ES2365258T3 - Derivados de tiazol condensados como inhibidores de quinasa. - Google Patents
Derivados de tiazol condensados como inhibidores de quinasa. Download PDFInfo
- Publication number
- ES2365258T3 ES2365258T3 ES07733382T ES07733382T ES2365258T3 ES 2365258 T3 ES2365258 T3 ES 2365258T3 ES 07733382 T ES07733382 T ES 07733382T ES 07733382 T ES07733382 T ES 07733382T ES 2365258 T3 ES2365258 T3 ES 2365258T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- amino
- dialkyl
- pyrazolyl
- pyridinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003112 inhibitor Substances 0.000 title description 5
- 238000011282 treatment Methods 0.000 claims abstract description 67
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 6
- 230000001363 autoimmune Effects 0.000 claims abstract description 5
- 230000002503 metabolic effect Effects 0.000 claims abstract description 5
- 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 5
- 230000003040 nociceptive effect Effects 0.000 claims abstract description 5
- 230000000771 oncological effect Effects 0.000 claims abstract description 5
- 229940124639 Selective inhibitor Drugs 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 3
- -1 haloarylpyrrolidinyl Chemical group 0.000 claims description 1893
- 125000000217 alkyl group Chemical group 0.000 claims description 556
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 352
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 322
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 282
- 150000001875 compounds Chemical class 0.000 claims description 233
- 125000004076 pyridyl group Chemical group 0.000 claims description 177
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 175
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 157
- 125000003118 aryl group Chemical group 0.000 claims description 133
- 125000003545 alkoxy group Chemical group 0.000 claims description 112
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 111
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 93
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 239000001257 hydrogen Substances 0.000 claims description 90
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 80
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 79
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 63
- 125000001424 substituent group Chemical group 0.000 claims description 58
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 51
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 48
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 44
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 150000002431 hydrogen Chemical class 0.000 claims description 41
- 125000002757 morpholinyl group Chemical group 0.000 claims description 39
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 38
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 125000003386 piperidinyl group Chemical group 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 125000002883 imidazolyl group Chemical group 0.000 claims description 26
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 24
- 125000004104 aryloxy group Chemical group 0.000 claims description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 22
- 125000000335 thiazolyl group Chemical group 0.000 claims description 22
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 21
- 125000006542 morpholinylalkyl group Chemical group 0.000 claims description 21
- 150000001721 carbon Chemical group 0.000 claims description 20
- 125000004193 piperazinyl group Chemical group 0.000 claims description 20
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 18
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 18
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 16
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 16
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 16
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 15
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000001425 triazolyl group Chemical group 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 11
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 125000001041 indolyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000002923 oximes Chemical class 0.000 claims description 10
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 8
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 8
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims description 8
- 125000003106 haloaryl group Chemical group 0.000 claims description 8
- 125000004996 haloaryloxy group Chemical group 0.000 claims description 8
- 125000005968 oxazolinyl group Chemical group 0.000 claims description 8
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 7
