TW201238951A - Heterocyclic inhibitors of MEK and methods of use thereof - Google Patents
Heterocyclic inhibitors of MEK and methods of use thereof Download PDFInfo
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- TW201238951A TW201238951A TW101112592A TW101112592A TW201238951A TW 201238951 A TW201238951 A TW 201238951A TW 101112592 A TW101112592 A TW 101112592A TW 101112592 A TW101112592 A TW 101112592A TW 201238951 A TW201238951 A TW 201238951A
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- Prior art keywords
- group
- alkyl
- aryl
- heteroaryl
- compound
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- 238000000034 method Methods 0.000 title claims abstract description 96
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 233
- 239000003112 inhibitor Substances 0.000 title description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
- 201000010099 disease Diseases 0.000 claims abstract description 49
- 238000011282 treatment Methods 0.000 claims abstract description 41
- 241000124008 Mammalia Species 0.000 claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 18
- -1 cyano, nitro, difluoroindolyl Chemical group 0.000 claims description 261
- 125000003118 aryl group Chemical group 0.000 claims description 251
- 125000001072 heteroaryl group Chemical group 0.000 claims description 245
- 125000000217 alkyl group Chemical group 0.000 claims description 207
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 125
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 111
- 238000006243 chemical reaction Methods 0.000 claims description 110
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 99
- 125000003342 alkenyl group Chemical group 0.000 claims description 88
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 85
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 75
- 239000002585 base Substances 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 69
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 65
- 239000002253 acid Substances 0.000 claims description 64
- 125000000304 alkynyl group Chemical group 0.000 claims description 64
- 229910052736 halogen Inorganic materials 0.000 claims description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 150000002367 halogens Chemical class 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 150000001412 amines Chemical class 0.000 claims description 53
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 51
- 239000000243 solution Substances 0.000 claims description 50
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 48
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 43
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 40
- 150000002431 hydrogen Chemical class 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 35
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 34
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 32
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 30
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 30
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 239000007789 gas Substances 0.000 claims description 25
- 125000004429 atom Chemical group 0.000 claims description 22
- 125000002837 carbocyclic group Chemical group 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 17
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 14
- 150000001350 alkyl halides Chemical class 0.000 claims description 13
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 13
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 150000002923 oximes Chemical class 0.000 claims description 11
- 229910052707 ruthenium Inorganic materials 0.000 claims description 11
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 11
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 10
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 10
- 150000001540 azides Chemical class 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- 239000002689 soil Substances 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 150000001345 alkine derivatives Chemical class 0.000 claims description 7
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 claims description 7
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 206010036790 Productive cough Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 210000003802 sputum Anatomy 0.000 claims description 6
- 208000024794 sputum Diseases 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 claims description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 4
- DNIORISUBCVZFN-UHFFFAOYSA-N OCCONCCCCCCCCCC Chemical compound OCCONCCCCCCCCCC DNIORISUBCVZFN-UHFFFAOYSA-N 0.000 claims description 4
- GUNJVIDCYZYFGV-UHFFFAOYSA-K antimony trifluoride Chemical group F[Sb](F)F GUNJVIDCYZYFGV-UHFFFAOYSA-K 0.000 claims description 4
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000006612 decyloxy group Chemical group 0.000 claims description 4
- BPXYEYJNCXITEY-UHFFFAOYSA-N diazonio(trifluoromethoxy)azanide Chemical compound FC(F)(F)ON=[N+]=[N-] BPXYEYJNCXITEY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 241000239226 Scorpiones Species 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical group OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 2
- 229930004069 diterpene Natural products 0.000 claims description 2
- 235000002949 phytic acid Nutrition 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 5
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 4
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims 4
- BGFHMYJZJZLMHW-UHFFFAOYSA-N 4-[2-[[2-(1-benzothiophen-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethyl]phenol Chemical compound N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 BGFHMYJZJZLMHW-UHFFFAOYSA-N 0.000 claims 2
- SPPCMVNDPDQNRG-UHFFFAOYSA-L [F-].[F-].[Sb++] Chemical compound [F-].[F-].[Sb++] SPPCMVNDPDQNRG-UHFFFAOYSA-L 0.000 claims 2
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 claims 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- 125000002474 dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 claims 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 claims 1
- BNOILACWFLPWCM-UHFFFAOYSA-N 9,10-difluoroanthracene Chemical compound C1=CC=C2C(F)=C(C=CC=C3)C3=C(F)C2=C1 BNOILACWFLPWCM-UHFFFAOYSA-N 0.000 claims 1
- KIBRYKKATAHOJR-UHFFFAOYSA-N COC(ON(OCF)OC(F)(F)F)(F)F Chemical compound COC(ON(OCF)OC(F)(F)F)(F)F KIBRYKKATAHOJR-UHFFFAOYSA-N 0.000 claims 1
- 102000016736 Cyclin Human genes 0.000 claims 1
- 108050006400 Cyclin Proteins 0.000 claims 1
- BLNBBWYGKBCMME-UHFFFAOYSA-N OCCONCCCCCCCCCC.N1=CC(=CC=C1)C(=O)O Chemical compound OCCONCCCCCCCCCC.N1=CC(=CC=C1)C(=O)O BLNBBWYGKBCMME-UHFFFAOYSA-N 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 125000005418 aryl aryl group Chemical group 0.000 claims 1
- 229940126545 compound 53 Drugs 0.000 claims 1
- 125000000567 diterpene group Chemical group 0.000 claims 1
- RNIXSZHNJLUJGC-UHFFFAOYSA-N hydroxy(nitro)cyanamide Chemical compound N#CN(O)[N+]([O-])=O RNIXSZHNJLUJGC-UHFFFAOYSA-N 0.000 claims 1
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims 1
- ZNPKAOCQMDJBIK-UHFFFAOYSA-N nitrocyanamide Chemical compound [O-][N+](=O)NC#N ZNPKAOCQMDJBIK-UHFFFAOYSA-N 0.000 claims 1
- OTTPWWFPWBCJBS-UHFFFAOYSA-N o-(trifluoromethyl)hydroxylamine Chemical compound NOC(F)(F)F OTTPWWFPWBCJBS-UHFFFAOYSA-N 0.000 claims 1
- 241000894007 species Species 0.000 claims 1
- 230000002087 whitening effect Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 53
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- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 abstract description 3
- 230000004968 inflammatory condition Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 190
- 238000005481 NMR spectroscopy Methods 0.000 description 142
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 130
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 118
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- 125000001424 substituent group Chemical group 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 56
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- 239000000460 chlorine Substances 0.000 description 27
- 238000005859 coupling reaction Methods 0.000 description 26
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 21
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical group NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 20
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- 230000004913 activation Effects 0.000 description 13
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
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- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 11
- 230000037361 pathway Effects 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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