INDAZOLYL-ISOXAZOLE DERIVATIVES FOR THE TREATMENT OF DISEASES SUCH AS CANCER
20220127254 · 2022-04-28
Assignee
Inventors
Cpc classification
C07D491/107
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D231/56
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
C07C47/575
CHEMISTRY; METALLURGY
International classification
A61P35/00
HUMAN NECESSITIES
C07D231/56
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
C07D491/107
CHEMISTRY; METALLURGY
Abstract
Compounds of the formula I
##STR00001##
are provided. These compounds can inhibit c-Kit kinase and can be employed for the treatment of cancer.
Claims
1. A compound of the formula I ##STR00348## wherein R.sup.1 denotes Hal, CF.sub.3, OA, Het.sup.1, COOR.sup.3, or CON(R.sup.2).sub.2, R.sup.2 denotes H, Hal, or CN, R.sup.3 denotes H or A, X denotes phenylene, pyridin-diyl, 1,3-thiazol-diyl, or pyrazol-diyl, each of which is unsubstituted or mono-, di-, or trisubstituted by Hal and/or A, Y is absent or denotes CO, O[C(R.sup.3).sub.2].sub.n, NR.sup.3CO, CONR.sup.3, CONR.sup.3[C(R.sup.3).sub.2].sub.n, CONHCH.sub.2C(CH.sub.3).sub.2, SO.sub.2, SO.sub.2N(R.sup.3), —N═, or S(═O, ═NR.sup.3), Z denotes H, A, Hal, OA, [C(R.sup.3).sub.2].sub.nHet.sup.2, or N═S(═O)A.sub.2, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH.sub.2-groups may be replaced by O-atoms and wherein 1-7 H-atoms may be replaced by R.sup.5, or denotes (CH.sub.2).sub.nCyc, Cyc denotes cyclic alkyl having 3-7 C atoms, R.sup.5 denotes F, Cl, OH, SO.sub.2A, or N(R.sup.3).sub.2, Het.sup.1 denotes pyrazolyl which nay be mono- or disubstituted by A, Het.sup.2 denotes a 4- to 7-membered monocyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-, or trisubstituted by A, Hal, CN, OR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nSO.sub.2A, [C(R.sup.3).sub.2].sub.nNR.sup.3SO.sub.2A, Het.sup.3, ═NR.sup.3, and/or ═O, or denotes a 7- to 10-membered bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by A, Hal, CN, OR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nSO.sub.2A, [C(R.sup.3).sub.2].sub.nNR.sup.3SO.sub.2A, Het.sup.3, ═NR.sup.3, and/or ═O, Het.sup.3 denotes a 4- to 7-membered monocyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono- or disubstituted by A, Hal, OR.sup.3, oxetanyl, and/or ═O, or denotes a 7- to 10-membered bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono- or disubstituted by A, Hal, OR.sup.3, oxetanyl, and/or ═O, Hal denotes F, Cl, Br, or I, n denotes 0, 1, 2, or 3, and pharmaceutically acceptable solvates, salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.
2. The compound according to claim 1, wherein Het.sup.2 denotes pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 6-oxa-2-azaspiro[3.4]octane-2-yl, 1-oxa-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-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]heptane-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonane-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3.3]heptane-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonane-5-yl, 1H-1,3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonane-7-yl, 2-oxa-6-azaspiro[3.4]octane-6-yl, 8-oxa-2-azaspiro[4.5]decane-2-yl, 2,6-diazaspiro[3.4]octane-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptane-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 7-oxa-2-azaspiro[3.5]nonane-2-yl, 6-oxa-1-azaspiro(3.3]heptane-1-yl, 2,7-diazaspiro[3.5]nonane-7-yl, 3-oxa-6-azabicyclo[3.1.1]heptane-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridine-2-yl, 2,7-diazaspiro[3.5]nonane-2-yl, hexahydro-1H-furo[3,4-c]pyrrole-5-yl, octahydropyrrolo[2,3-c]pyrrole-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-yl, 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-yl, octahydropyrano[3,4-c]pyrrole-2-yl, octahydrofuro[3,4-c]pyridine-5-yl, octahydropyrrolo[3,4-c]pyrrole-2-yl, hexahydro-1H-2lambda6-thieno[3,4-c]pyrrole-5-yl, or tetrahydrofuro[3,4-c]pyrrole-5-yl, each of which ray be unsubstituted or mono-, di-, or trisubstituted by A, Hal, CN, OR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nSO.sub.2A, [C(R.sup.3)].sub.nNR.sup.3SO.sub.2A, Het.sup.3, ═NR.sup.3, and/or ═O, and pharmaceutically acceptable solvates, salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.
3. The compound according to claim 1, wherein Het.sup.3 denotes morpholinyl, 1H-pyrazolyl, 1lambda6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, oxan-4-yl, 1,2,3-triazolyl, or 1,2,4-triazolyl, each of which may be unsubstituted or mono- or disubstituted by A, Hal, OR.sup.3, oxetanyl, and/or ═O, and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.
4. The compound according to claim 1, wherein R.sup.1 denotes Hal, CF.sub.3, OCH.sub.3, OCH.sub.2CH.sub.2OCH.sub.3, OCH.sub.2CH.sub.2OH, 1-methyl-1H-pyrazol-4-yl, COOCH.sub.3, CONH.sub.2, CONHCH.sub.3, or CONHCH.sub.2CH.sub.2OCH.sub.3, R.sup.2 denotes H, Hal or CN, R.sup.3 denotes H or CH.sub.3, X denotes 1,4-phenylene, 1,3-phenylene, 2-fluoro-1,4-phenylene, 2-methyl-1,4-phenylene, pyridine-3,6-diyl, 1,3-thiazol-3,5-diyl, 1,3-thiazol-2,4-diyl, 1,3-thiazol-2,5-diyl, or pyrazol-1,4-diyl, each of which is unsubstituted or mono-, di-, or trisubstituted by Hal and/or A, Y is absent or denotes CO, SO.sub.2, NHCO, NCH.sub.3, CONH(CH.sub.2).sub.n, CONHCH.sub.2C(CH.sub.3).sub.2, CON(CH.sub.3)(CH.sub.2).sub.n, O, OCH.sub.2, OCH.sub.2CH.sub.2, S(═O)(═NH), —N═, or SO.sub.2N(CH.sub.3), Z denotes H, A, Hal, OA, [C(R.sup.3).sub.2].sub.nHet.sup.2, or N═S(═O)A.sub.2, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH.sub.2-groups may be replaced by O-atoms and wherein 1-7 H-atoms may be replaced by R.sup.5, or denotes (CH.sub.2).sub.nCyc, Cyc denotes cyclic alkyl having 3-7 C atoms, R.sup.5 denotes F, Cl, OH, SO.sub.2A, or N(R.sup.3).sub.2, Het.sup.1 denotes pyrazolyl which may be mono- or disubstituted by A, Het.sup.2 denotes pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 6-oxa-2-azaspiro[3.4]octane-2-yl, 1-oxa-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-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]heptane-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonane-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3,3]heptane-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonane-5-yl, 1H-1,3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonane-7-yl, 2-oxa-6-azaspiro[3.4]octane-6-yl, 8-oxa-2-azaspiro[4.5]decane-2-yl, 2,6-diazaspiro[3.4]octane-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptane-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 7-oxa-2-azaspiro[3.5]nonane-2-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2,7-diazaspiro[3.5]nonane-7-yl, 3-oxa-6-azabicyclo[3.1.1]heptane-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridine-2-yl, 2,7-diazaspiro[3.5]nonane-2-yl, hexahydro-1H-furo[3,4-c]pyrrole-5-yl, octahydropyrrolo[2,3-c]pyrrole-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-yl, 1H, 4H, 5H,6H-pyrrolo[3,4-c]pyrazole-5-yl, octahydropyrano[3,4-c]pyrrole-2-yl, octahydrofuro[3,4-c]pyridine-5-yl, octahydropyrrolo[3,4-c]pyrrole-2-yl, hexahydro-1H-2lambda6-thieno[3,4-c]pyrrole-5-yl, or tetrahydrofuro[3,4-c]pyrrole-5-yl, each of which may be unsubstituted or mono-, di-, or trisubstituted by A, Hal, CN, OR.sup.3, [C(R.sup.8).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nSO.sub.2A, [C(R.sup.3).sub.2].sub.nNR.sup.3SO.sub.2A, Het.sup.3, ═NR.sup.3, and/or ═O, Het.sup.3 denotes morpholinyl, 1H-pyrazolyl, 1lambda6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, oxan-4-yl, 1,2,3-triazolyl, or 1,2,4-triazolyl, each of which may be unsubstituted or mono- or disubstituted by A, Hal, OR, oxetanyl, and/or ═O, Hal denotes F, Cl, Br, or I, n denotes 0, 1, 2 or 3, and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.
