EA025098B1 - Имидазоламины в качестве модуляторов киназной активности - Google Patents

Info

Publication number

EA025098B1

EA025098B1 EA201400339A EA201400339A EA025098B1 EA 025098 B1 EA025098 B1 EA 025098B1 EA 201400339 A EA201400339 A EA 201400339A EA 201400339 A EA201400339 A EA 201400339A EA 025098 B1 EA025098 B1 EA 025098B1

Authority

EA

Eurasian Patent Office

Prior art keywords

ethyl

imidazol

piperidin

azetidin

fluoro

Prior art date

2011-09-12

Links

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• -1 Imidazole amines Chemical class 0.000 title claims abstract description 1164
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title abstract 4
• 230000000694 effects Effects 0.000 title description 10
• 108091000080 Phosphotransferase Proteins 0.000 title description 8
• 102000020233 phosphotransferase Human genes 0.000 title description 8
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 22
• 201000011510 cancer Diseases 0.000 claims abstract description 19
• 150000001875 compounds Chemical class 0.000 claims description 525
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 171
• 150000003839 salts Chemical class 0.000 claims description 44
• 150000001408 amides Chemical class 0.000 claims description 40
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
• 125000004076 pyridyl group Chemical group 0.000 claims description 32
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 238000000034 method Methods 0.000 claims description 29
• 238000006243 chemical reaction Methods 0.000 claims description 28
• 229910052736 halogen Inorganic materials 0.000 claims description 28
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 150000002367 halogens Chemical group 0.000 claims description 27
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 20
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 20
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 20
• MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 claims description 19
• 125000004273 azetidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C1([H])* 0.000 claims description 19
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
• 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 14
• 229910052731 fluorine Inorganic materials 0.000 claims description 14
• 239000011737 fluorine Substances 0.000 claims description 14
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 13
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
• 239000000460 chlorine Substances 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 13
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 13
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 13
• 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
• 125000001153 fluoro group Chemical group F* 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
• 239000004480 active ingredient Substances 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 7
• 150000003254 radicals Chemical class 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
• 208000026310 Breast neoplasm Diseases 0.000 claims description 5
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
• XYZFWUNBADWKLH-UHFFFAOYSA-N 6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-5-propan-2-yloxypyrimidin-4-amine Chemical compound CC(C)OC1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C(F)=CC=2)C(F)(F)F)CCN2CCC2)CC1 XYZFWUNBADWKLH-UHFFFAOYSA-N 0.000 claims description 4
• NUPWMMJWFAYJED-UHFFFAOYSA-N 6-[4-[1-[2-(dimethylamino)ethyl]-4-(4-fluoro-3-methylphenyl)imidazol-2-yl]piperidin-1-yl]-5-(1h-pyrazol-4-yl)pyrimidin-4-amine Chemical compound CN(C)CCN1C=C(C=2C=C(C)C(F)=CC=2)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C=1C=NNC=1 NUPWMMJWFAYJED-UHFFFAOYSA-N 0.000 claims description 4
• 206010009944 Colon cancer Diseases 0.000 claims description 4
• 206010038389 Renal cancer Diseases 0.000 claims description 4
• 201000010982 kidney cancer Diseases 0.000 claims description 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• WTXODCJICMVXLA-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(2-methoxyethylamino)ethyl]imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile Chemical compound COCCNCCN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C#N WTXODCJICMVXLA-UHFFFAOYSA-N 0.000 claims description 3
