H), 0.70 (s, 3H) "A231": White solid; [M+H] + 479; 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.70 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.67 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 7.1 Hz, 1H), 4.32 - 4.23 (m, 2H), 3.79 - 3.69 (m, 2H), 3.33 (s, 3H), 2.97 - 2.89 (m, 1H), 2.44 - 2.34 (m, 2H), 2.28 - 2.13 (m, 4H), 1.92 - 1.75 (m, 2H), 1.53 - 1.43 (m, 1H), 0.86 (s, 3H), 0.72 (s, 3H).

[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") [ka] Trifluoroacetate; white powder; UPLC / MS 0.47 min, [M+H]+ 540. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 9.65 (broad, 1H), 8.13 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 10.9 Hz, 1H), 7.76 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 5.40 (broad, 2H), 4.51 (broad, 1H), 4.38 - 4.21 (m, 2H), 3.80 (d, J = 5.0 Hz, 4H), 3.78 - 3.75 (m, 2H), 3.54 (broad signal), 3.36 (s, 3H).

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

[0424] To a solution of terephthalaldehydic acid (300 mg, 2.00 mmol) in DMF (10 ml) is added 1-(oxetan-3-yl)piperazine (313 mg, 2.20 mmol), 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 min. The reaction mixture is evaporated to dryness. The residue is treated with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to give 4-[4-(oxetan-3-yl)piperazine-1-carbonyl]benzaldehyde 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 and 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 h. The reaction mixture is neutralized with 1N 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 3-ethynyl-5-fluoro-6-(2-methoxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (41.6 mg, 0.11 mmol) and N-({4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}methylidene)hydroxylamine in dichloromethane (500 μl) is added dropwise an aqueous solution of sodium hypochlorite (content approx. 14%, 143 μl, approx. 0.33 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is treated with water and dichloromethane. The aqueous phase is separated and extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated. The residue is chromatographed on a 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) is added sodium hydroxide (9.26 mg, 0.23 mmol) and the mixture is stirred at room temperature for 2 h. The reaction mixture is treated with saturated ammonium chloride solution. The resulting precipitate is 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") [ka] Off-white crystals; HPLC / MS 1.34 min (A), [M+H] + 492. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.66 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 11.0 Hz, 1H), 7.74 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.1 Hz, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.67 (broad, 2H), 3.47 (p, J = 6.2 Hz, 1H), 3.40 (broad, 2H), 2.31 (broad, 4H), 1.43 (t, J = 6.9 Hz, 3H).

[0429] Example 22 - Salt formation [ka] To a suspension 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") (104 mg, 0.20 mmol) in 2-propanol (3 ml), methanesulfonic acid (18.6 μl, 0.28 mmol) is added and the suspension is stirred at 75° C. for 1 h. The mixture is allowed to reach room temperature. The solid is filtered off, washed with water and dried under vacuum to give (4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone mesylate as a white powder. 1 H NMR (500 MHz, DMSO-d 6 , very broad signal not annotated) δ 13.71 (s, 1H), 10.79 (s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 10.9 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 4.74 (s, 4H), 4.41 - 4.24 (m, 2H), 3.80 - 3.72 (m, 2H), 3.36 (s, 3H), 3.03 (broad, 4H), 2.31 (s, 3H).

[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 similarly: - Hydrochloride - Maleart - Hemi-ethane disulfonate - 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 prepared similarly: - Methanesulfonate - Trifluoroacetate.

[0432] The following examples relate to pharmaceuticals: Example A: Injection vial A solution of 100 g of the active ingredient of formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilized under sterile conditions and sealed under sterile conditions, each injection vial containing 5 mg of the active ingredient. Example B: Suppositories A mixture of 20 g of an active ingredient of formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

[0433] Example C: Solution In 940 ml of double distilled water, 1 g of the active ingredient of formula I, 9.38 g of NaH 2 PO 4 2H 2 O, 28.48g Na 2 HPO 4 12H 2 A solution is prepared from 0 and 0.1 g of benzalkonium chloride. The pH is adjusted to 6.8, the solution is made up to 1 liter and sterilized by radiation. This solution can be used in the form of eye drops. Example D: Ointment 500 mg of an active ingredient of formula I is mixed with 99.5 g of petrolatum under sterile conditions.

[0434] Example E: Tablets A mixture of 1 kg of active ingredient of 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 containing 10 mg of the active ingredient each. Example F: Sugar-coated tablets Tablets are compressed similarly to Example E and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

[0435] Example G: Capsule 2 kg of the active ingredient of formula I are conventionally introduced into hard gelatin capsules so that each capsule contains 20 mg of the active ingredient. Example H: Ampoule A solution of 1 kg of the active ingredient of formula I in 60 l of double-distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions, each ampoule containing 10 mg of the active ingredient.