5. The compound according to claim 1 of the formula Ib ##STR00349## wherein R.sup.1 denotes Hal, CF.sub.3, OCH.sub.3, OCH.sub.2CH.sub.2OCH.sub.3, OCH.sub.2CH.sub.2OH, 1-methyl-1H-pyrazol-4-yl, COOCH.sub.3, CONH.sub.2, CONHCH.sub.3, or CONHCH.sub.2CH.sub.2OCH.sub.3, R.sup.2 denotes H, Hal, or CN, R.sup.3 denotes H or CH.sub.3, X denotes 1,4-phenylen, 1,3-phenylen, 2-fluoro-1,4-phenylen, 2-methyl-1,4-phenylen, pyridine-3,6-diyl, 1,3-thiazol-3,5-diyl, 1,3-thiazol-2,4-diyl, 1,3-thiazol-2,5-diyl or pyrazol-1,4-diyl, each of which is unsubstituted or mono-, di-, or trisubstituted by Hal and/or A, Y is absent or denotes CO, SO.sub.2, NHCO, NCH.sub.3, CONH(CH.sub.2).sub.n, CONHCH.sub.2C(CH.sub.3).sub.2, CON(CH.sub.3)(CH.sub.2).sub.n, O, OCH.sub.2, OCH.sub.2CH.sub.2, S(═O)(═NH), —N═, or SO.sub.2N(CH.sub.3), Z denotes H, A, Hal, OA, [C(R.sup.3).sub.2].sub.nHet.sup.2 or N═S(═O)A.sub.2, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH.sub.2-groups may be replaced by O-atoms and wherein 1-7 H-atoms may be replaced by R.sup.5, or denotes (CH.sub.2).sub.nCyc, Cyc denotes cyclic alkyl having 3-7 C atoms, R.sup.5 denotes F, Cl, OH, SO.sub.2A, or N(R.sup.3).sub.2, Het.sup.1 denotes pyrazolyl which ray be mono- or disubstituted by A, Het.sup.2 denotes pyrrolidinyl, piperazinyl, piperidinyl, triazolyl, azetidinyl, morpholinyl, thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 6-oxa-2-azaspiro[3.4]octane-2-yl, 1-oxa-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaspiro[3.3]heptane-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]heptane-1-yl, 1H-pyrazolyl, thiazolidinyl, 2-oxa-7-azaspiro[3.5]nonane-7-yl, 1,4-oxazepanyl, 2-thia-6-azaspiro[3,3]heptane-6-yl, 2,8-dioxa-5-azaspiro[3.5]nonane-5-yl, 1H-1.3-benzodiazol-2-yl, 2-oxa-7-azaspiro[4.4]nonane-7-yl, 2-oxa-6-azaspiro[3.4]octane-6-yl, 8-oxa-2-azaspiro[4.5]decane-2-yl, 2,6-diazaspiro[3,4]octane-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptane-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 7-oxa-2-azaspiro[3.5]nonane-2-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2,7-diazaspiro[3.5]nonane-7-yl, 3-oxa-6-azabicyclo[3.1.1]heptane-6-yl, 1H,2H,3H-pyrrolo[3,4-c]pyridine-2-yl, 2,7-diazaspiro[3.5]nonane-2-yl, hexahydro-1H-furo[3,4-c]pyrrole-5-yl, octahydropyrrolo[2,3-c]pyrrole-5-yl, 5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-yl, 1H, 4H, 5H,6H-pyrrolo[3,4-c]pyrazole-5-yl, octahydropyrano[3,4-c]pyrrole-2-yl, octahydrofuro[3,4-c]pyridine-5-yl, octahydropyrrolo[3,4-c]pyrrole-2-yl, hexahydro-1H-2lambda6-thieno[3,4-c]pyrrole-5-yl, or tetrahydrofuro[3,4-c]pyrrole-5-yl, each of which may be unsubstituted or mono-, di-, or trisubstituted by A, Hal, CN, OR.sup.3, [C(R.sup.3).sub.2].sub.nN(R.sup.3).sub.2, [C(R.sup.3).sub.2].sub.nSO.sub.2A, [C(R.sup.3).sub.2].sub.nNR.sup.3SO.sub.2A, Het.sup.3, ═NR.sup.3, and/or ═O, Het.sup.3 denotes morpholinyl, 1H-pyrazolyl, lambda6-thiomorpholinyl, imidazolyl, azetidinyl, piperazinyl, piperidinyl, pyridinyl, oxetanyl, 1,2,4-oxadiazolyl, pyrimidinyl, oxolanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, oxan-4-yl, 1,2,3-triazolyl, or 1,2,4-triazolyl, each of which may be unsubstituted or mono- or disubstituted by A, Hal, OR.sup.3, oxetanyl, and/or ═O, Hal denotes F, Ca, Br, or I, n denotes 0, 1, 2 or 3, and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.
6. The compound according to claim 1, wherein the compound is selected from the group consisting of TABLE-US-00003 No. Name “A1” 2-[1-(4-{5-[6-(trifluoromethyl)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)pyrrolidin-2-yl]propan-2-ol “A2” 2-[(2R)-1-(4-{5-[6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)pyrrolidin-2-yl]propan-2-ol “A3” 3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5- yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole “A4” {4-[5-(6-bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-[(S)-2-(1- hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone “A5” 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 “A6” 4-{5-[5-cyano-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethylbenzamide “A7” 5-fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)pyrrolidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A8” 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 “A9” 3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5- yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole “A10” 5-chloro-3-(5-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2- oxazol-3-yl)-6-(2-methoxyethoxy)-1H-indazole “A11” 3-(5-(4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-3- yl)-6-(2-methoxyethoxy)-1H-indazole-5-carbonitrile “A12” 4-{5-[5-chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethylbenzamide “A13” 5-chloro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol- 5-yl]-1H-indazole “A14” 5-chloro-6-(2-methoxyethoxy)-3-{3-[4-(1H-1,2,4-triazol-1-yl)phenyl]- 1,2-oxazol-5-yl}-1H-indazole “A15” 5-chloro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2- methoxyethoxy)-1H-indazole “A16” 5-fluoro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2- methoxyethoxy)-1H-indazole “A17” N-(4-{5-[5-chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)acetamide “A18” N-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)acetamide “A19” methyl 3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-1H- indazole-6-carboxylate “A20” 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethylbenzamide “A21” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(1H-1,2,4-triazol-1-yl)phenyl]- 1,2-oxazol-5-yl}-1H-indazole “A22” 5-fluoro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol- 5-yl]-1H-indazole “A23” N-(2-methoxyethyl)-3-(3-{4-[(2-methoxyethyl)carbamoyl]phenyl}-1,2- oxazol-5-yl)-1H-indazole-6-carboxamide “A24” 3-[3-(4-dimethylcarbamoyl-phenyl)-isoxazol-5-yl]-1H-indazole-6- carboxylic acid methylamide “A25” 3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-N-(2- methoxyethyl)-1H-indazole-6-carboxamide “A26” 5-fluoro-3-{3-[4-(3-fluoroazetidine-1-carbonyl)phenyl]-1,2-oxazol-5- yl}-6-(2-methoxyethoxy)-1H-indazole “A27” 5-fluoro-3-(3-{4-[(3R)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2- oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A28” 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)azetidine-3-carbonitrile “A29” 5-fluoro-3-{3-[4-(3-methanesulfonylazetidine-1-carbonyl)phenyl]-1,2- oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole “A30” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-1lambda6-thiomorpholine-1,1-dione “A31” N-cyclopropyl-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]- 1,2-oxazol-3-yl}-N-methylbenzamide “A32” 5-fluoro-3-(3-{4-[(3S)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2- oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A33” 5-fluoro-3-{3-[4-(3-methoxyazetidine-1-carbonyl)phenyl]-1,2-oxazol-5- yl}-6-(2-methoxyethoxy)-1H-indazole “A34” 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-3-methylazetidin-3-ol “A35” N-[dimethyl(oxo)-lambda6-sulfanylidene]-4-{5-[5-fluoro-6-(2- methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide “A36” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazine-1- carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole “A37” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazin-1-yl)phenyl]- 1,2-oxazol-5-yl}-1H-indazole “A38” 3-[3-(6-ethoxypyridin-3-yl)-1,2-oxazol-5-yl]-5-fluoro-6-(2- methoxyethoxy)-1H-indazole “A39” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[6-(4-methylpiperazin-1-yl)pyridin- 3-yl]-1,2-oxazol-5-yl}-1H-indazole “A40” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(morpholin-4- yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A41” 1-(4-{5-[5-Fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3- yl}-phenyl)-1H-pyridin-2-one “A42” 3-{3-[4-(1,4-diazepan-1-yl)phenyl]-1,2-oxazol-5-yl}-5-fluoro-6-(2- methoxyethoxy)-1H-indazole “A43” (4-{3-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}- phenyl)-morpholin-4-yl-methanone “A44” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(1,4-oxazepane-4- carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole “A45” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A46” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(piperazine-1-carbonyl)phenyl]- 1,2-oxazol-5-yl}-1H-indazole “A47” [(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)imino]dimethyl-lambda6-sulfanone “A48” 5-fluoro-6-(2-methoxyethoxy)-3-[3-(1,3-thiazol-5-yl)-1,2-oxazol-5-yl]- 1H-indazole “A49” 4-{5-[5-fluoro-6-(3-hydroxy-2-methoxypropoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}-N,N-dimethylbenzamide “A50” 3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5- yl)-6-(trifluoromethyl)-1H-indazole “A51” [(2S)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methanol “A52” [(2R)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methanol “A53” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A54” [1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-4-methylpiperazin-2-yl]methanol “A55” 5-fluoro-3-(3-(4-[(2R)-2-(methanesulfonylmethyl)pyrrolidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A56” 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-3-methylazetidin-3-amine “A57” 4-[1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol- 3-yl}benzoyl)azetidin-3-yl]-1lambda6-thiomorpholine-1,1-dione “A58” 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 “A59” 2-[(2S)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)azetidin-2-yl]propan-2-ol “A60” 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 “A61” 5-fluoro-6-methoxy-3-(3-{4-[3-(morpholin-4-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A62” (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 “A63” (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 “A64” (4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- phenyl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone “A65” (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 “A66” (4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- phenyl)-((S)-3-hydroxymethyl-morpholin-4-yl)-methanone “A67” (4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- phenyl)-((R)-3-hydroxymethyl-morpholin-4-yl)-methanone “A68” (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 “A69” (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 “A70” (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 “A71” (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 “A72” N-[2-(dimethylamino)ethyl]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H- indazol-3-yl]-1,2-oxazol-3-yl}benzamide “A73” 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N-(1-methylazetidin-3-yl)benzamide “A74” 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 “A75” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(1H-pyrazol-1-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A76” 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-N,N-dimethylazetidin-3-amine “A77” 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 “A78” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-1lambda4-thiomorpholin-1-one “A79” 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 “A80” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-1-imino-1lambda6-thiomorpholin-1-one “A81” 5-fluoro-3-{3-[5-(3-fluoroazetidine-1-carbonyl)pyridin-2-yl]-1,2-oxazol- 5-yl}-6-(2-methoxyethoxy)-1H-indazole “A82” 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 “A83” 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 “A84” 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 “A85” 5-fluoro-3-(3-{4-[3-(1H-imidazol-1-yl)azetidine-1-carbonyl]phenyl}- 1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A86” 5-fluoro-3-{3-[5-(3-fluoroazetidine-1-carbonyl)-1,3-thiazol-2-yl]-1,2- oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole “A87” 5-fluoro-3-{3-[4-(3-fluoroazetidine-1-carbonyl)-1,3-thiazol-2-yl]-1,2- oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole “A88” 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 “A89” (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 “A90” 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 “A91” 6-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethylpyridine-3-carboxamide “A92” 2-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethyl-1,3-thiazole-5-carboxamide “A93” 2-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethyl-1,3-thiazole-4-carboxamide “A94” 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 “A95” [(2S)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)azetidin-2-yl]methan “A96” 1-(5-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3- yl}-pyridine-2-carbonyl)-azetidine-3-carbonitrile “A97” [(2R)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)azetidin-2-yl]methanol “A98” (3-fluoro-azetidin-1-yl)-(5-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H- indazol-3-yl]-isoxazol-3-yl}-pyridin-2-yl)-methanone “A99” 5-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- pyridine-2-carboxylic acid dimethylamide “A100” 5-fluoro-3-(3-{6-[(3R)-3-fluoropyrrolidine-1-carbonyl]pyridin-3-yl}- 1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A101” 5-fluoro-3-[3-(4-{3-fluoro-[1,3′-biazetidine]-1′-carbonyl}phenyl)-1,2- oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole “A102” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(4-methylpiperazin-1- yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A103” 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 “A104” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-carbonyl)phenyl]- 1,2-oxazol-5-yl}-1H-indazole “A105” [(3R)-4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)morpholin-3-yl]methanol “A106” [(3S)-4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)morpholin-3-yl]methanol “A107” 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 “A108” 6-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-3lambda6-thia-6-azabicyclo[3.1.1]heptane-3,3-dione “A109” (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 “A110” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3- (methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H- indazole “A111” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3R)-3- (methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H- indazole “A112” 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 “A113” (4-{3-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}- phenyl)-(4-methyl-piperazin-1-yl)-methanone “A114” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3R)-3-methylmorpholine-4- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A115” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-methylmorpholine-4- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A116” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-1-methylpiperazin-2-one “A117” 5-fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)pyrrolidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-6-methoxy-1H-indazole “A118” (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 “A119” (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 “A120” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-4-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A121” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-3-methyl-1lambda6-thiomorpholine-1,1-dione “A122” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)-1lambda6-thiomorpholine-1,1-dione “A123” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methyl-1,4-diazepan-1- yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole “A124” 3-(3-{4-[(cis)-4-methyl-octahydro-1H-pyrrolo[3,2-b]pyridin-1- yl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole “A125” 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 “A126” 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 “A127” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)-1lambda4-thiomorpholin-1-one “A128” 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)piperidin-4-ol “A129” 1-[(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)imino]-1lambda6-thiomorpholin-1-one “A130” 5-fluoro-6-(2-methoxy-ethoxy)-3-[3-(6-methoxy-pyridin-3-yl)-isoxazol- 5-yl]-1H-indazole “A131” 4-(5-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}pyridin-2-yl)-1lambda6-thiomorpholine-1,1-dione “A132” 4-[2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol- 3-yl}phenoxy)ethyl]-1lambda6-thiomorpholine-1,1-dione “A133” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(4-methylpiperazin-1- yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A134” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(piperazin-1- yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A135” 3-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- N,N-dimethyl-benzamide “A136” 2-(4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3- yl}-phenyl)-6-methyl-2H-pyridazin-3-one “A137” 5-fluoro-6-(2-methoxy-ethoxy)-3-[3-(1-methyl-1H-pyrazol-4-yl)- isoxazol-5-yl]-1H-indazole “A138” 2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)-1lambda6,2-thiazolidine-1,1-dione “A139” 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)morpholin-3-one “A140” 4-(5-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}pyridin-2-yl)-1lambda4-thiomorpholin-1-one “A141” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[6-(morpholin-4-yl)pyridin-3-yl]- 1,2-oxazol-5-yl}-1H-indazole “A142” 2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)-2,3-dihydropyridazin-3-one “A143” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(pyridin-2-yloxy)phenyl]-1,2- oxazol-5-yl}-1H-indazole “A144” 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N,N-dimethylbenzene-1-sulfonamide “A145” 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 “A146” (4-{3-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}- phenyl)-(3-morpholin-4-yl-azetidin-1-yl)-methanone “A147” (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 “A148” (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 “A149” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-2-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A150” 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}- N-(2-methanesulfonylethyl)-N-methylbenzamide “A151” 6-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-2lambda6-thia-6-azaspiro[3.3]heptane-2,2-dione “A152” 5-fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A153” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)pyrrolidine- 1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A154” 5-fluoro-3-(3-{4-[(2R)-2-(methanesulfonylmethyl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole “A155” 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 “A156” 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 “A157” 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 “A158” 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 “A159” 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 “A160” 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 “A161” 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 “A162” 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 “A163” 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 “A164” 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 “A165” 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 “A166” 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 “A167” (4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- phenyl)-(4-methyl-piperazin-1-yl)-methanone “A168” (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 “A169” (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 “A170” (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 “A171” (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 “A172” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrimidin-4-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A173” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(2-methylpyrimidin-4- yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A174” 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 “A175” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxolan-3-yl)piperazine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A176” 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 “A177” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrrolidin-1-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A178” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrrolidin-1-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A179” 3-(3-{4-[4-(cyclopropylmethyl)piperazine-1-carbonyl]phenyl}-1,2- oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole “A180” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2R)-2-methylmorpholine-4- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A181” 1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}benzoyl)-N,N,3-trimethylazetidin-3-amine “A182” 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 “A183” 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 “A184” (4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- phenyl)-((R)-3-methanesulfonylmethyl-morpholin-4-yl)-methanone “A185” 5-fluoro-6-(2-methoxyethoxy)-3-[3-(4-{4-[(3R)-oxolan-3-yl]piperazine- 1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole “A186” 5-fluoro-6-(2-methoxyethoxy)-3-[3-(4-{4-[(3S)-oxolan-3-yl]piperazine- 1-carbonyl}phenyl)-1,2-oxazol-5-yl]-1H-indazole “A187” 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 “A188” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxan-4-yl)piperazine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A189” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2S)-2-methylmorpholine-4- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A190” 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 “A191” 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-indazo “A192” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-3-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A193” (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 “A194” (4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}- phenyl)-(4-oxetan-3-yl-piperazin-1-yl)-methanone “A195” 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 “A196” (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 “A197” 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 “A198” 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 “A199” 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 “A200” 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 “A201” 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 “A202” 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 “A203” (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 “A204” 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 “A205” 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 “A206” 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 “A207” 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 “A208” 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 “A209” 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 “A210” 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 “A211” 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 “A212” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrimidin-5-yl)azetidine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A213” 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 “A214” 3-(3-{4-[(cis)-octahydropyrano[3,4-c]pyrrole-2-carbonyl]phenyl}-1,2- oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole “A215” 3-(3-{4-[(cis)-octahydrofuro[3,4-c]pyridine-5-carbonyl]phenyl}-1,2- oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole “A216” 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 “A217” (cis)-5-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2- oxazol-3-yl}benzoyl)-hexahydro-1H-2lambda6-thieno[3,4-c]pyrrole- 2,2-dione “A218” 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 “A219” {4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-(4- oxetan-3-yl-piperazin-1-yl)-methanone “A220” {4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}- (cis)-tetrahydro-furo[3,4-c]pyrrol-5-yl-methanone “A221” 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 “A222” {[1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol- 3-yl}benzoyl)pyrrolidin-2-yl]methyl}(methyl)amine “A223” 3-(3-{4-[(cis)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl}-1,2- oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole “A224” 2-[(5-fluoro-3-{3-[4-(piperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}- 1H-indazol-6-yl)oxy]ethan-1-ol “A225” {4-[5-(5-fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}- piperazin-1-yl-methanone “A226” (4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3- yl}phenyl)(imino)methyl-lambda6-sulfanone “A227” 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-sulfonyl)phenyl]- 1,2-oxazol-5-yl}-1H-indazole “A228” 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 “A229” 6-ethoxy-5-fluoro-3-(3-{4-[4-(oxetan-3-yl)piperazine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A230” 3-{3-[4-(3,3-dimethyl-piperidin-4-yl)-phenyl]-isoxazol-5-yl}-5-fluoro-6- (2-methoxy-ethoxy)-1H-indazole “A231” 5-fluoro-6-(2-methoxy-ethoxy)-3-{3-[4-(1,3,3-trimethyl-piperidin-4-yl)- phenyl]-isoxazol-5-yl}-1H-indazole “A232” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2,2,3,3,5,5,6,6-.sup.2H.sub.8)piperazine- 1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A233” 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)(2,2,3,3,5,5,6,6- .sup.2H.sub.8)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole “A234” 2-{[5-fluoro-3-(3-{4-[4-(oxetan-3-yl)(2,2,3,3,5,5,6,6-.sup.2H8)piperazine-1- carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazol-6-yl]oxy}ethan-1-ol and pharmaceutically acceptable solvates, salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.
