US 12,486,260 B2
Indazolyl-isoxazole derivatives for the treatment of diseases such as cancer
Dieter Dorsch, Ober-Ramstadt (DE); and Andreas Blum, Bensheim (DE)
Assigned to Merck Patent GmbH, Darmstadt (DE)
Appl. No. 17/429,938
Filed by Merck Patent GmbH, Darmstadt (DE)
PCT Filed Feb. 10, 2020, PCT No. PCT/EP2020/053241
§ 371(c)(1), (2) Date Aug. 10, 2021,
PCT Pub. No. WO2020/165062, PCT Pub. Date Aug. 20, 2020.
Claims priority of application No. 19156318 (EP), filed on Feb. 11, 2019.
Prior Publication US 2022/0127254 A1, Apr. 28, 2022
Int. Cl. C07D 413/14 (2006.01); A61P 35/00 (2006.01); C07D 231/56 (2006.01); C07D 401/14 (2006.01); C07D 403/14 (2006.01); C07D 413/04 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 487/10 (2006.01); C07D 491/048 (2006.01); C07D 491/08 (2006.01); C07D 491/107 (2006.01); C07D 495/04 (2006.01); C07D 495/08 (2006.01); C07D 495/10 (2006.01); C07D 498/10 (2006.01)
CPC C07D 413/14 (2013.01) [A61P 35/00 (2018.01); C07D 231/56 (2013.01); C07D 401/14 (2013.01); C07D 403/14 (2013.01); C07D 413/04 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 487/10 (2013.01); C07D 491/048 (2013.01); C07D 491/08 (2013.01); C07D 491/107 (2013.01); C07D 495/04 (2013.01); C07D 495/08 (2013.01); C07D 495/10 (2013.01); C07D 498/10 (2013.01)] 11 Claims
 
1. A compound of the formula Ib

OG Complex Work Unit Chemistry
wherein
R1 denotes Hal, CF3, OCH3, OCH2CH2OCH3, OCH2CH2OH, 1-methyl-1H-pyrazol-4-yl, COOCH3, CONH2, CONHCH3, or CONHCH2CH2OCH3,
R2 denotes H, Hal, or CN,
R3 denotes H or CH3,
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, SO2, NHCO, NCH3, CONH(CH2)n, CONHCH2C(CH3)2, CON(CH3)(CH2)n, O, OCH2, OCH2CH2, S(═O)(═NH), —N═, or SO2N(CH3),
Z denotes H, A, Hal, OA, [C(R3)2]nHet2 or N═S(═O)A2,
A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH2-groups may be replaced by O-atoms and wherein 1-7 H-atoms may be replaced by R5,
or denotes (CH2)nCyc,
Cyc denotes cyclic alkyl having 3-7 C atoms,
R5 denotes F, Cl, OH, SO2A, or N(R3)2,
Het1 denotes pyrazolyl which may be mono- or disubstituted by A,
Het2 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, OR3, [C(R3)2]nN(R3)2, [C(R3)2]nSO2A, [C(R3)2]nNR3SO2A, Het3, ═NR3, and/or ═O,
Het3 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, OR3, oxetanyl, and/or ═O,
Hal denotes F, Cl, Br, or I,
n denotes 0, 1, 2, or 3,
or pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios.