WO2024064091A1 - Novel pyrimidine compound as kinase inhibitors with biological activities on egfr mutants - Google Patents
Novel pyrimidine compound as kinase inhibitors with biological activities on egfr mutants Download PDFInfo
- Publication number
- WO2024064091A1 WO2024064091A1 PCT/US2023/033057 US2023033057W WO2024064091A1 WO 2024064091 A1 WO2024064091 A1 WO 2024064091A1 US 2023033057 W US2023033057 W US 2023033057W WO 2024064091 A1 WO2024064091 A1 WO 2024064091A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- pyrimidin
- enamide
- indol
- dimethylamino
- Prior art date
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- -1 pyrimidine compound Chemical class 0.000 title claims description 195
- 108060006698 EGF receptor Proteins 0.000 title description 16
- 230000004071 biological effect Effects 0.000 title description 2
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 141
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
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- 230000015572 biosynthetic process Effects 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- NIIFPFOKZFFNMN-UHFFFAOYSA-N 4-piperidin-1-ylbut-2-enamide Chemical compound NC(=O)C=CCN1CCCCC1 NIIFPFOKZFFNMN-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 56
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 37
- 230000009467 reduction Effects 0.000 description 29
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- 239000000203 mixture Substances 0.000 description 17
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical group C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 16
- 102000001301 EGF receptor Human genes 0.000 description 16
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- FYSIGSQCZXQTIH-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitroaniline Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 description 15
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- 239000007832 Na2SO4 Substances 0.000 description 9
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 238000013459 approach Methods 0.000 description 7
- 125000003386 piperidinyl group Chemical group 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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- 238000000746 purification Methods 0.000 description 6
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- DOTGZROJTAUYFQ-OWOJBTEDSA-N (e)-4-bromobut-2-enoic acid Chemical compound OC(=O)\C=C\CBr DOTGZROJTAUYFQ-OWOJBTEDSA-N 0.000 description 1
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- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical group ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 1
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical group FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical group FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GDIIPKWHAQGCJF-UHFFFAOYSA-N 4-Amino-2-nitrotoluene Chemical compound CC1=CC=C(N)C=C1[N+]([O-])=O GDIIPKWHAQGCJF-UHFFFAOYSA-N 0.000 description 1
- FOHHWGVAOVDVLP-UHFFFAOYSA-N 4-chloro-3-nitroaniline Chemical group NC1=CC=C(Cl)C([N+]([O-])=O)=C1 FOHHWGVAOVDVLP-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
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- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical group ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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- 239000005711 Benzoic acid Substances 0.000 description 1
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- 238000007125 Buchwald synthesis reaction Methods 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
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- 241000124008 Mammalia Species 0.000 description 1
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- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
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- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 1
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- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
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- 235000010233 benzoic acid Nutrition 0.000 description 1
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- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
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- 230000008859 change Effects 0.000 description 1
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- 238000010168 coupling process Methods 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 108700021358 erbB-1 Genes Proteins 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000010667 large scale reaction Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- SZTYQQYYIMVETL-UHFFFAOYSA-N n-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 SZTYQQYYIMVETL-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- DQJCHOQLCLEDLL-UHFFFAOYSA-N tricyclazole Chemical compound CC1=CC=CC2=C1N1C=NN=C1S2 DQJCHOQLCLEDLL-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This present invention relates to compounds that feature the inhibition of protein tyrosine kinases (PTKs), including EGFR mutants, their pharmaceutical compositions that comprising a therapeutically effective amount of the corresponding compounds and methods of use therefor.
- PTKs protein tyrosine kinases
- PTKs Protein tyrosine kinases
- EGFR Epidermal growth factor receptor
- RTKs receptor tyrosine kinases
- a ligand such as epidermal growth factor (EGF)
- EGF epidermal growth factor
- EGFR overexpression or activation and acquired EGFR T790M mutation is observed in human cancers and is associated with high rates of cancer cell proliferation and drug resistance.
- the EGFR T790M mutation was present in approximately 50 to 60 % of resistant cases which are acquired gatekeeper mutations of threonine-to-methionine (T790M) in the EGFR gene.
- This present invention disclosed herein are compounds with inhibitory activity against EGFR mutants, such as L858R, T790M, C797S, exon 20 insertions, HER2, etc.
- Examples of compounds that are similar in structure to those of the present invention are disclosed in the following literatures: WO2009158571, WO2013014448, WO2015127872, WO2015188777, WO2015195228, WO2016023422, WO2016029839, WO2016054987, WO2016070816, WO2016173438, WO2017086830, WO2017120429, WO2017162510,
- Q is a bicyclic heterocyclyl, selected from:
- R is selected from H, halogen, halogen-lower alkyl, -CN, carboxylic acid, carboxylic ester or carboxylic amide;
- X is selected from direct bond, -O-, -S-, or -N(R')-;
- R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl, hydroxyl, lower alkoxy, amino, hydroxyl alkylamino, aryl or heterocyclyl;
- R is selected from:
- Q’ is a heterocyclyl, selected from pyrimidinyl and pyridinyl:
- Y is selected from H, or -NR’R’.
- R’R’ can form an aliphatic, heterocyclic ring; or a pharmaceutically acceptable salt thereof
- the present invention is the directed to compounds which can inhibit protein tyrosine kinase, such as various EGFR mutants.
- Q is a bicyclic heterocyclyl, selected from:
- R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, carboxylic lower alkyl ester or carboxylic lower alkyl amide with nitrogen mono or dual substituted; preferably selected from Cl, Br and carboxylic acid.