7. A method for preparing the compound of the formula I according to claim 1 and pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers thereof, a) wherein in the compound of the formula I, when X denotes phenylene, Y denotes CO, Z denotes [C(R).sub.2].sub.nHet.sup.2, and n denotes 0, the method comprises: reacting a compound of the formula II ##STR00350## wherein R.sup.1 and R.sup.2 have the meanings indicated in claim 1, with a compound of formula III
Het.sup.2 II wherein Het.sup.2 has the meaning indicated in claim 1, b) wherein in the compound of the formula I, when R.sup.1 denotes Het.sup.1, the method comprises: reacting a compound of the formula IV ##STR00351## wherein R.sup.2, X, Y, and Z have the meanings indicated in claim 1, with a compound of formula V ##STR00352## wherein Het.sup.1 has the meanings indicated in claim 1, c) wherein when in the compound of the formula Ia, ##STR00353## wherein R.sup.1, R.sup.2, X, Y, and Z have the meanings indicated in claim 1, the method comprises: reacting a compound of the formula VI ##STR00354## wherein R.sup.1 and R.sup.2 have the meanings indicated in claim 1, with a compound of formula VII ##STR00355## wherein X, Y, and Z have the meanings indicated in claim 1, or d) wherein in the compound of the formula Ib, ##STR00356## wherein R.sup.1, R.sup.2, X, Y, and Z have the meanings indicated in claim 1, the method comprises: reacting a compound of the formula VIII ##STR00357## wherein R.sup.1 and R.sup.2 have the meanings indicated in claim 1, with a compound of formula IX
HO—N═CH—X—Y—Z IX wherein X, Y, and Z have the meanings indicated in claim 1, and/or a base or acid of the formula I is converted into one of its salts.
8. A medicament comprising at least one compound of the formula I according to claim 1 and/or pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient, or vehicle.
9. A method, comprising: administering, to a patient in need thereof, a compound of the formula I according to claim 1 and pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios, for the treatment and/or prevention of cancer.
10. The method according to claim 9, wherein the cancer is a gastrointestinal stromal tumor.
11. The medicament of claim 8, further comprising at least one medicament active ingredient.
12. A kit consisting of separate packs of (a) an effective amount of a compound of the formula I according to claim 1 and/or pharmaceutically acceptable salts, solvates, salts, and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
13. An intermediate selected from the group consisting of 2-bromo-5-fluoro-4-(2-methoxyethoxy)benzaldehyde ##STR00358## N′-[(1E)-[2-bromo-5-fluoro-4-(2-methoxyethoxy)phenyl]methylidene]-4-methylbenzene-1-sulfonohydrazide ##STR00359## 5-fluoro-6-(2-methoxyethoxy)-1-(4-methylbenzenesulfonyl)-1H-indazole ##STR00360## 5-fluoro-6-(2-methoxyethoxy)-1H-indazole ##STR00361## 5-fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole ##STR00362## tert-butyl 5-fluoro-3-iodo-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate ##STR00363## tert-butyl 5-fluoro-6-(2-methoxyethoxy)-3-[2(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate ##STR00364## 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole ##STR00365## tert-butyl 3-ethynyl-5-fluoro-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate ##STR00366## tert-butyl 5-fluoro-3-{3-[4-(methoxycarbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole-1-carboxylate ##STR00367## methyl 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoate ##STR00368## and 4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoic acid ##STR00369##
Description
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”)
[0310] ##STR00104##
[0311] 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 hydrogen carbonate solution is added. The solid is filtered off, washed with water and dried. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-[1-(4-{5-[6-(trifluoromethyl)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]propan-2-ol as off-white powder; UPLC/MS 0.87 min, [M+H].sup.+ 485.
[0312] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0313] The following compounds are prepared analogously:
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”)
[0314] ##STR00105##
[0315] off-white solid; HPLC/MS 1.60 min (A), [M+H].sup.+ 491.
[0316] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (“A3”)
[0317] ##STR00106##
[0318] off-white solid; HPLC/MS 1.27 min (A), [M+H].sup.+ 494.
[0319] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
{4-[5-(6-bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-[(R)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone (“A3a”)
[0320] ##STR00107##
[0321] off-white solid; UPLC/MS 0.86 min, [M+H].sup.+ 495/497.
{4-[5-(6-bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-[(S)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-methanone (“A4”)
[0322] ##STR00108##
[0323] UPLC/MS 0.86 min, [M+H].sup.+ 495/497.
[0324] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0325] ##STR00109##
[0326] white solid; HPLC/MS 1.27 min (A), [M+H].sup.+ 509.
[0327] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
{4-[5-(6-bromo-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-((S)-2,4-dimethyl-piperazin-1-yl)-methanone (“A5a”)
[0328] ##STR00110##
[0329] off-white solid; UPLC/MS 0.54 min, [M+H].sup.+ 480/482.
[0330] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
4-{5-[5-cyano-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (“A6”)
[0331] ##STR00111##
[0332] off-white powder; HPLC/MS 2.01 min (A), [M+H].sup.+ 432.
[0333] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
5-fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A7”)
[0334] ##STR00112##
[0335] white powder; HPLC/MS 1.55 min (A), [M+H].sup.+ 543.
[0336] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
3-(3-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(trifluoromethyl)-1H-indazole (“A50”)
[0337] ##STR00113##
[(2S)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methanol (“A51”)
[0338] ##STR00114##
[0339] off-white solid; UPLC/MS 0.70 min, [M+H].sup.+ 481.
[0340] .sup.1H NMR (400 MHz, DMSO-d.sub.6, rotational isomers) 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).
[(2R)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)pyrrolidin-2-yl]methanol (“A52”)
[0341] ##STR00115##
[0342] off-white solid; UPLC/MS 0.70 min, [M+H].sup.+ 481.
[0343] .sup.1H NMR (400 MHz, DMSO-d.sub.6, rotational isomers) 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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A53”)
[0344] ##STR00116##
[0345] white crystals; HPLC/MS 1.33 min (A), [M+H].sup.+ 522.
[0346] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-4-methylpiperazin-2-yl]methanol (“A54”)
[0347] ##STR00117##
[0348] pale brown solid; HPLC/MS 1.22 min (A), [M+H].sup.+ 510.
[0349] .sup.1H NMR (500 MHz, DMSO-d.sub.6, rotational isomers, selection of signals) 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).
5-fluoro-3-(3-{4-[(2R)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A55”)
[0350] ##STR00118##
[0351] white solid; UPLC/MS 0.73 min, [M+H].sup.+ 543.
[0352] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methylazetidin-3-amine (“A56”)
[0353] ##STR00119##
[0354] trifluoroacetate; white solid; HPLC/MS 2.24 min (A), [M+H].sup.+ 465.
[0355] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
4-[1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-3-yl]-1lambda6-thiomorpholine-1,1-dione (“A57”)
[0356] ##STR00120##
[0357] white powder; UPLC/MS 0.68 min, [M+H].sup.+ 570.
[0358] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0359] ##STR00121##
[0360] white solid; HPLC/MS 1.59 min (A), [M+H].sup.+ 495.
[0361] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
2-[(2S)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]propan-2-ol (“A59”)
[0362] ##STR00122##
[0363] pale yellow powder; UPLC/MS 0.76 min, [M+H].sup.+ 495.
[0364] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0365] ##STR00123##
[0366] off-white solid; UPLC/MS 0.72 min, [M+H].sup.+ 507.
[0367] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-methoxy-3-(3-{4-[3-(morpholin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A61”)
[0368] ##STR00124##
(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”)
[0369] ##STR00125##
(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”)
[0370] ##STR00126##
(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”)
[0371] ##STR00127##
[0372] white solid; m. p. 200-201° C., [M+H].sup.+ 538.
[0373] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0374] ##STR00128##
(4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-((S)-3-hydroxymethyl-morpholin-4-yl)-methanone (“A66”)
[0375] ##STR00129##
[0376] white solid; m. p. 115-116° C., [M+H].sup.+ 513.
[0377] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) 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).
(4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-((R)-3-hydroxymethyl-morpholin-4-yl)-methanone (“A67”)
[0378] ##STR00130##
(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”)
[0379] ##STR00131##
(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”)
[0380] ##STR00132##
(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”)
[0381] ##STR00133##
(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”)
[0382] ##STR00134##
3-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-N,N-dimethyl-benzamide (“A135”)
[0383] ##STR00135##
[0384] white solid; m.p. 160-165° C., [M+H].sup.+ 424.
[0385] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0386] ##STR00136##
[0387] 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. in a microwave reactor for 1 hour. 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 ethylacetate/methanol to afford 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 white powder; UPLC/MS 0.75 min, [M+H].sup.+ 497.
[0388] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).
[0389] The following compound is prepared analogously:
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”)
[0390] ##STR00137##
[0391] pale yellow solid; UPLC/MS 0.50 min (A), [M+H].sup.+ 482.
[0392] .sup.1H NMR (500 MHz, DMSO-d.sub.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, OH), 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).
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”)
[0393] ##STR00138##
[0394] brown solid; UPLC/MS 0.91 min, [M+H].sup.+ 510.