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 7
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 7
- 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 7
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 7
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 6
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 101100294104 Caenorhabditis elegans nhr-34 gene Proteins 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 2
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000004987 dibenzofuryl group Chemical group C1(=CC=CC=2OC3=C(C21)C=CC=C3)* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 30
- 125000005129 aryl carbonyl group Chemical group 0.000 claims 5
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 3
- 125000005016 hydroxyalkynyl group Chemical group 0.000 claims 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 2
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims 2
- 241001024304 Mino Species 0.000 claims 1
- CHVAWSWMXBIOLB-UHFFFAOYSA-N n-phenyl-1,3-oxazol-2-amine Chemical compound C=1C=CC=CC=1NC1=NC=CO1 CHVAWSWMXBIOLB-UHFFFAOYSA-N 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract description 5
- QGUSXKFSPVAZOB-UHFFFAOYSA-N 6,7-dihydro-5h-[1,3]thiazolo[5,4-c]pyridin-4-one Chemical class O=C1NCCC2=C1SC=N2 QGUSXKFSPVAZOB-UHFFFAOYSA-N 0.000 abstract description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 abstract 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 abstract 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 68
- 125000005843 halogen group Chemical group 0.000 description 59
- 238000000034 method Methods 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000012071 phase Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 35
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 33
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 31
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 229910052794 bromium Inorganic materials 0.000 description 29
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 28
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 125000006301 indolyl methyl group Chemical group 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000000746 purification Methods 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 16
- 125000001153 fluoro group Chemical group F* 0.000 description 16
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 16
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 16
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000005605 benzo group Chemical group 0.000 description 15
- 125000001309 chloro group Chemical group Cl* 0.000 description 15
- 235000019253 formic acid Nutrition 0.000 description 15
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 125000003944 tolyl group Chemical group 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 9
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 125000006278 bromobenzyl group Chemical group 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229910052681 coesite Inorganic materials 0.000 description 7
- 229910052906 cristobalite Inorganic materials 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 7
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 7
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 7
- 235000012239 silicon dioxide Nutrition 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 229910052682 stishovite Inorganic materials 0.000 description 7
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| GB0620062A GB0620062D0 (en) | 2006-10-10 | 2006-10-10 | Therapeutic agents |
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| WO2009071890A1 (en) * | 2007-12-04 | 2009-06-11 | Ucb Pharma S.A. | Tricyclic kinase inhibitors |
| WO2009071895A1 (en) * | 2007-12-04 | 2009-06-11 | Ucb Pharma S.A. | Fused thiazole and thiophene derivatives as kinase inhibitors |
| MX2010006457A (es) | 2007-12-19 | 2010-07-05 | Amgen Inc | Compuestos fusionados de piridina, pirimidina y triazina como inhibidores de ciclo celular. |
| MX2010010975A (es) | 2008-04-07 | 2010-11-01 | Amgen Inc | Amino piridinas/pirimidinas gem-disustituidas y espirociclicas como inhibidores de ciclo celular. |
| JPWO2009130900A1 (ja) * | 2008-04-24 | 2011-08-11 | 日本曹達株式会社 | オキシム誘導体、中間体化合物および植物病害防除剤 |
| WO2010011871A2 (en) * | 2008-07-23 | 2010-01-28 | The Regents Of The University Of California | Methods and compositions for providing salicylic acid-independent pathogen resistance in plants |
| US20110172217A1 (en) * | 2008-09-05 | 2011-07-14 | Shionogi & Co., Ltd. | Ring-fused morpholine derivative having pi3k-inhibiting activity |