- X is selected from -O-, or -N(R’)-; preferably -NH-;
- R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl; preferably lower alkoxy or a halogen.
- R is selected from: preferably the
- Q’ is selected from pyrimidinyl and pyridinyl:
- Y is selected from H, or -NR’R’, R’R’ can form an aliphatic, heterocyclic ring; preferably the -NR’R’ group is selected from substituted or unsubstituted N,N- dimethyl amino (-NMe 2 ), pyrrolidine, morpholine, piperidine and piperazine or a pharmaceutically acceptable salt thereof.
- X is -NH-
- R is selected from chlorine, bromine,
- R’ is selected from: H, F, Cl, -CH 3 , -0CH 3 , -C00H;
- R is ; Y is selected from: or a pharmaceutically acceptable salt thereof.
- halogen includes fluoro (-F), chloro (-C1), bromo (-Br) or iodo (-1), such as fluoro (-F) and chloro (-C1).
- lower alkyl includes 1 to 6 saturated monovalent hydrocarbon radicals having straight or branched moieties, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like.
- halogen-lower alkyl includes 1 to 6 halogen substituted alkyl, such as trifluoromethyl (-CF 3 ).
- carboxyl acid, carboxyl acid lower alkyl ester as used herein, unless otherwise indicated, includes a carboxylic acid and/or carboxyl acid lower alkyl ester.
- lower alkoxy as used herein, unless otherwise indicated, includes -O-lower alkyl groups wherein lower alkyl is as defined above, such as methoxy (-OCH 3 ) and ethoxy (- OCH 2 CH 3 ).
- amino includes -NH 2 group, -NH-lower alkyl group, or -N(lower alkyl) 2 group wherein lower alkyl is as defined above, such as methylamino (-NHMe), dimethylamino (-NMe 2 ) and diethylamino (-NEt 2 ).
- hydroxyl alkylamino includes HO-lower alkyl-NH 2 group, HO-lower alkyl-NH-lower alkyl group, or HO- lower alkyl-N(lower alkyl) 2 group wherein lower alkyl is as defined above, such as -NH- CH 2 CH 2 OH.
- aliphatic is selected from lower alkyl, lower alkenyl, lower alkynyl or cyclic alkyl, alkenyl, alkynyl.
- aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, preferably phenyl, and is un-substituted or substituted by one or two substituents, selected from halogen, halogeno-lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cyano, lower alkylcyano, hydroxy, lower alkoxy, carboxy, carboxyalkyl, amino, carbamoyl, cabamate, ureido, mercapto, sulfo, lower alkysulfinyl, lower alkanesulfonyl, sulfonamide; aryl includes one aromatic ring fused with an aliphatic ring, such as a saturated or partially saturated ring.
- heterocyclyl or “heterocyclic”, as used herein, unless otherwise indicated, includes ring contains from about 3 to 12 atoms, preferred 4 to 8 atoms, wherein one or more atoms are selected from 0, N and S, whereas the remain of the ring atoms are carbon.
- the conception of heterocyclyl maybe a monocyclic, a bicyclic, a spirocyclic or even a bridged ring system.
- a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring which may be aromatic or partially saturated or saturated.
- a bicyclic or tricyclic ring system may include a carbocyclic ring.
- Carbocyclic ring includes cycloalkyl, cycloalkenyl or aryl ring.
- heterocyclyl groups include but not limited: azetidine, pyrrolidine, pyrrolidione, piperidine, piperidinone, piperazine, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine and hydantoin, pyrrole, indole, pyrazole, indazole, trizole, benzotrizole, imidazole, benzoimdazole, thiophene, benzothiophene, thiozole, benzothiozole, furan, benzofuran, oxazole, bezoxazole, isoxazole, tetrazole, pyridine, pyrimidine, trizine, quinoline, isoquinoline, quinazoline, indoline,
- This invention also discloses a method of treating a PTK expression related disease or disorder in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I.
- the term “subject” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.
- PTKs receptor tyrosine kinases
- the compounds in the following examples can be administered to the subjects via various routes. These routes include but not limited to orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraocularly, via local administration, subcutaneously, intraadiposally, intraarticularly, intraperitoneally or intrathecally. In this described embodiment, the compounds are preferred to be administered orally.
- the pharmaceutical compositions feature Formula I or their pharmaceutically acceptable salts suitable for oral administration include, but not limited to tablets, capsules, dusts, granulates, drip pills, pastes, powders and tinctures.
- the preferred pharmaceutical compositions among them are tablets and capsule.
- epidermal growth factor receptor (EGFR) mutants including L858R, T790M of example compounds are listed in the table below.
- R, R’, R”, X, Q and Q’ are as defined previously.
- DIPEA diisopropylethylamine
- DCM di chloromethane
- DMF N,N- dimethylformamide
- DMAP 4- N,N-dimethylaminopyridine
- MsCl methanesulfonyl chloride
- THF tetrahydrofuran
- TFA trifluoroacetic acid
- TEA triethylamine
- Pd/C Palladium on active carbon
- EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
- CDI 1,1'-carbonyldiimidazole
- DCC N,N'-dicyclohexylcarbodiimide
- HBTU 2-(1h- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- BOC tert- Butyloxycarbonyl protecting group
- eq equivalent
- g gram, mg
- N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine 580 mg, 1.50 mmol was dissolved in a mixing solvent of MeOH and DCM (20 mL, 1 : 1 ratio). This solution was cooled with ice bath and well stirred. Zinc powder (400 mg, 6.25 mmol, 5.0 eq) and ammonium formate (400 mg, 6.25 mmol, 5.0 eq) were added in sequence. The reaction progress was monitored with TLC and it was indicated to be accomplished within half an hour. The resulting solution was worked up with sat NaHCO 3 solution (20 mL) and brine (20 mL).
- N 1 -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6- methoxybenzene- 1,3 -diamine can be accomplished by following this protocol: the crude product was dissolved into minimum amount of DMF (0.5 mL in this case) and the solution was added into large amount of water (10 mL in this case) to precipitate the product. Suction filtration was applied to isolate the product and it was dried by running air. A second purification might be necessary if the purity did not meet the criteria.
- N 1 -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3- diamine 500 mg, 1.2 mmol
- potassium carbonate 400 mg, 3.0 mmol
- THF:H 2 O 5 mL: 2.5 mL
- the solution was cooled in ice bath and the pre-prepared acidic chloride solution in THF was added dropwised until TLC indicated no amine remained.
- a seal tube was charged with N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine (300 mg, 0.75 mmol, 1.0 eq), dimethylamine hydrochloric acid salt (600 mg, 10 eq), K 2 CO 3 (1.0 g, 10 eq) and acetonitrile (20 mL). The resulting mixture was stirred at about 75-80 °C for 12 hours. The resulting mixture was filtered and the filtrate was diluted with DCM (20 mL). After worked up with brine (10 mL), the organic layer was dried over anhydrous Na 2 SO 4 and condensed.
- Example 17 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- methylphenyl)-4-(dimethylamino)but-2-enamide This compound was similarly prepared following Example 1 by substituting 2-methoxy-4- methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 457.
- Example 24 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- morpholinophenyl)-4-morpholinobut-2-enamide
- This compound was similarly prepared following Example 1, with an addition of a S N Ar step with morpholine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 570.
- Example 35 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide
- This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a S N Ar step with diethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E.
- Example 42 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-( 1 -methyl- 1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide
- This compound was similarly prepared following Example 35, with an addition of a S N Ar step with 2-aminoethanol before the reduction step (Method C). Mass: (M + 1), 558.
- CDI CDI
- HBTU can be used as coupling reagent instead of EDC hydrochloride in some scenario.
- the starting material acrylic acid (20 mg, ⁇ 1.1 eq) and HOBt hydrate (32 mg, -1.0 eq) were added into DCM (2 mL). Meanwhile, EDC hydrochloride (70 mg, ⁇ 1.5 eq) was added and followed by the starting material 2-((2-amino-5-methoxy-4-((4-(1 -methyl- 1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (130 mg, 0.25 mmol, 1.0 eq). The resulting mixture was stirred overnight until the starting material amine completely consumed from TLC analysis.
- the starting material 2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (30 mg, 0.05 mmol) was dissolved in a mixing solvent of methanol:H 2 O (0.9 mL:0.1 mL). Meanwhile, LiOH (2.5 mg, 2.0 eq) was added in the solution and stirred under room temperature for 2 hours. TLC analysis indicated the reaction was accomplished and the resulting mixture was condensed to dryness.
- Example 57 2-((4-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5- methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol
- This compound was similarly prepared following Example 49 by substituting 5-fluoro-1- m ethyl- 1H-indole for 1 -methyl-1H-indole in Method A. Mass: (M + 1), 501.
- This compound was similarly prepared following Example 62 by adding addition a S N Ar step with ammonium before the reduction step (Method C) and the -NH 2 group was then protected via -Boc. Other steps were accomplished via routine protocol and the -Boc group was removed with an additional step with TFA after Method E. Mass: (M + 1), 502.
Abstract
This present invention relates to compounds of Formula I that feature the inhibition of protein tyrosine kinases (PTKs), including EGFR mutants, their pharmaceutical compositions that comprising a therapeutically effective amount of the corresponding compounds and methods of use therefor.
Description
Novel Pyrimidine Compound as Kinase Inhibitors with Biological Activities on EGFR Mutants
This application claims the benefit of U.S. provisional application: 63/376,253 filed on September 19, 2022.
FIELD OF THE INVENTION
This present invention relates to compounds that feature the inhibition of protein tyrosine kinases (PTKs), including EGFR mutants, their pharmaceutical compositions that comprising a therapeutically effective amount of the corresponding compounds and methods of use therefor.
BACKGROUND OF THE INVENTION
Protein tyrosine kinases (PTKs) are a large series of enzymes that catalyze the phosphorylation process of transferring phosphate groups from nucleoside triphosphates (often ATP) to protein amino acid residues. They span the cell membrane and play roles as “switches” in the cellular signal transduction cascades from extracellular signals through membrane to the cytoplasm part and even the inner nucleus. Epidermal growth factor receptor (EGFR) belongs to a family of receptor tyrosine kinases (RTKs) that include EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The binding of a ligand, such as epidermal growth factor (EGF), induces a conformational change in EGFR that facilitates receptor homo- or heterodimer formation, leading to activation of EGFR tyrosine kinase activity. EGFR overexpression or activation and acquired EGFR T790M mutation is observed in human cancers and is associated with high rates of cancer cell proliferation and drug resistance. The EGFR T790M mutation was present in approximately 50 to 60 % of resistant cases which are acquired gatekeeper mutations of threonine-to-methionine (T790M) in the EGFR gene.