[0395] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0396] The following compound is prepared analogously:
3-(5-{4-[(2S)-2,4-dimethylpiperazine-1-carbonyl]phenyl}-1,2-oxazol-3-yl)-6-(2-methoxyethoxy)-1H-indazole-5-carbonitrile (“A11”)
[0397] ##STR00139##
[0398] brown solid; HPLC/MS 2.21 min (A), [M+H].sup.+ 501.
[0399] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
EXAMPLE 4
4-{5-[5-chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (“A12”)
[0400] ##STR00140##
[0401] 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) is added bis(trifluoroacetoxy)-iodobenzene (224 mg, 0.52 mmol) in four portions every two hours and the reaction mixture is stirred for 16 hours at room temperature. The reaction mixture is filtered. The residue is washed with methanol and dried under vacuum to afford 4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-N,N-dimethyl-benzamide as brown solid; HPLC/MS 2.61 min (A), [M+H].sup.+ 441.
[0402] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0403] The following compounds are prepared analogously
5-chloro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol-5-yl]-1H-indazole (“A13”)
[0404] ##STR00141##
[0405] pale brown solid; UPLC/MS 0.99 min, [M+H].sup.+ 385.
[0406] .sup.1H NMR (700 MHz, DMSO-d.sub.6) 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).
5-chloro-6-(2-methoxyethoxy)-3-{3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A14”)
[0407] ##STR00142##
[0408] off-white solid; HPLC/MS 2.73 min (A), [M+H].sup.+ 437.
[0409] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
5-chloro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole (“A15”)
[0410] ##STR00143##
[0411] off-white solid; HPLC/MS 2.61 min (A), [M+H].sup.+ 448.
[0412] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-3-[3-(4-methanesulfonylphenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole (“A16”)
[0413] ##STR00144##
[0414] off-white solid; HPLC/MS 2.52 min (A), [M+H].sup.+ 432.
[0415] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
N-(4-{5-[5-chloro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)acetamide (“A17”)
[0416] ##STR00145##
[0417] off-white solid; HPLC/MS 2.56 min (A), [M+H].sup.+ 427.
[0418] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
N-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)acetamide (“A18”)
[0419] ##STR00146##
[0420] off-white solid; HPLC/MS 2.43 min (A), [M+H].sup.+ 411.
[0421] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
methyl 3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole-6-carboxylate (“A19”)
[0422] ##STR00147##
[0423] off-white solid; UPLC/MS 1.01 min, [M−H].sup.− 389.
[0424] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (“A20”)
[0425] ##STR00148##
[0426] off-white solid; HPLC/MS 2.47 min (A), [M+H].sup.+ 425.
[0427] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A21”)
[0428] ##STR00149##
[0429] off-white solid; UPLC/MS 1.04 min, [M+H].sup.+ 421.
[0430] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-[3-(6-methylpyridin-3-yl)-1,2-oxazol-5-yl]-1H-indazole (“A22”)
[0431] ##STR00150##
[0432] white solid; HPLC/MS 2.08 min (A), [M+H].sup.+ 425.
[0433] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)(imino)methyl-lambda6-sulfanone (“A226”)
[0434] ##STR00151##
EXAMPLE 5
N-(2-methoxyethyl)-3-(3-{4-[(2-methoxyethyl)carbamoyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole-6-carboxamide (“A23”)
[0435] ##STR00152##
[0436] white powder; UPLC/MS 0.85 min, [M−H].sup.− 374.
[0437] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
[0438] The following compounds are prepared analogously:
3-[3-(4-dimethylcarbamoyl-phenyl)-isoxazol-5-yl]-1H-indazole-6-carboxylic acid methylamide (“A24”)
[0439] ##STR00153##
[0440] white solid; HPLC/MS 2.16 min (A), [M+H].sup.+ 390.
[0441] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
3-{3-[4-(dimethylcarbamoyl)phenyl]-1,2-oxazol-5-yl}-N-(2-methoxyethyl)-1H-indazole-6-carboxamide (“A25”)
[0442] ##STR00154##
[0443] white solid; HPLC/MS 2.21 min (A), [M+H].sup.+ 434.
[0444] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
EXAMPLE 6
5-fluoro-3-{3-[4-(3-fluoroazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (“A26”)
[0445] ##STR00155##
[0446] 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′-tetramethyl-uronium-hexafluorophosphate (36 mg, 0.09 mmol). The reaction mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated under vacuum and the residue is chromatographed on a silica gel column with ethyl acetate/methanol as eluent to afford (3-fluoro-azetidin-1-yl)-(4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-methanone none as white powder; HPLC/MS 2.51 min (A), [M+H].sup.+ 455.
[0447] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
[0448] The following compounds are prepared analogously:
5-fluoro-3-(3-{4-[(3R)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A27”)
[0449] ##STR00156##
[0450] white solid; HPLC/MS 2.52 min (A), [M+H].sup.+ 469.
[0451] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidine-3-carbonitrile (“A28”)
[0452] ##STR00157##
[0453] white solid; HPLC/MS 2.45 min (A), [M+H].sup.+ 462.
[0454] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
5-fluoro-3-{3-[4-(3-methanesulfonylazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (“A29”)
[0455] ##STR00158##
[0456] off-white solid; HPLC/MS 2.38 min (A), [M+H].sup.+ 515.
[0457] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1lambda6-thiomorpholine-1,1-dione (“A30”)
[0458] ##STR00159##
[0459] white solid; HPLC/MS 2.55 min (A), [M+H].sup.+ 515.
[0460] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
N-cyclopropyl-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-methylbenzamide (“A31”)
[0461] ##STR00160##
[0462] white solid; HPLC/MS 2.61 min (A), [M+H].sup.+ 451.
[0463] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-3-(3-{4-[(3S)-3-fluoropyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A32”)
[0464] ##STR00161##
[0465] white solid; HPLC/MS 2.53 min (A), [M+H].sup.+ 469.
[0466] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-3-{3-[4-(3-methoxyazetidine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (“A33”)
[0467] ##STR00162##
[0468] white solid; HPLC/MS 2.51 min (A), [M+H].sup.+ 467.
[0469] 1H NMR (500 MHz, DMSO-d.sub.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).
1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methylazetidin-3-ol (“A34”)
[0470] ##STR00163##
[0471] white solid; HPLC/MS 2.38 min (A), [M+H].sup.+ 467.
[0472] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
N-[dimethyl(oxo)-lambda6-sulfanylidene]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide (“A35”)
[0473] ##STR00164##
[0474] white solid; HPLC/MS 2.49 min (A), [M+H].sup.+ 473.
[0475] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A36”) Trifluoroacetate
[0476] ##STR00165##
[0477] white solid; HPLC/MS 2.19 min (A), [M+H].sup.+ 480.
[0478] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
N-[2-(dimethylamino)ethyl]-4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzamide (“A72”)
[0479] ##STR00166##
[0480] trifluoroacetate; white solid; HPLC/MS 2.24 min (A), [M+H].sup.+ 468.
[0481] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-(1-methylazetidin-3-yl)benzamide (“A73”)
[0482] ##STR00167##
[0483] trifluoroacetate; white solid; UPLC/MS 0.86 min; [M+H].sup.+ 466.
[0484] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0485] ##STR00168##
[0486] white solid; HPLC/MS 2.55 min (A), [M+H].sup.+ 479.
[0487] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0488] ##STR00169##
[0489] white solid; HPLC/MS 2.62 min (A), [M+H].sup.+ 503.
[0490] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-N,N-dimethylazetidin-3-amine (“A76”)
[0491] ##STR00170##
[0492] trifluoroacetate; white solid; UPLC/MS 0.84 min, [M+H].sup.+ 480.
[0493] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0494] ##STR00171##
[0495] colorless resin; HPLC/MS 2.63 min (A), [M+H].sup.+ 493.
[0496] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1lambda4-thiomorpholin-1-one (“A78”)
[0497] ##STR00172##
[0498] colorless resin; HPLC/MS 2.38 min (A), [M+H].sup.+ 499.
[0499] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0500] ##STR00173##
[0501] colorless resin; HPLC/MS 2.61 min (A), [M+H].sup.+ 479.
[0502] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1-imino-1lambda6-thiomorpholin-1-one (“A80”)
[0503] ##STR00174##
[0504] white solid; HPLC/MS 2.32 min (A), [M+H].sup.+ 514.
[0505] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
5-fluoro-3-{3-[5-(3-fluoroazetidine-1-carbonyl)pyridin-2-yl]-1,2-oxazol-5-yl}-6-(2-methoxyethoxy)-1H-indazole (“A81”)
[0506] ##STR00175##
[0507] white foam; HPLC/MS 2.56 min (A), [M+H].sup.+ 456.
[0508] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0509] ##STR00176##
[0510] trifluoroacetate, pale yellow foam; HPLC/MS 2.19 min (A), [M+H].sup.+ 523.
[0511] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0512] ##STR00177##
[0513] trifluoroacetate, white foam; HPLC/MS 2.23 min (A), [M+H].sup.+ 529.
[0514] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0515] ##STR00178##
[0516] trifluoroacetate, white foam; HPLC/MS 2.33 min (A), [M+H].sup.+ 529.
[0517] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0518] ##STR00179##
[0519] trifluoroacetate, white foam; HPLC/MS 2.26 min (A), [M+H].sup.+ 503.
[0520] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0521] ##STR00180##
[0522] white foam; HPLC/MS 2.66 min (A), [M+H].sup.+ 462.
[0523] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0524] ##STR00181##
[0525] white foam; HPLC/MS 2.74 min (A), [M+H].sup.+ 462.
[0526] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
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”)
[0527] ##STR00182##
[0528] trifluoroacetate, white foam; HPLC/MS 2.24 min (A), [M+H].sup.+ 492.