• GNOBRAMAIHJFOP-UHFFFAOYSA-N 5-chloro-6-[4-[1-[2-(cyclopropylamino)ethyl]-4-[2-(trifluoromethyl)pyridin-4-yl]imidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine Chemical compound NC1=NC=NC(N2CCC(CC2)C=2N(C=C(N=2)C=2C=C(N=CC=2)C(F)(F)F)CCNC2CC2)=C1Cl GNOBRAMAIHJFOP-UHFFFAOYSA-N 0.000 claims description 3
• MGYJNZHGAIGKBJ-UHFFFAOYSA-N 5-ethoxy-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(propan-2-ylamino)ethyl]imidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine Chemical compound CCOC1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C(F)=CC=2)C(F)(F)F)CCNC(C)C)CC1 MGYJNZHGAIGKBJ-UHFFFAOYSA-N 0.000 claims description 3
• JNWSILMDEXPLAM-UHFFFAOYSA-N 5-ethyl-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-piperidin-4-ylimidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine Chemical compound CCC1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C(F)=CC=2)C(F)(F)F)C2CCNCC2)CC1 JNWSILMDEXPLAM-UHFFFAOYSA-N 0.000 claims description 3
• XDCFPLHPOOPKGK-UHFFFAOYSA-N 6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-(2-propan-2-ylpyridin-4-yl)imidazol-2-yl]piperidin-1-yl]-5-ethenylpyrimidin-4-amine Chemical compound C1=NC(C(C)C)=CC(C=2N=C(N(CCN3CCC3)C=2)C2CCN(CC2)C=2C(=C(N)N=CN=2)C=C)=C1 XDCFPLHPOOPKGK-UHFFFAOYSA-N 0.000 claims description 3
• CLVJQNXBLQVWOL-UHFFFAOYSA-N 6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-(2-propan-2-ylpyridin-4-yl)imidazol-2-yl]piperidin-1-yl]-5-ethylpyrimidin-4-amine Chemical compound CCc1c(N)ncnc1N1CCC(CC1)c1nc(cn1CCN1CCC1)-c1ccnc(c1)C(C)C CLVJQNXBLQVWOL-UHFFFAOYSA-N 0.000 claims description 3
• MERNKFHEABWVHR-UHFFFAOYSA-N 6-[4-[1-[2-(azetidin-1-yl)ethyl]-4-[2-(trifluoromethyl)pyridin-4-yl]imidazol-2-yl]piperidin-1-yl]-5-chloropyrimidin-4-amine Chemical compound NC1=NC=NC(N2CCC(CC2)C=2N(C=C(N=2)C=2C=C(N=CC=2)C(F)(F)F)CCN2CCC2)=C1Cl MERNKFHEABWVHR-UHFFFAOYSA-N 0.000 claims description 3
• 206010006187 Breast cancer Diseases 0.000 claims description 3
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
• LLCTYWGXCGTFPX-UHFFFAOYSA-N NC1=NC=NC(=C1C(=O)O)N1CCC(CC1)C=1N(C=C(N=1)C1=CC(=C(C=C1)F)C)CCNCC1CC1 Chemical compound NC1=NC=NC(=C1C(=O)O)N1CCC(CC1)C=1N(C=C(N=1)C1=CC(=C(C=C1)F)C)CCNCC1CC1 LLCTYWGXCGTFPX-UHFFFAOYSA-N 0.000 claims description 3
• 208000024313 Testicular Neoplasms Diseases 0.000 claims description 3
• 206010057644 Testis cancer Diseases 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
• 201000003120 testicular cancer Diseases 0.000 claims description 3
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
• MRYHAUHEHQAMRQ-UHFFFAOYSA-N 4-amino-6-[4-[4-(4-fluoro-3-methylphenyl)-1-[2-(methylamino)ethyl]imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carboxamide Chemical compound CNCCN1C=C(C=2C=C(C)C(F)=CC=2)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C(N)=O MRYHAUHEHQAMRQ-UHFFFAOYSA-N 0.000 claims description 2
• MOQRMWMUHUDDJL-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(propan-2-ylamino)ethyl]imidazol-2-yl]piperidin-1-yl]pyrimidine-5-carboxamide Chemical compound CC(C)NCCN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C(N)=O MOQRMWMUHUDDJL-UHFFFAOYSA-N 0.000 claims description 2
• GAYRMKRSQCSTHF-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-pyrrolidin-3-ylimidazol-2-yl]piperidin-1-yl]pyrimidine-5-carboxamide Chemical compound NC(=O)C1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C(F)=CC=2)C(F)(F)F)C2CNCC2)CC1 GAYRMKRSQCSTHF-UHFFFAOYSA-N 0.000 claims description 2
• YOXMBPVKSDWRAV-UHFFFAOYSA-N 6-[4-[1-(2-aminoethyl)-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-5-ethylpyrimidin-4-amine Chemical compound CCC1=C(N)N=CN=C1N1CCC(C=2N(C=C(N=2)C=2C=C(C(F)=CC=2)C(F)(F)F)CCN)CC1 YOXMBPVKSDWRAV-UHFFFAOYSA-N 0.000 claims description 2
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
• 206010005003 Bladder cancer Diseases 0.000 claims description 2
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
• 208000032612 Glial tumor Diseases 0.000 claims description 2
• 206010018338 Glioma Diseases 0.000 claims description 2
• 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