This present invention disclosed herein are compounds with inhibitory activity against EGFR mutants, such as L858R, T790M, C797S, exon 20 insertions, HER2, etc. Examples of compounds that are similar in structure to those of the present invention are disclosed in the following literatures: WO2009158571, WO2013014448, WO2015127872, WO2015188777, WO2015195228, WO2016023422, WO2016029839, WO2016054987,
WO2016070816, WO2016173438, WO2017086830, WO2017120429, WO2017162510,
WO2017205459.
SUMMARY OF THE INVENTION
Several embodiments disclosed herein pertain to inhibitors of PTKs, mainly inhibition to EGFR mutants, represented by Formula I:
Formula I
Wherein:
R is selected from H, halogen, halogen-lower alkyl, -CN, carboxylic acid, carboxylic ester or carboxylic amide;
X is selected from direct bond, -O-, -S-, or -N(R')-;
R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl, hydroxyl, lower alkoxy, amino, hydroxyl alkylamino, aryl or heterocyclyl;
Q’ is a heterocyclyl, selected from pyrimidinyl and pyridinyl:
Y is selected from H, or -NR’R’. R’R’ can form an aliphatic, heterocyclic ring; or a pharmaceutically acceptable salt thereof
DETAILED DESCRIPTION OF THE INVENTION
The present invention is the directed to compounds which can inhibit protein tyrosine kinase, such as various EGFR mutants.
R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, carboxylic lower alkyl ester or carboxylic lower alkyl amide with nitrogen mono or dual substituted; preferably selected from Cl, Br and carboxylic acid.
X is selected from -O-, or -N(R’)-; preferably -NH-;
R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl; preferably lower alkoxy or a halogen.
Q’ is selected from pyrimidinyl and pyridinyl:
Y is selected from H, or -NR’R’, R’R’ can form an aliphatic, heterocyclic ring; preferably the -NR’R’ group is selected from substituted or unsubstituted N,N- dimethyl amino (-NMe2), pyrrolidine, morpholine, piperidine and piperazine or a pharmaceutically acceptable salt thereof.
Formula I
X is -NH-;
R is selected from chlorine, bromine,;
The term “halogen”, as used herein, unless otherwise indicated, includes fluoro (-F), chloro (-C1), bromo (-Br) or iodo (-1), such as fluoro (-F) and chloro (-C1).
The term “lower alkyl”, as used herein, unless otherwise indicated, includes 1 to 6 saturated monovalent hydrocarbon radicals having straight or branched moieties, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, and the like.
The term “lower alkenyl”, as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon double bond, such as -CH2-CH=CH2.
The term “lower alkynyl”, as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon triple bond, such as CH2- C = CH.
The term “halogen-lower alkyl”, as used herein, unless otherwise indicated, includes 1 to 6 halogen substituted alkyl, such as trifluoromethyl (-CF3).
The term “carboxyl acid, carboxyl acid lower alkyl ester” as used herein, unless otherwise indicated, includes a carboxylic acid and/or carboxyl acid lower alkyl ester.The term “lower alkoxy”, as used herein, unless otherwise indicated, includes -O-lower alkyl groups wherein lower alkyl is as defined above, such as methoxy (-OCH3) and ethoxy (- OCH2CH3).
The term “amino”, as used herein, unless otherwise indicated, includes -NH2 group, -NH-lower alkyl group, or -N(lower alkyl)2 group wherein lower alkyl is as defined above, such as methylamino (-NHMe), dimethylamino (-NMe2) and diethylamino (-NEt2).
The term “hydroxyl alkylamino”, as used herein, unless otherwise indicated, includes HO-lower alkyl-NH2 group, HO-lower alkyl-NH-lower alkyl group, or HO- lower alkyl-N(lower alkyl)2 group wherein lower alkyl is as defined above, such as -NH- CH2CH2OH.
The term “aliphatic”, as used herein, is selected from lower alkyl, lower alkenyl, lower alkynyl or cyclic alkyl, alkenyl, alkynyl.
The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, preferably phenyl, and is un-substituted or substituted by one or two substituents, selected from halogen, halogeno-lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cyano, lower alkylcyano, hydroxy, lower alkoxy, carboxy, carboxyalkyl, amino, carbamoyl, cabamate, ureido, mercapto, sulfo, lower alkysulfinyl, lower alkanesulfonyl, sulfonamide; aryl includes one aromatic ring fused with an aliphatic ring, such as a saturated or partially saturated ring.
The term “heterocyclyl” or “heterocyclic”, as used herein, unless otherwise indicated, includes ring contains from about 3 to 12 atoms, preferred 4 to 8 atoms, wherein one or more atoms are selected from 0, N and S, whereas the remain of the ring atoms are carbon. The conception of heterocyclyl maybe a monocyclic, a bicyclic, a spirocyclic or even a bridged ring system. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring which may be aromatic or partially saturated or saturated. A bicyclic or tricyclic ring system may include a carbocyclic ring. Carbocyclic ring includes cycloalkyl, cycloalkenyl or aryl ring. Examples of heterocyclyl groups include but not limited: azetidine, pyrrolidine, pyrrolidione, piperidine, piperidinone, piperazine, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine and hydantoin, pyrrole, indole, pyrazole, indazole, trizole, benzotrizole, imidazole, benzoimdazole, thiophene, benzothiophene, thiozole, benzothiozole, furan, benzofuran, oxazole, bezoxazole, isoxazole, tetrazole, pyridine, pyrimidine, trizine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, methylene-dioxyphenyl. The heterocyclic and heterocyclic rings may be optionally substituted and substituents selected from the group defined above as substituents for aryl.