[0529] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
(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”)
[0530] ##STR00183##
[0531] UPLC/MS 0.65 min, [M+H].sup.+ 506.
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”)
[0532] ##STR00184##
[0533] off-white solid; HPLC/MS 1.53 min (A), [M+H].sup.+ 558.
[0534] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
6-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylpyridine-3-carboxamide (“A91”)
[0535] ##STR00185##
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”)
[0536] ##STR00186##
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”)
[0537] ##STR00187##
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”)
[0538] ##STR00188##
[(2S)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]methanol (“A95”)
[0539] ##STR00189##
[0540] off-white solid; HPLC/MS 1.94 min (A), [M+H].sup.+ 467.
[0541] .sup.1H NMR (700 MHz, DMSO-d.sub.6, rotational isomer, selection of signals) 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).
1-(5-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridine-2-carbonyl)-azetidine-3-carbonitrile (“A96”)
[0542] ##STR00190##
[(2R)-1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)azetidin-2-yl]methanol (“A97”)
[0543] ##STR00191##
[0544] off-white solid; HPLC/MS 1.45 min (A), [M+H].sup.+ 467.
[0545] .sup.1H NMR (700 MHz, DMSO-d.sub.6, rotational isomer, selection of signals) 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).
(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”)
[0546] ##STR00192##
5-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-pyridine-2-carboxylic acid dimethylamide (“A99”)
[0547] ##STR00193##
5-fluoro-3-(3-{6-[(3R)-3-fluoropyrrolidine-1′-carbonyl]pyridin-3-yl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A100”)
[0548] ##STR00194##
5-fluoro-3-[3-(4-{3-fluoro-[1,3′-biazetidine]-1-carbonyl}phenyl)-1,2-oxazol-5-yl]-6-(2-methoxyethoxy)-1H-indazole (“A101”)
[0549] ##STR00195##
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”)
[0550] ##STR00196##
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”)
[0551] ##STR00197##
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A104”)
[0552] ##STR00198##
[0553] white solid; UPLC/MS 0.72 min, [M+H].sup.+ 467.
[0554] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[(3R)-4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)morpholin-3-yl]methanol (“A105”)
[0555] ##STR00199##
[(3S)-4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)morpholin-3-yl]methanol (“A106”)
[0556] ##STR00200##
[0557] off-white solid; HPLC/MS 1.42 min (A), [M+H].sup.+ 497.
[0558] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0559] ##STR00201##
[0560] off-white solid; m. p. 119-121° C., [M+H].sup.+ 510.
[0561] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
6-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3lambda6-thia-6-azabicyclo[3.1.1]heptane-3,3-dione (“A108”)
[0562] ##STR00202##
[0563] off-white solid; UPLC/MS 0.70 min, [M+H].sup.+ 527.
[0564] 1H NMR (500 MHz, DMSO-d.sub.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).
(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”)
[0565] ##STR00203##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-(methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A110”)
[0566] ##STR00204##
[0567] off-white solid; HPLC/MS 1.56 min (A), [M+H].sup.+ 511.
[0568] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3R)-3-(methoxymethyl)morpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A111”)
[0569] ##STR00205##
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”)
[0570] ##STR00206##
[0571] white crystals; HPLC/MS 1.54 min (A), [M+H].sup.+ 479.
[0572] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3R)-3-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A114”)
[0573] ##STR00207##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(3S)-3-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A115”)
[0574] ##STR00208##
[0575] white solid; UPLC/MS 0.74 min, [M+H].sup.+ 481.
[0576] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-1-methylpiperazin-2-one (“A116”)
[0577] ##STR00209##
5-fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-methoxy-1H-indazole (“A117”)
[0578] ##STR00210##
(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”)
[0579] ##STR00211##
(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”)
[0580] ##STR00212##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A120”)
[0581] ##STR00213##
[0582] white solid; UPLC/MS 0.54 min, [M+H].sup.+ 514.
[0583] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-3-methyl-1lambda6-thiomorpholine-1,1-dione (“A121”)
[0584] ##STR00214##
[0585] white solid; UPLC/MS 0.72 min, [M+H].sup.+ 529.
[0586] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
EXAMPLE 7
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A37”)
[0587] ##STR00215##
[0588] off-white powder; HPLC/MS 1.68 min (A), [M+H].sup.+ 452.
[0589] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
[0590] The following compounds are prepared analogously:
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1lambda6-thiomorpholine-1,1-dione (“A122”)
[0591] ##STR00216##
[0592] pale yellow solid; HPLC/MS 2.06 min (A), [M+H].sup.+ 487.
[0593] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A123”)
[0594] ##STR00217##
[0595] off-white solid; HPLC/MS 1.31 min (A), [M+H].sup.+ 487.
[0596] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
3-(3-{4-[(cis)-4-methyl-octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (“A124”)
[0597] ##STR00218##
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”)
[0598] ##STR00219##
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”)
[0599] ##STR00220##
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1lambda4-thiomorpholin-1-one (“A127”)
[0600] ##STR00221##
[0601] pale yellow solid; HPLC/MS 1.95 min (A), [M+H].sup.+ 471.
[0602] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
1-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)piperidin-4-ol (“A128”)
[0603] ##STR00222##
1-[(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)imino]-1lambda6-thiomorpholin-1-one (“A129”)
[0604] ##STR00223##
[0605] hydrochloride, off-white solid; HPLC/MS 1.29 min (A), [M+H].sup.+ 486.
[0606] 1H NMR (400 MHz, DMSO-d.sub.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).
EXAMPLE 8
3-[3-(6-ethoxypyridin-3-yl)-1,2-oxazol-5-yl]-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (“A38”)
[0607] ##STR00224##
[0608] off-white solid; UPLC/MS 0.68 min, [M+H].sup.+ 399.
[0609] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
[0610] The following compound is prepared analogously:
5-fluoro-6-(2-methoxy-ethoxy)-3-[3-(6-methoxy-pyridin-3-yl)-isoxazol-5-yl]-1H-indazole (“A130”)
[0611] ##STR00225##
[0612] white solid; m.p. 210-213° C.; [M+H].sup.+ 385.
[0613] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0614] ##STR00226##
[0615] off-white powder; UPLC/MS 0.49 min, [M+H].sup.+ 453.
[0616] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 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).
[0617] The following compound is prepared analogously:
4-(5-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridin-2-yl)-1lambda6-thiomorpholine-1,1-dione (“A131”)
[0618] ##STR00227##
[0619] off-white solid; UPLC/MS 0.73 min, [M+H].sup.+ 488.
[0620] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
EXAMPLE 10
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A40”)
[0621] ##STR00228##
[0622] off-white powder; HPLC/MS 1.29 min (A), [M+H].sup.+ 483.
[0623] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0624] The following compounds are prepared analogously:
4-[2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenoxy)ethyl]-1lambda6-thiomorpholine-1,1-dione (“A132”)
[0625] ##STR00229##
[0626] white powder; HPLC/MS 2.06 min (A), [M+H].sup.+ 531.
[0627] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A133”)
[0628] ##STR00230##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A134”)
[0629] ##STR00231##
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
[0630] ##STR00232##
[0631] off-white solid; HPLC/MS 1.54 min (A), [M+H].sup.+ 447.
[0632] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
[0633] The following compounds are prepared analogously:
2-(4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-6-methyl-2H-pyridazin-3-one (“A136”)
[0634] ##STR00233##
5-fluoro-6-(2-methoxy-ethoxy)-3-[3-(1-methyl-1H-pyrazol-4-yl)-isoxazol-5-yl]-1H-indazole (“A137”)
[0635] ##STR00234##
2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-1lambda6,2-thiazolidine-1,1-dione (“A138”)
[0636] ##STR00235##
4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)morpholin-3-one (“A139”)
[0637] ##STR00236##
[0638] off-white solid; HPLC/MS 0.71 min, [M+H].sup.+ 453.
[0639] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
4-(5-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}pyridin-2-yl)-1lambda4-thiomorpholin-1-one (“A140”)
[0640] ##STR00237##
[0641] off-white powder; HPLC/MS 1.43 min (A), [M+H].sup.+ 472.
[0642] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-{3-[6-(morpholin-4-yl)pyridin-3-yl]-1,2-oxazol-5-yl}-1H-indazole (“A141”)
[0643] ##STR00238##
2-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)-2,3-dihydropyridazin-3-one (“A142”)
[0644] ##STR00239##
[0645] white solid; HPLC/MS 1.55 min (A), [M+H].sup.+ 448.
[0646] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(pyridin-2-yloxy)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A143”)
[0647] ##STR00240##
4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzene-1-sulfonamide (“A144”)
[0648] ##STR00241##
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”)
[0649] ##STR00242##
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(morpholine-4-sulfonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A227”)
[0650] ##STR00243##
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
[0651] ##STR00244##
[0652] pale orange solid; HPLC/MS 1.32 min (A), [M+H].sup.+ 452.
[0653] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
EXAMPLE 13
(4-{3-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-morpholin-4-yl-methanone (“A43”)
[0654] ##STR00245## ##STR00246##
[0655] white solid; m.p. 220-221° C., [M+H].sup.+ 467.
[0656] 1H NMR (400 MHz, DMSO-d.sub.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).
[0657] The following compounds are prepared analogously:
(4-{3-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-5-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (“A113”)
[0658] ##STR00247##
[0659] off-white solid; m.p. 210-211° C., [M+H].sup.+ 480.
[0660] 1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0661] ##STR00248##
[0662] white solid; m.p. 229-230° C., [M+H].sup.+ 522.
[0663] 1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0664] ##STR00249##
[0665] off-white solid; m.p. 210-211° C., [M+H].sup.+ 495.