| CA2752596A1 (en) | 2009-02-17 | 2010-08-26 | Vertex Pharmaceuticals Incorporated | Tetrahydrothiazolopyridine inhibitors of phosphatidylinositol 3-kinase |
| US20120022057A1 (en) * | 2009-03-18 | 2012-01-26 | Schering Corporation | Bicyclic compounds as inhibitors of diacyglycerol acyltransferase |
| UY32582A (es) * | 2009-04-28 | 2010-11-30 | Amgen Inc | Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero |
| US8410095B2 (en) * | 2009-05-20 | 2013-04-02 | Glaxosmithkline Llc | Thiazolopyrimidinone derivatives as PI3 kinase inhibitors |
| GB0912946D0 (en) | 2009-07-24 | 2009-09-02 | Addex Pharmaceuticals Sa | New compounds 5 |
| AU2010286168B2 (en) | 2009-08-20 | 2014-05-15 | Karus Therapeutics Limited | Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors |
| WO2011073347A1 (en) * | 2009-12-18 | 2011-06-23 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mglur5 receptors |
| AU2010332811B2 (en) | 2009-12-18 | 2014-07-24 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mGluR5 receptors |
| WO2011157663A1 (de) | 2010-06-15 | 2011-12-22 | Bayer Cropscience Ag | Neue ortho-substituierte arylamid-derivate |
| US20130184320A1 (en) | 2010-10-01 | 2013-07-18 | Basf Se | Imine Compounds |
| WO2012051410A2 (en) * | 2010-10-13 | 2012-04-19 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
| KR20140004661A (ko) * | 2010-11-24 | 2014-01-13 | 엑셀리시스, 인코포레이티드 | mTOR의 억제제로서의 벤즈옥사제핀 및 그의 이용 방법 및 제법 |
| CN102649777B (zh) * | 2011-02-25 | 2014-03-12 | 中国中化股份有限公司 | 一种制备1-芳基-3-羧基-5-吡唑啉酮类化合物的方法 |
| DK2937349T3 (en) | 2011-03-23 | 2017-02-20 | Amgen Inc | CONDENSED TRICYCLIC DUAL INHIBITORS OF CDK 4/6 AND FLT3 |
| MY170922A (en) | 2011-12-22 | 2019-09-18 | Novartis Ag | Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives |
| US9120757B2 (en) | 2013-03-14 | 2015-09-01 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US20160039767A1 (en) | 2013-03-14 | 2016-02-11 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
| EP2970136A1 (en) | 2013-03-14 | 2016-01-20 | Epizyme, Inc. | Arginine methyl transferase inhibtors and uses thereof |
| JP2016514164A (ja) | 2013-03-14 | 2016-05-19 | エピザイム，インコーポレイティド | アルギニンメチルトランスフェラーゼ阻害剤としてのピラゾール誘導体およびその使用 |
| US9394258B2 (en) | 2013-03-14 | 2016-07-19 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| WO2014153226A1 (en) | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US9023883B2 (en) | 2013-03-14 | 2015-05-05 | Epizyme, Inc. | PRMT1 inhibitors and uses thereof |
| EP2970131B1 (en) | 2013-03-14 | 2017-11-15 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| EP2970181B1 (en) | 2013-03-14 | 2017-06-07 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US9447079B2 (en) | 2013-03-14 | 2016-09-20 | Epizyme, Inc. | PRMT1 inhibitors and uses thereof |
| US20160257650A1 (en) * | 2013-10-21 | 2016-09-08 | Umicore Ag & Co. Kg | Monoarylation of aromatic amines |
| GB201402431D0 (en) | 2014-02-12 | 2014-03-26 | Karus Therapeutics Ltd | Compounds |
| GB201514760D0 (en) | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds and method of use |
| GB201514754D0 (en) * | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds |
| GB201514758D0 (en) | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Formulation |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| CN108570043A (zh) * | 2018-06-20 | 2018-09-25 | 王延娇 | 一种化合物及其作为选择性pi3k抑制剂在治疗肿瘤中的应用 |
| EP3849548A1 (en) | 2018-09-13 | 2021-07-21 | Stemline Therapeutics Inc. | Methods for treating centronuclear myopathy |
| CN113164448A (zh) | 2018-12-19 | 2021-07-23 | 利奥制药有限公司 | 作为il-17的小分子调节剂的氨基酸苯胺类化合物 |
| PH12021551324A1 (en) * | 2019-01-08 | 2022-04-25 | Kyorin Seiyaku Kk | 15-pgdh inhibitor |
| US12304897B2 (en) | 2019-01-31 | 2025-05-20 | Kyorin Pharmaceutical Co., Ltd. | 15-PGDH inhibitors |
| GB201909468D0 (en) | 2019-07-01 | 2019-08-14 | Karus Therapeutics Ltd | Compounds for treating cancer |
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| EP2170906A1 (en) | 2010-04-07 |
| DK2170906T3 (da) | 2013-06-24 |
| CA2692085A1 (en) | 2008-12-31 |
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| US8338592B2 (en) | 2012-12-25 |
| CA2692085C (en) | 2015-10-13 |
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| CY1114419T1 (el) | 2016-08-31 |
| EP2170906B1 (en) | 2013-04-03 |
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| US20130079330A1 (en) | 2013-03-28 |
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| US20110003785A1 (en) | 2011-01-06 |
| CN101687885B (zh) | 2012-08-22 |
| ES2416364T3 (es) | 2013-07-31 |
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| PT2170906E (pt) | 2013-06-25 |
| ME01592B (me) | 2014-09-20 |
| AU2008269577B2 (en) | 2012-12-20 |
| EP2035436B1 (en) | 2011-05-25 |
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