This invention also discloses a method of treating a PTK expression related disease or disorder in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I. As used herein, the term “subject” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.
Compounds listed in the following examples are able to show inhibition against receptor tyrosine kinases (PTKs). The compounds can be administered to the subjects in the form of free base. It can also be administered in the form of salts, hydrates and/or prodrugs (which will be converted into the active form in vivo).
The compounds in the following examples can be administered to the subjects via various routes. These routes include but not limited to orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraocularly, via local administration,
subcutaneously, intraadiposally, intraarticularly, intraperitoneally or intrathecally. In this described embodiment, the compounds are preferred to be administered orally.
The pharmaceutical compositions feature Formula I or their pharmaceutically acceptable salts suitable for oral administration include, but not limited to tablets, capsules, dusts, granulates, drip pills, pastes, powders and tinctures. The preferred pharmaceutical compositions among them are tablets and capsule.
The following examples are intended to illustrate further certain embodiments of the invention and are not considered to limit the scope of the invention. Any feature, structure, component, material, step, or method that is described and/or illustrated in any embodiment in this specification can be used with or instead of any feature, structure, component, material, step, or method that is described and/or illustrated in any other embodiment in this specification.
The inhibition results to epidermal growth factor receptor (EGFR) mutants including L858R, T790M of example compounds are listed in the table below.
*: Inhabitation percentage of enzyme activity (relative to DMSO controls) of each compound at 0.05 pM concentration. The lower percentage, the higher inhibitory activity.
The following examples of Formula I, but not limited, can be prepared according to the methods described in Scheme I - Scheme II which are used to provide possible synthetic routes for this series of compounds and in no way to be interpreted as restrictive. These series of compounds might be synthesized from other alternative approaches as well.
Formula I
Wherein R, R’, R”, X, Q and Q’ are as defined previously.
The following examples, but not limited, can be prepared according to the chemistry process scope described above in Scheme I - II.
EtOH: ethanol, MeOH: methanol, IPA: isopropanol, EtOAc: ethyl acetate, RT: room temperature,
DIPEA: diisopropylethylamine, DCM: di chloromethane, DMF: N,N- dimethylformamide, DMAP: 4- N,N-dimethylaminopyridine, MsCl: methanesulfonyl chloride, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TEA: triethylamine, Pd/C: Palladium on active carbon, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, CDI: 1,1'-carbonyldiimidazole, DCC: N,N'-dicyclohexylcarbodiimide, HBTU: 2-(1h- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, BOC: tert- Butyloxycarbonyl protecting group, eq: equivalent, g: gram, mg: milligram, ml: milliliter, min: minutes, mmol: millimolar, bis=di: two or double,
TLC: thin layer chromatography,
Example 1(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
The solution of 2,4-dichloropyrimidine (4.0g) and 1H-indole (4.0g, 2.0 eq of pyrimidine) in anhydrous THF (10 mL) was cooled in ice/salt bath and the solution of methyl magnesium bromide (12 mL, 3N in Hexanes) was added dropwise. After the addition was accomplished, the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with ethyl acetate (50 mL) and washed thoroughly with saturated NaHCO3 (25mL) and brine (25mL). The organic layer was dried over with anhydrous Na2SO4 and concentrated to dryness, yielding yellow solid as 3-(2- chloropyrimidin-4-yl)-1H-indole (4.4 g). Mass: (M + 1), 231.
In a 100 mL seal tube was charged with 3-(2-chloropyrimidin-4-yl)-1H-indole (4.0 g, 17 mmol), 4-fluoro-2-methoxy-5-nitroaniline (4.8 g, 26 mmol), methanesulfonic acid (0.9 mL) and isopropanol (15 mL). The resulting mixture was stirred at 120 °C for 10 hours and TLC indicated that no starting material 3-(2-chloropyrimidin-4-yl)-1H-indole remained. This reaction was ceased at this point. The resulting mixture was condensed and diluted with ethyl acetate (250 mL). The organic layer was thoroughly washed with HC1 (1M, 50 mL x 3), brine (50 mL) and dried over with anhydrous Na2SO4. After concentrated to dryness, yellow sold was obtained as crude product N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H- indol-3-yl)pyrimidin-2-amine (~ 4g). Mass: (M + 1), 380.
The N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (580 mg, 1.50 mmol) was dissolved in a mixing solvent of MeOH and DCM (20 mL, 1 : 1 ratio). This solution was cooled with ice bath and well stirred. Zinc powder (400 mg, 6.25 mmol, 5.0 eq) and ammonium formate (400 mg, 6.25 mmol, 5.0 eq) were added in sequence. The reaction progress was monitored with TLC and it was indicated to be accomplished within half an hour. The resulting solution was worked up with sat NaHCO3 solution (20 mL) and brine (20 mL). After being dried with anhydrous Na2SO4, the solution was allowed to pass through celite to remove the high polarity impurities at the baseline of TLC. Hereby, the solvent was removed by rotary evaporation and yielding sticky brown solid (450 mg) as crude product. Further purification could be accomplished with column chromatography (eluent: hexanes to Hexanes: EtOAc = 2:1), giving tan colored solid as product N1-(4-(1H-
indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene- 1,3 -diamine (340 mg). Mass: (M + 1), 350.