[0666] 1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0667] ##STR00250##
EXAMPLE 14
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(1,4-oxazepane-4-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A44”)
[0668] ##STR00251##
[0669] 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 for 16 hours at room temperature. Water is added to the reaction mixture. The resultant precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane to afford (4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-[1,4]oxazepan-4-yl-methanone as white solid; UPLC/MS 0.71 min, [M+H].sup.+ 481.
[0670] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0671] The following compounds are prepared analogously:
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A45”)
[0672] ##STR00252##
[0673] white powder; HPLC/MS 1.26 min (A), [M+H].sup.+ 522.
[0674] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-2-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A149”)
[0675] ##STR00253##
[0676] white solid; UPLC/MS 0.67 min, [M+H].sup.+ 514.
[0677] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N-(2-methanesulfonylethyl)-N-methylbenzamide (“A150”)
[0678] ##STR00254##
6-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-2lambda6-thia-6-azaspiro[3.3]heptane-2,2-dione (“A151”)
[0679] ##STR00255##
5-fluoro-3-(3-{4-[(2S)-2-(methanesulfonylmethyl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A152”)
[0680] ##STR00256##
[0681] white solid; UPLC/MS 0.71 min, [M+H].sup.+ 529.
[0682] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(morpholin-4-yl)pyrrolidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A153”)
[0683] ##STR00257##
[0684] white powder; HPLC/MS 1.25 min, [M+H].sup.+ 536.
[0685] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.70 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 8.02 (d, J=11.0 Hz, OH), 7.76 (s, OH), 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).
5-fluoro-3-(3-{4-[(2R)-2-(methanesulfonylmethyl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-6-(2-methoxyethoxy)-1H-indazole (“A154”)
[0686] ##STR00258##
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”)
[0687] ##STR00259##
[0688] white solid; UPLC/MS 0.73 min, [M+H].sup.+ 509.
[0689] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0690] ##STR00260##
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”)
[0691] ##STR00261##
[0692] white solid; HPLC/MS 1.54 min (A), [M+H].sup.+ 507.
[0693] .sup.1H NMR (400 MHz, DMSO-d.sub.6; mixture of rotational isomers) 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).
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”)
[0694] ##STR00262##
[0695] white solid; HPLC/MS 1.48 min (A), [M+H].sup.+ 493.
[0696] .sup.1H NMR (700 MHz, DMSO-d.sub.6; mixture of rotational isomers) 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).
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”)
[0697] ##STR00263##
[0698] white solid; HPLC/MS 1.50 min (A), [M+H].sup.+ 521.
[0699] .sup.1H NMR (700 MHz, DMSO-d.sub.6; mixture of rotational isomers) 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).
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”)
[0700] ##STR00264##
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”)
[0701] ##STR00265##
[0702] white solid; UPLC/MS 0.69 min, [M+H].sup.+ 479.
[0703] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0704] ##STR00266##
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”)
[0705] ##STR00267##
[0706] white solid; UPLC/MS 0.69 min, [M+H].sup.+ 479.
[0707] .sup.1H NMR (500 MHz, DMSO-d.sub.6, mixture of rotational isomers) 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).
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”)
[0708] ##STR00268##
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”)
[0709] ##STR00269##
[0710] white solid; HPLC/MS 1.57 min (A), [M+H].sup.+ 507.
[0711] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0712] ##STR00270##
[0713] white solid; HPLC/MS 1.57 min, [M+H].sup.+ 519.
[0714] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
(4-{5-[5-chloro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (“A167”)
[0715] ##STR00271##
[0716] white solid; m. p. 105-106° C., [M+H].sup.+ 496.
[0717] .sup.1H NMR (400 MHz, DMSO-d.sub.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), 3.41-0.33 (m, 5H), 2.43-2.26 (m, 4H), 2.22 (s, 3H).
(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”)
[0718] ##STR00272##
[0719] white solid; m. p. 119-120° C., [M+H].sup.+ 540.
[0720] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0721] ##STR00273##
[0722] white solid; m. p. 129-130° C., [M+H].sup.+ 493.
[0723] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0724] ##STR00274##
(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”)
[0725] ##STR00275##
[0726] white solid; m. p. 125-126° C., [M+H].sup.+ 536.
[0727] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrimidin-4-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A172”)
[0728] ##STR00276##
[0729] white solid; HPLC/MS 1.49 min (A), [M+H].sup.+ 515.
[0730] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0731] ##STR00277##
[0732] trifluoroacetate, yellow powder; UPLC/MS 0.71 min, [M+H].sup.+ 529.
[0733] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0734] ##STR00278##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxolan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A175”)
[0735] ##STR00279##
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”)
[0736] ##STR00280##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(piperidin-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A177”)
[0737] ##STR00281##
[0738] white solid; HPLC/MS 1.28 min (A), [M+H].sup.+ 520.
[0739] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrrolidin-1-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A178”)
[0740] ##STR00282##
[0741] white solid; HPLC/MS 1.27 min (A), [M+H].sup.+ 506.
[0742] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
3-(3-{4-[4-(cyclopropylmethyl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-5-fluoro-6-(2-methoxyethoxy)-1H-indazole (“A179”)
[0743] ##STR00283##
[0744] white solid; UPLC/MS 0.51 min, [M+H].sup.+ 520.
[0745] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2R)-2-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A180”)
[0746] ##STR00284##
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”)
[0747] ##STR00285##
[0748] trifluoroacetate, white solid; UPLC/MS 0.79 min, [M+H].sup.+ 494.
[0749] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0750] ##STR00286##
[0751] white solid; HPLC/MS 1.54 min (A), [M+H].sup.+ 479.
[0752] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0753] ##STR00287##
[0754] white solid; HPLC/MS 1.34 min (A), [M+H].sup.+ 500.
[0755] .sup.1H NMR (500 MHz, DMSO-d.sub.6, mixture of rotational isomers), δ 13.71 (s, 1H), 8.72 (s, 0.5H), 8.60-8.51 (m, 1.5H), 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).
(4-{5-[5-fluoro-6-(2-methoxy-ethoxy)-1H-indazol-3-yl]-isoxazol-3-yl}-phenyl)-((R)-3-methanesulfonylmethyl-morpholin-4-yl)-methanone (“A184”)
[0756] ##STR00288##
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”)
[0757] ##STR00289##
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”)
[0758] ##STR00290##
[0759] white solid; HPLC/MS 1.26 min (A), [M+H].sup.+ 536.
[0760] 1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0761] ##STR00291##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxan-4-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A188”)
[0762] ##STR00292##
[0763] off-white solid; HPLC/MS 1.23 min (A), [M+H].sup.+ 550.
[0764] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2S)-2-methylmorpholine-4-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A189”)
[0765] ##STR00293##
[0766] white solid; UPLC/MS 0.73 min, [M+H].sup.+ 481.
[0767] .sup.1H NMR (500 MHz, DMSO-d.sub.6, rotational isomers, selection of peaks) 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).
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”)
[0768] ##STR00294##
[0769] white solid; HPLC/MS 1.34 min, [M+H].sup.+ 536.
[0770] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0771] ##STR00295##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyridin-3-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A192”)
[0772] ##STR00296##
[0773] white powder; UPLC/MS 0.57 min, [M+H].sup.+ 514.
[0774] .sup.1H NMR (700 MHz, DMSO-d.sub.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).
(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”)
[0775] ##STR00297##
[0776] white solid; m. p. 138-139° C., [M+H].sup.+ 536.
[0777] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
(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”)
[0778] ##STR00298##
[0779] white solid; m. p. 123-124° C., [M+H].sup.+ 538.
[0780] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0781] ##STR00299##
(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”)
[0782] ##STR00300##
[0783] yellow solid; m. p. 161-162° C., [M+H].sup.+ 540.
[0784] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0785] ##STR00301##
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”)
[0786] ##STR00302##
[0787] white solid; HPLC/MS 1.24 min (A), [M+H].sup.+ 536.
[0788] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0789] ##STR00303##
[0790] white solid; HPLC/MS 1.23 min (A), [M+H].sup.+ 562.
[0791] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0792] ##STR00304##
[0793] trifluoroacetate, white solid; HPLC/MS 1.27 min (A), [M+H].sup.+ 536.
[0794] .sup.1H NMR (500 MHz, DMSO-d.sub.6, partially very broad signals, 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).
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”)
[0795] ##STR00305##
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”)
[0796] ##STR00306##
[0797] white solid; UPLC/MS 0.69 min, [M+H].sup.+ 493.
[0798] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
(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”)
[0799] ##STR00307##
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”)
[0800] ##STR00308##
[0801] white solid; HPLC/MS 1.41 min (A), [M+H].sup.+ 536.
[0802] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0803] ##STR00309##
[0804] white solid; HPLC/MS 1.13 min (A), [M+H].sup.+ 508.
[0805] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0806] ##STR00310##
[0807] off-white solid; HPLC/MS 1.27 min (A), [M+H].sup.+ 530.
[0808] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
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”)
[0809] ##STR00311##
[0810] off-white solid; UPLC/MS 0.66 min (A), [M+H].sup.+ 501.
[0811] .sup.1H NMR (500 MHz, DMSO-d.sub.6, mixture of rotational isomers) 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).
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”)
[0812] ##STR00312##
[0813] off-white solid; UPLC/MS 0.65 min (A), [M+H].sup.+ 489.
[0814] .sup.1H NMR (500 MHz, DMSO-d.sub.6, mixture of rotational isomers) 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).
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”)
[0815] ##STR00313##
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”)
[0816] ##STR00314##
[0817] white solid; HPLC/MS 1.30 min (A), [M+H].sup.+ 536.