Claims

1. Formula Ia: 【Chemistry 1】 or Formula Ib: 【Chemistry 2】 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; A compound represented by the following formula: 【Chemistry 3】 or a pharma- ceutically acceptable solvate, salt, tautomer or stereoisomer thereof, or 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, 2. A compound according to claim 1, or a pharma- ceutically acceptable solvate, salt, tautomer or stereoisomer thereof, or 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, or a pharma- ceutically acceptable salt, tautomer or stereoisomer thereof, or 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. A compound according to claim 1, or a pharma- ceutically acceptable salt, tautomer or stereoisomer thereof, or mixtures thereof in any ratio.

5. Formula Ib 【Chemistry 4】 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, wherein the compound is: or a pharma- ceutically acceptable salt, tautomer or stereoisomer thereof, or a mixture thereof in any ratio.

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】 or a pharma- ceutically acceptable solvate, salt, tautomer or stereoisomer thereof, or mixtures thereof in any ratio.

7. The compound of claim 1, wherein the compound is "A45" 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole, or a pharma- ceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, or mixtures thereof in any ratio.

8. Formula I 【Chemistry 5】 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 which is unsubstituted or mono-, di- or trisubstituted by Hal and / or A, Y represents CO; Z is [C(R ３ ) ２ ] ｎ Het 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; For the preparation of a compound represented by Formula II 【Chemistry 6】 In the formula, R １ and R ２ has the meaning given in formula I above, The compound represented by formula III 【Chemistry 7】 In the formula, Het ２ has the meaning given in formula I above, reacting a compound represented by and / or Converting a base or acid of formula I into one of its salts; 1. A process for the preparation of a compound of formula I, or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, characterized in that

9. Formula I 【Chemistry 8】 During the ceremony, R １ Het １ 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; For the preparation of a compound represented by Formula IV 【Chemistry 9】 During the ceremony, R ２ , X, Y and Z have the meanings given in formula I above, The compound represented by formula V 【Chemistry 10】 In the formula, Het １ has the meaning given in formula I above, reacting a compound represented by and / or Converting a base or acid of formula I into one of its salts; 1. A process for the preparation of a compound of formula I or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, characterized in that

10. Formula Ia 【Chemistry 11】 During the ceremony, R １ , R ２ , X, Y and Z have the meanings given in claim 1; A compound represented by the following formula: 【Chemistry 12】 For the preparation of a compound represented by the formula Formula VI 【Chemistry 13】 During the ceremony, R １ and R ２ has the meaning given in claim 1, The compound represented by formula VII 【Chemistry 14】 During the ceremony, X, Y and Z have the meanings indicated in claim 1. reacting a compound represented by or Formula Ib 【Chemistry 15】 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 16】 During the ceremony, R １ and R ２ has the meaning given in claim 1, The compound represented by formula IX 【Chemistry 17】 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 Ia or Ib into one of its salts, 8. A process for the preparation of a compound according to claims 1 to 7, or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, characterized in that

11. A medicament comprising at least one compound according to claim 1 or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, or mixtures thereof in any ratio, and optionally a pharma- ceutically acceptable carrier, excipient or vehicle.

12. 2. A compound according to claim 1 or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, or a mixture thereof in any ratio, for use for the treatment and / or prevention of cancer.

13. 13. The compound for use according to claim 12 for the treatment and / or prevention of cancer, wherein the cancer is a gastrointestinal stromal tumor.

14. 10. A medicament comprising at least one compound according to claim 1 or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, or mixtures thereof in any ratio, and at least one further pharma- ceutical active ingredient.

15. (a) an effective amount of a compound according to claim 1 or a pharma- ceutically acceptable salt, solvate, tautomer or stereoisomer thereof, or 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:

16. group 2-Bromo-5-fluoro-4-(2-methoxyethoxy)benzaldehyde 【Chemistry 18】 N'-[(1E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylidene]-4-methylbenzene-1-sulfonohydrazide 【Chemistry 19】 5-Fluoro-6-(2-methoxyethoxy)-1-(4-methylbenzenesulfonyl)-1H-indazole 【Chemistry 20】 5-Fluoro-6-(2-methoxyethoxy)-1H-indazole 【Chemistry 21】 5-Fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole 【Chemical 22】 tert-Butyl 5-fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate 【Chemistry 23】 tert-Butyl 5-fluoro-6-(2-methoxyethoxy)-3-[2-(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate 【Chemistry 24】 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole 【Chemistry 25】 tert-Butyl 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate 【Chemistry 26】 tert-Butyl 5-fluoro-3-{3-[4-(methoxycarbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate 【Chemistry 27】 Methyl 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoate 【Chemistry 28】 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid 【Chemical 29】 An intermediate selected from:

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