In large scale reaction, the purification of N1-(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6- methoxybenzene- 1,3 -diamine can be accomplished by following this protocol: the crude product was dissolved into minimum amount of DMF (0.5 mL in this case) and the solution was added into large amount of water (10 mL in this case) to precipitate the product. Suction filtration was applied to isolate the product and it was dried by running air. A second purification might be necessary if the purity did not meet the criteria.
In a 50 mL round bottom flask was charged with 4-bromo crotonic acid (500 mg, 3,0 mmol), THF (3 mL) and anhydrous DMF (180 μL). The mixture was cooled in ice bath and oxalyl chloride (260 μL, 1.0 eq of acid) was added dropwise. Large amount of air bubbles were formed during the addition. The resulting mixture was stirred in ice bath for half an hour and then at room temperature for another half an hour to achieve a bright yellow solution. The excess amount of oxalyl chloride was removed by rotary evaporation and extracted with toluene (~ ImL), yielding yellow oil as crude acidic chloride, which was diluted with anhydrous THF and kept aside for further reactions.
On the other side, N1-(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3- diamine (500 mg, 1.2 mmol) and potassium carbonate (400 mg, 3.0 mmol) were dissolved into a mixing solvent of THF:H2O (5 mL: 2.5 mL). The solution was cooled in ice bath and the pre-prepared acidic chloride solution in THF was added dropwised until TLC indicated no amine remained.
The resulting mixture was diluted with DCM (20 mL). After being worked up with sat NaHCO3 (~ 10 mL) and brine (~ 10mL), the organic layer was dried over with anhydrous Na2SO4 and allowed to pass through silica gel plug to remove the high polarity impurities at the baseline of TLC. Removal of the solvent by rotary evaporation yielded 500 mg crude
product as brown solid. Further purification could be accomplished with column chromatography (Eluent: hexanes to Hexanes: EtOAc = 1 :2), giving tan colored solid (250 mg) as product (E)-4-bromo-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)but-2-enamide. Mass: (M + 1), 497,
(E)-4-bromo-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)but-2-enamide (1.0 g, 2.0 mmol) was dissolved in DMF (1.0 mL). N,N- dimethyl amine hydrochloride (500 mg, 6.0 mmol, 3.0 eq) and A,N-diisopropylethylamine (1.1 mL, 6.0 mmol, 3.0 eq) were added in sequence and the resulting mixture was stirred at room temperature overnight. Meanwhile, TLC analysis indicated the starting material was completely consumed. Large amount of water (mL) was added inside to precipice the product. Filtration was applied to isolate the crude product as tan solid (1.0 g). Further purification could be accomplished with column chromatography (eluent: DCM to 10% MeOH in DCM), giving tan colored solid (400 mg) as desired product (E)-N-(5-((4-(1H- indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2- enamide.
At this stage, the purity of the product varies from 95% - 99%. A second purification could be done by a recrystallization from EtOH (260 mg pure product in this case, >99% HPLC purity).
Mass: (M + 1), 461.
Due to the limitation of length and space, only the full preparation procedures of (E)-N-(5- ((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide was disclosed in details in Examples 1. Other compounds can be prepared via similar approach, by changing particular chemicals in specific steps, which will be shown in the following examples, respectively.
About Protection Groups
It is worthwhile to mention that in some special scenario the protection of reactive function groups may be necessary to achieve some of the abovementioned reactions. In general, the need for such protecting groups will be obvious to those skilled in the field of organic synthesis as well as the conditions for addition and/or removal of such groups.
Example 2 (E)-4- (dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H-indole in Method A. Mass: (M + 1), 475.
Example 3 (E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was prepared following Example 1, by substituting 2,4-dichloro-5- methylpyrimidine for 2,4-dichloropyrimidine for in Method A. Mass: (M + 1), 445.
Example 4 (E)-N-(5-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1, by substituting 2,4-dichloro- 5-(trifluoromethyl)pyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 529. Example 5 (E)-4- (dimethylamino)-N-(2-fhroro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2- yl)amino)-4-methoxyphenyl)but-2-enamide
This compound was similarly prepared following Example 1, by substituting 2,4-dichloro- 5-fluoropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 479.
Example 6 (E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1, by substituting 2,4,5- tri chloropyrimidine for 5- 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 495.
Example 7 (E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1, by substituting 5-bromo-2,4- dichloropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M + 1), 495.
Example 8 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H- indole in Method A, with an addition of a SN Ar step with dimethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 542.
A seal tube was charged with N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine (300 mg, 0.75 mmol, 1.0 eq), dimethylamine hydrochloric acid salt (600 mg, 10 eq), K2CO3 (1.0 g, 10 eq) and acetonitrile (20 mL). The resulting mixture was stirred at about 75-80 °C for 12 hours. The resulting mixture was filtered and the filtrate was diluted with DCM (20 mL). After worked up with brine (10 mL), the organic layer was dried over anhydrous Na2SO4 and condensed. Column chromatography give brown solid (200 mg) as desired product 2-methoxy-N4,N4-dimethyl-N1-(4-(1-methyl- 177-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-l,4-diamine.
Example 9 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4- (dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 2,4- dimethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 473.
Example 10 (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- (methylamino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for1H- indole in Method A, with an addition of a SN Ar step with methylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 528.
Example 11 (E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H-indol in Method A, with an addition of a SN Ar step with methylamine before the reduction step (Method C). Mass: (M + 1), 486.