[0818] .sup.1H NMR (500 MHz, DMSO-d.sub.6, mixture of rotational isomers) 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).
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”)
[0819] ##STR00315##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[3-(pyrimidin-5-yl)azetidine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A212”)
[0820] ##STR00316##
[0821] white solid; HPLC/MS 1.40 min (A), [M+H].sup.+ 515.
[0822] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0823] ##STR00317##
[0824] off-white solid; UPLC/MS 0.69 min, [M+H].sup.+ 503.
[0825] .sup.1H NMR (500 MHz, DMSO-d.sub.6, mixture of rotational isomers) 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).
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”)
[0826] ##STR00318##
[0827] white solid; HPLC/MS 1.54 min (A), [M+H].sup.+ 507.
[0828] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0829] ##STR00319##
[0830] white solid; HPLC/MS 1.53 min (A), [M+H].sup.+ 507.
[0831] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
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”)
[0832] ##STR00320##
[0833] trifluoroacetate, white solid; UPLC/MS 0.48 min, [M+H].sup.+ 548.
[0834] .sup.1H NMR (500 MHz, DMSO-d.sub.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 signals, 8H), 3.80-3.70 (m, 2H), 3.36 (s, 3H).
(cis)-5-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)-hexahydro-1H-2lambda6-thieno[3,4-c]pyrrole-2,2-dione (“A217”)
[0835] ##STR00321##
[0836] white solid; UPLC/MS 0.66 min, [M+H].sup.+ 541.
[0837] .sup.1H NMR (500 MHz, DMSO-d.sub.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 signals), 3.12 (bs, 3H).
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”)
[0838] ##STR00322##
[0839] white solid; UPLC/MS 0.70 min, [M+H].sup.+ 517.
[0840] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
{4-[5-(5-Fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-(4-oxetan-3-yl-piperazin-1-yl)-methanone (“A219”)
[0841] ##STR00323##
{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”)
[0842] ##STR00324##
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”)
[0843] ##STR00325##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)(2,2,3,3,5,5,6,6-.SUP.2.H.SUB.8.)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A233”)
[0844] ##STR00326##
2-{[5-fluoro-3-(3-{4-[4-(oxetan-3-yl)(2,2,3,3,5,5,6,6-.SUP.2.H8)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazol-6-yl]oxy}ethan-1-ol (“A234”)
[0845] ##STR00327##
EXAMPLE 15
5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(piperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazole (“A46”) Hydrochloride
[0846] ##STR00328##
[0847] 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 for 16 hours at room temperature. Saturated sodium hydrogen carbonate solution is added to the reaction mixture. The resultant precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford tert-butyl 4-(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}benzoyl)piperazine-1-carboxylate as white solid; HPLC/MS 1.75 min, [M+H].sup.+ 566.
[0848] 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 for 2.5 hours at room temperature. The solvent is removed under reduced pressure to afford 5-fluoro-6-(2-methoxyethoxy)-3-{3-[4-(piperazine-1-carbonyl)-phenyl]-1,2-oxazol-5-yl}-1H-indazole hydrochloride as white solid; HPLC/MS 1.21 min (A), [M+H].sup.+ 466.
[0849] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0850] The following compounds are prepared analogously:
{[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”)
[0851] ##STR00329##
[0852] pale yellow solid; HPLC/MS 1.31 min (A), [M+H].sup.+ 494.
[0853] .sup.1H NMR (500 MHz, DMSO-d.sub.6, rotational isomers, selection of peaks) 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).
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
[0854] ##STR00330##
2-[(5-fluoro-3-{3-[4-(piperazine-1-carbonyl)phenyl]-1,2-oxazol-5-yl}-1H-indazol-6-yl)oxy]ethan-1-ol (“A224”)
[0855] ##STR00331##
{4-[5-(5-fluoro-6-methoxy-1H-indazol-3-yl)-isoxazol-3-yl]-phenyl}-piperazin-1-yl-methanone (“A225”)
[0856] ##STR00332##
5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[(2,2,3,3,5,5,6,6-.SUP.2.Hs)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole hydrochloride (“A232”)
[0857] ##STR00333##
EXAMPLE 16
[(4-{5-[5-fluoro-6-(2-methoxyethoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}phenyl)imino]dimethyl-lambda6-sulfanone (“A47”)
[0858] ##STR00334##
[0859] white solid; HPLC/MS 2.52 min (A), [M+H].sup.+ 445.
[0860] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 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).
EXAMPLE 17
5-fluoro-6-(2-methoxyethoxy)-3-[3-(1,3-thiazol-5-yl)-1,2-oxazol-5-yl]-1H-indazole (“A48”)
[0861] ##STR00335##
[0862] pale brown solid; HPLC/MS 2.61 min (A), [M+H].sup.+ 361.
[0863] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
EXAMPLE 18
4-{5-[5-fluoro-6-(3-hydroxy-2-methoxypropoxy)-1H-indazol-3-yl]-1,2-oxazol-3-yl}-N,N-dimethylbenzamide (“A49”)
[0864] ##STR00336## ##STR00337## ##STR00338##
[0865] pale yellow solid; UPLC/MS 0.65 min (A), [M+H].sup.+ 455.
[0866] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
EXAMPLE 19
3-{3-[4-(3,3-dimethyl-piperidin-4-yl)-phenyl]-isoxazol-5-yl}-5-fluoro-6-(2-methoxy-ethoxy)-1H-indazole (“A230”)
[0867] ##STR00339##
and
5-fluoro-6-(2-methoxy-ethoxy)-3-{3-[4-(1,3,3-trimethyl-piperidin-4-yl)-phenyl]-isoxazol-5-yl}-1H-indazole (“A231”)
[0868] ##STR00340##
Synthetic Scheme:
[0869] ##STR00341## ##STR00342##
[0870] “A230”:
[0871] yellow solid; [M+H].sup.+ 465; .sup.1H NMR (400 MHz, DMSO-d.sub.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)
[0872] “A231”:
[0873] white solid; [M+H].sup.+ 479; .sup.1H NMR (300 MHz, DMSO-d.sub.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).
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”)
[0874] ##STR00343##
[0875] trifluoroacetate; white powder; UPLC/MS 0.47 min, [M+H].sup.+ 540.
[0876] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
EXAMPLE 21
Alternative Synthesis of “A45”:
[0877] ##STR00344## ##STR00345##
[0878] 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-dimethyl-aminopropyl)-N′-ethylcarbodiimide hydrochloride (403 mg, 2.10 mmol). The reaction mixture is stirred for 90 minutes at room temperature. The reaction mixture is evaporated to dryness. The residue is treated with saturated sodium hydrogen carbonate solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to afford 4-[4-(oxetan-3-yl)piperazine-1-carbonyl]benzaldehyde as yellow oil; HPLC/MS 0.82 min (A), [M+H].sup.+ 275.
[0879] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
[0880] 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 resultant 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 for 1 hour at room temperature. The reaction mixture is neutralized with 1 N sodium hydroxide solution (2 ml). The resultant precipitate is filtered off, washed with water and dried under vacuum to afford N-({4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}methylidene)hydroxylamine as white powder; UPLC/MS 0.30 min, [M+H].sup.+ 290.
[0881] .sup.1H NMR (400 MHz, DMSO-d.sub.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).
[0882] 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) aqueous sodium hypochlorite solution (content approx. 14%, 143 μl, approx. 0.33 mmol) is added dropwise. The reaction mixture is stirred for 18 hours at room temperature. 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 with dichloromethane/methanol as eluent to afford 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 colorless resin; UPLC/MS 0.69 min, [M+H].sup.+ 622.
[0883] 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 for 2 hours at room temperature. The reaction mixture is treated with saturated ammonium chloride solution. The resultant precipitate is filtered off, washed with water and dried under vacuum to afford 5-fluoro-6-(2-methoxyethoxy)-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole as off-white solid; UPLC/MS 0.53 min. [M+H].sup.+ 522.
[0884] The following compound is prepared analogously:
6-ethoxy-5-fluoro-3-(3-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]phenyl}-1,2-oxazol-5-yl)-1H-indazole (“A229”)
[0885] ##STR00346##
[0886] off-white crystals; HPLC/MS 1.34 min (A), [M+H].sup.+ 492.
[0887] .sup.1H NMR (500 MHz, DMSO-d.sub.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).
EXAMPLE 22—SALT FORMATION
[0888] ##STR00347##
[0889] 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) is added methanesulfonic acid (18.6 μl, 0.28 mmol) and the suspension is stirred for 1 hour at 75° C. The mixture is allowed to reach room temperature. The solids are filtered off, washed with water and dried under vacuum to afford (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 white powder.
[0890] .sup.1H NMR (500 MHz, DMSO-d.sub.6, very broad signals 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).
[0891] 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”) are prepared similarly: [0892] hydrochloride [0893] maleate [0894] hemi-ethanedisulfonate [0895] hemi-phosphate [0896] sulfate [0897] benzenesulfonate [0898] para-toluenesulfonate
[0899] 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: [0900] methanesulfonate [0901] trifluoroacetate.
[0902] The following examples relate to medicaments:
EXAMPLE A: INJECTION VIALS
[0903] A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.
EXAMPLE B: SUPPOSITORIES
[0904] A mixture of 20 g of an active ingredient of the 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.
EXAMPLE C: SOLUTION
[0905] A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH.sub.2PO.sub.4.2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.
EXAMPLE D: OINTMENT
[0906] 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
EXAMPLE E: TABLETS
[0907] A mixture of 1 kg of active ingredient of the 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 pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.
EXAMPLE F: DRAGEES
[0908] Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.
EXAMPLE G: CAPSULES
[0909] 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.
EXAMPLE H: AMPOULES
[0910] A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.