EA032577B1 - Гетероарильные соединения, пригодные в качестве ингибиторов sumo-активирующего фермента - Google Patents

Info

Publication number

EA032577B1

EA032577B1 EA201690129A EA201690129A EA032577B1 EA 032577 B1 EA032577 B1 EA 032577B1 EA 201690129 A EA201690129 A EA 201690129A EA 201690129 A EA201690129 A EA 201690129A EA 032577 B1 EA032577 B1 EA 032577B1

Authority

EA

Eurasian Patent Office

Prior art keywords

amino

carbonyl

pyrimidin

methyl sulfamate

pyrazol

Prior art date

2013-07-02

Links

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• 125000001072 heteroaryl group Chemical group 0.000 title claims description 28
• 108090000790 Enzymes Proteins 0.000 title description 8
• 102000004190 Enzymes Human genes 0.000 title description 8
• 239000003112 inhibitor Substances 0.000 title description 6
• 230000003213 activating effect Effects 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 172
• 150000003839 salts Chemical class 0.000 claims abstract description 44
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
• 201000011510 cancer Diseases 0.000 claims abstract description 25
• 238000011282 treatment Methods 0.000 claims abstract description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
• 239000003937 drug carrier Substances 0.000 claims abstract description 9
• 239000003814 drug Substances 0.000 claims abstract description 7
• 238000004519 manufacturing process Methods 0.000 claims abstract description 7
• 206010006187 Breast cancer Diseases 0.000 claims abstract description 5
• 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 5
• 206010009944 Colon cancer Diseases 0.000 claims abstract description 4
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
• 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 4
• 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 4
• 201000009613 breast lymphoma Diseases 0.000 claims abstract description 4
• 201000005202 lung cancer Diseases 0.000 claims abstract description 4
• 208000020816 lung neoplasm Diseases 0.000 claims abstract description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 819
• -1 indolisinyl Chemical group 0.000 claims description 765
• FIYXUOWXHWJDAM-UHFFFAOYSA-N methyl sulfamate Chemical compound COS(N)(=O)=O FIYXUOWXHWJDAM-UHFFFAOYSA-N 0.000 claims description 456
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 230
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 175
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 159
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 88
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 88
• 229910052739 hydrogen Inorganic materials 0.000 claims description 83
• 239000001257 hydrogen Substances 0.000 claims description 82
• 229910052757 nitrogen Inorganic materials 0.000 claims description 70
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 68
• 238000000034 method Methods 0.000 claims description 67
• 125000001931 aliphatic group Chemical group 0.000 claims description 61
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 59
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 55
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
• 125000000623 heterocyclic group Chemical group 0.000 claims description 52
• 229910052717 sulfur Chemical group 0.000 claims description 51
• 125000005842 heteroatom Chemical group 0.000 claims description 50
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 49
• 239000011593 sulfur Chemical group 0.000 claims description 49
• 229910052760 oxygen Inorganic materials 0.000 claims description 47
• 239000001301 oxygen Chemical group 0.000 claims description 47
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 46
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 46
• 125000001424 substituent group Chemical group 0.000 claims description 44
• 125000000217 alkyl group Chemical group 0.000 claims description 31
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 229920006395 saturated elastomer Polymers 0.000 claims description 31
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 29
• 229910052736 halogen Inorganic materials 0.000 claims description 29
• 150000002431 hydrogen Chemical group 0.000 claims description 24
• 125000004076 pyridyl group Chemical group 0.000 claims description 24
• 150000002367 halogens Chemical class 0.000 claims description 21
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 19
• 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 claims description 17
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 17
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 16
• 239000000460 chlorine Substances 0.000 claims description 16
• 125000002947 alkylene group Chemical group 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 14
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• 239000011737 fluorine Chemical group 0.000 claims description 13
• 125000001847 2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1([H])C([H])([H])C1([H])* 0.000 claims description 12
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
• 125000006162 fluoroaliphatic group Chemical group 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• 239000012634 fragment Substances 0.000 claims description 11
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 9
• 125000002950 monocyclic group Chemical group 0.000 claims description 9
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 7
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
• 125000006165 cyclic alkyl group Chemical group 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
• HSFWRNGVRCDJHI-UHFFFAOYSA-N Acetylene Chemical compound C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 4
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
• 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 3
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 3
• 208000029742 colonic neoplasm Diseases 0.000 claims description 3
• 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 claims description 3
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
• 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 claims description 3
• 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 claims description 3
• 125000000532 dioxanyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
• 229910052740 iodine Inorganic materials 0.000 claims description 3
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
• 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
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• 125000002971 oxazolyl group Chemical group 0.000 claims description 3
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• 125000004193 piperazinyl group Chemical group 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 3
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• 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
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• TVSLNRQODQRVJZ-UHFFFAOYSA-N 2-(3,4,5-trifluorophenyl)acetonitrile Chemical group FC1=CC(CC#N)=CC(F)=C1F TVSLNRQODQRVJZ-UHFFFAOYSA-N 0.000 claims description 2
• 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
• 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
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• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
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• 239000000543 intermediate Substances 0.000 description 172
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