Example 12 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (methylamino)phenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1 with an addition of a SN Ar step with methylamine before the reduction step (Method C). Mass: (M + 1), 472,
Example 13 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4- dimethoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 9 by substituting 7-azaindole for 1H-indol in Method A. Mass: (M + 1), 474.
Example 14 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 13 by substituting 2-methoxy- 4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 458.
Example 15 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-
4-methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 13 by substituting 4-chloro-2- m ethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5 -nitroaniline in Method B. Mass: (M + 1), 478.
Example 16 (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 13 by substituting 2-methoxy-
5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 444.
Example 17 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- methylphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 2-methoxy-4- methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 457.
Example 18(E)- 4-(dimethylamino)-N-(4-methoxy-2-methyl-5-((4-( 1 -methyl-1H-indol -3 - yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide
This compound was similarly prepared following Example 17 by substituting 1-methyl-1H-indol for 1H-indol in Method A. Mass: (M + 1), 471.
Example 19 (E)-4-(dimethylamino)-N-(4-methoxy-3-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide
This compound was prepared following Example 8 by substituting 2-methoxy-5- nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 457.
Example 20 (E)-N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 2-methoxy-5- nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 443.
Example 21 (E)-N-(2-chloro-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(dimethylamino)but-2-enamide
This compound was prepared following Example 19, by substituting 4-chloro-5- nitroaniline for 2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 491.
Example 22 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-chloro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 4-chloro-2- m ethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5 -nitroaniline in Method B. Mass: (M + 1), 477.
Example 23 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 1, with an addition of a SN Ar step with dimethylamine before the reduction step (Method C) and substituting piperazine for dimethylamine in Method E. Mass: (M + 1), 527.
Example 24 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- morpholinophenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1, with an addition of a SN Ar step with morpholine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 570.
Example 25(E)- N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- morpholinophenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for 1H-indole in Method A, with an addition of a SN Ar step with morpholine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 584.
Example 26(E)- N-(5-((4-(1H-pyrrolo[2,3-/]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-(methylamino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 7-azaindole for1H- indole in Method A, with an addition of a SN Ar step with methylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 515.
Example 27 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (methylamino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1, with an addition of a SN Ar step with methylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 514.
Example 28 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide
This compound was similarly prepared following Example 1, with an addition of a SN Ar step with dimethylamine before the reduction step (Method C) and substituting piperidine for dimethylamine in Method E. Mass: (M + 1), 526.
Example 29 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 1, with an addition of a SN Ar step with dimethylamine before the reduction step (Method C) and substituting 1- methylpiperazine for dimethylamine in Method E. Mass: (M + 1), 541.
Example 30 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1, with an addition of a SN Ar step with dimethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 528.
Example 31 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(piperidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a SN Ar step with diethylamine before the reduction step (Method C) and substituting piperidine for dimethylamine in Method E. Mass: (M + 1), 568.
Example 32 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a SN Ar step with diethylamine before the reduction step (Method C) and substuting 1 -methylpiperazine for dimethylamine in Method E. Mass: (M + 1), 583.
Example 33 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a SN Ar step with diethylamine before the reduction step (Method C) and substituting piperazine for dimethylamine in Method E. Mass: (M + 1), 569.
Example 34(E)- N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide
This compound was prepared following Example 1 by substituting 1 -methyl- IH-indole for ///-indole in Method A with an addition of a SN Ar step with diethylamine before the reduction step (Method C) and substituting pyrrolidine for dimethylamine in Method E. Mass: (M + 1), 554.
Example 35 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for 1H-indole in Method A with an addition of a SN Ar step with diethylamine before the reduction step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 570.
Example 36 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2- (dimethylamino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 29 by substituting 7-azaindole for1H- indole in Method A. Mass: (M + 1), 542.
Example 37 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2- (dimethylamino)-4-methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 23 by substituting 7-azaindole for1H- indole in Method A. Mass: (M + 1), 528.
Example 38 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2- (dimethylamino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 34, by substituting 7-azaindole for1H- indole in Method A and substituting dimethylamine for di ethylamine to in Method E. Mass: (M + 1), 513.
Example 39 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2- (dimethylamino)-4-methoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 30 by substituting 7-azaindole for1H- indole in Method A. Mass: (M + 1), 529.
Example 40 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 29 by substituting 1-methyl- IH-indole for 1H-indole in Method A. Mass: (M + 1), 555.
Example 41 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enamide
This compound was similarly prepared following Example 23 by substituting 1-methyl- IH-indole for 1H-indole in Method A. Mass: (M + 1), 541.
Example 42 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-( 1 -methyl- 1H-indol-3 - yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 35, with an addition of a SN Ar step with 2-aminoethanol before the reduction step (Method C). Mass: (M + 1), 558.
Example 43 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-( 1 -methyl-1H-indol -3 - yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 34, with an addition of a SN Ar step with 2-aminoethanol before the reduction step (Method C). Mass: (M + 1), 542.
Example 44 (E)- 4-(dimethylamino)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1-methyl-1H- indole for1H- indole in Method A with an addition of a SN Ar step with dimethylamine before the reduction step (Method C). Mass: (M + 1), 500.
Example 45 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 44 by substituting pyrrolidine for dimethylamine in Method E. Mass: (M + 1), 526.
Example 46(E)- N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 1, by substituting 1 -methyl-1H- indole for1H- indole in Method A and substituting 2,4-dimethoxy-5-nitroaniline for 4- fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 487.