• 208000034578 Multiple myelomas Diseases 0.000 claims description 2
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
• 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
• 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
• 201000004101 esophageal cancer Diseases 0.000 claims description 2
• 230000002489 hematologic effect Effects 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 208000020816 lung neoplasm Diseases 0.000 claims description 2
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• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 210000000066 myeloid cell Anatomy 0.000 claims description 2
• 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 206010038038 rectal cancer Diseases 0.000 claims description 2
• 201000001275 rectum cancer Diseases 0.000 claims description 2
• 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
• 208000017572 squamous cell neoplasm Diseases 0.000 claims description 2
• 201000002510 thyroid cancer Diseases 0.000 claims description 2
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
• 206010046766 uterine cancer Diseases 0.000 claims description 2
• BXVSAYBZSGIURM-UHFFFAOYSA-N 2-phenoxy-4h-1,3,2$l^{5}-benzodioxaphosphinine 2-oxide Chemical compound O1CC2=CC=CC=C2OP1(=O)OC1=CC=CC=C1 BXVSAYBZSGIURM-UHFFFAOYSA-N 0.000 claims 7
• 125000006018 1-methyl-ethenyl group Chemical group 0.000 claims 6
• KOQMBAGMXLUQDS-UHFFFAOYSA-N 2-benzhydrylidenepropanedinitrile Chemical compound C=1C=CC=CC=1C(=C(C#N)C#N)C1=CC=CC=C1 KOQMBAGMXLUQDS-UHFFFAOYSA-N 0.000 claims 5
• 125000001246 bromo group Chemical group Br* 0.000 claims 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims 4
• WWYVZTLIFYLZFM-UHFFFAOYSA-N 1-methylazetidine Chemical compound CN1CCC1 WWYVZTLIFYLZFM-UHFFFAOYSA-N 0.000 claims 3
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 2
• 208000014829 head and neck neoplasm Diseases 0.000 claims 2
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• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
• 206010060862 Prostate cancer Diseases 0.000 claims 1
• 208000029742 colonic neoplasm Diseases 0.000 claims 1
• 206010017758 gastric cancer Diseases 0.000 claims 1
• 210000004907 gland Anatomy 0.000 claims 1
• 201000007270 liver cancer Diseases 0.000 claims 1
• 208000014018 liver neoplasm Diseases 0.000 claims 1
• 201000005202 lung cancer Diseases 0.000 claims 1
• 230000003211 malignant effect Effects 0.000 claims 1
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
• 208000026037 malignant tumor of neck Diseases 0.000 claims 1
• UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims 1
• JYXKYKIDIKVWNY-UHFFFAOYSA-N n'-tert-butylethane-1,2-diamine Chemical compound CC(C)(C)NCCN JYXKYKIDIKVWNY-UHFFFAOYSA-N 0.000 claims 1
• RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims 1
• 201000002528 pancreatic cancer Diseases 0.000 claims 1
• 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
• 201000011549 stomach cancer Diseases 0.000 claims 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 16
• 201000010099 disease Diseases 0.000 abstract description 13
• 230000003463 hyperproliferative effect Effects 0.000 abstract description 7
• 238000004519 manufacturing process Methods 0.000 abstract description 4
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 432
• QPFXUEVSBFKNJV-UHFFFAOYSA-N 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidine Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 QPFXUEVSBFKNJV-UHFFFAOYSA-N 0.000 description 125
• SWAZPZDRQOTKRL-UHFFFAOYSA-N 5-bromo-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]pyrimidin-4-amine Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1Br SWAZPZDRQOTKRL-UHFFFAOYSA-N 0.000 description 118
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 117
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• 239000011541 reaction mixture Substances 0.000 description 57
• LPZBVVARVJQTAW-UHFFFAOYSA-N 4-amino-6-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]pyrimidine-5-carbonitrile Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C(CC1)CCN1C1=NC=NC(N)=C1C#N LPZBVVARVJQTAW-UHFFFAOYSA-N 0.000 description 56
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