Example 47 (E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for1H- indole in Method A and by substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 517.
Example 48 (E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 1 by substituting 1 -methyl-1H- indole for1H- indole in Method A and by substituting pyrrolidine for dimethylamine in Method E. Mass: (M + 1), 501.
Example 49 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2- yl)amino)-2-(pyridin-2-ylamino)phenyl)amino)ethan-1-ol
This compound was similarly prepared following Example 43, with substitution of 1- methyl-1H-pyrrolo[2,3-b]pyridine for 1 -methyl- 1H-indole and changing Method D to a pyridine displacement approach with 2-chloropyridine. Mass: (M + 1), 483.
2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)amino)ethyl benzoate (100 mg, 0.22 mmol, 1.0 eq), 2-chloropyridine (25 mg, 1.0 eq), K3PO4 (140 mg, 3.0 eq), Pd2 (dba)3 (10 mg, -10% wt) and BINAP (10 mg, -10% wt) were added into Toluene (2 mL). The resulting mixture was flushed via nitrogen and heated at about 110 °C in a seal tube for 12 hours. The reaction was ceased at this time and the resulting mixture was worked up with sat NaHCO3 (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Prep-TLC gave off yellow solid as desire product (55 mg, 48 % yield).
Example 50 N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-((4-(1 -methyl- 1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide
This compound was similarly prepared following Example 8, by substituting 1 -methyl-1H- pyrrolo[2,3-b]pyridine for 1 -methyl-1H-indole in Method A altogether with the substitution of 2-(methylamino)ethan-1-ol for dimethylamine in the S^Ar step. The following steps were applied as well to get access to the final product. Mass: (M + 1), 473.
A round bottom flask was charged with 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)ethan-1-ol (450 mg, 1.0 mmol), benzoic acid (145 mg, 1.2 mmol, 1.2 eq.), EDC hydrochloride (290 mg, 1.5 mmol, 1.5 eq), 4-dimethylaminopyridine (12 mg, 0.1 mmol, 0.1 eq), and DCM (10 mL). The resulting mixture was stirred at room temperature overnight (~ 12 hours) and TLC analysis indicated that the starting material 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)ethan-1-ol was completely consumed. The reaction was ceased at this time and the resulting mixture was worked up with sat NaHCO3 (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Column chromatography gave off white solid as desire product (390 mg, 0.7 mmol, 70 % yield).
*DCC, CDI or HBTU can be used as coupling reagent instead of EDC hydrochloride in some scenario.
The reduction procedure was performed similarly as described in Method C of Example 1. Starting with 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2- yl)amino)-2-nitrophenyl)(methyl)amino)ethyl benzoate (280 mg, 0.5 mmol) to get desired product 2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin- 2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (200 mg, 0.38 mmol, 76 % yield).
Typical Method of EDC coupling reaction for amide formation:
The starting material acrylic acid (20 mg, ~1.1 eq) and HOBt hydrate (32 mg, -1.0 eq) were added into DCM (2 mL). Meanwhile, EDC hydrochloride (70 mg, ~1.5 eq) was added and followed by the starting material 2-((2-amino-5-methoxy-4-((4-(1 -methyl- 1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (130 mg, 0.25 mmol, 1.0 eq). The resulting mixture was stirred overnight until the starting material amine completely consumed from TLC analysis. The reaction was ceased at this time and the resulting mixture was worked up with sat NaHCCE (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Prep-TLC gave off white solid as desire product (82 mg, 0.14 mmol, 56 % yield).
The starting material 2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (30 mg, 0.05 mmol) was dissolved in a mixing solvent of methanol:H2O (0.9 mL:0.1 mL). Meanwhile, LiOH (2.5 mg, 2.0 eq) was added in the solution and stirred under room temperature for 2 hours. TLC analysis indicated the reaction was accomplished and the resulting mixture was condensed to dryness. The residue was dissolved in DCM (5mL) and worked up with sat NH4Cl (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated to dryness. Prep-TLC gave off white solid as desire product (15 mg, 0.03 mmol, 60 % yield).
Example 51 N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide
This compound was similarly prepared following Example 42, by changing Method D to a EDC catalyzed coupling reaction with acrylic acid. Mass: (M + 1), 459.
Example 52 N1 -(2-(dimethylamino)ethyl)-5-methoxy-N4-(4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)-N2 -(pyrimidin-4-yl)benzene-1,2,4-triamine
This compound was similarly prepared following Example 48, with an addition of a SN Ar step with N1,N1 -dimethylethane- 1,2-diamine before the reduction step (Method C) and changing Method D to a Buchwald approach with a 4-chloropyrimidine. Mass: (M + 1), 510.
Example 53 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- (pyridin-2-ylamino)phenyl)amino)ethan- 1 -ol
This compound was similarly prepared following Example 42 by changing Method D to Buchwald approach with a 2-chloropyridine. Mass: (M + 1), 482.
Example 54 N1 -(2-(dimethylamino)ethyl)-5-methoxy-N1 -methyl -N4 -(4-(1-methyl-1H- indol-3-yl)pyrimidin-2-yl) -N2 -(pyridin-2-yl)benzene-1,2,4-triamine
This compound was similarly prepared following Example 43, with an addition of a SN Ar step with N1,N1 -dimethylethane- 1,2-diamine before the reduction step (Method C) and changing Method D to a Buchwald approach with 4-chloropyrimidine. Mass: (M + 1), 523. Example 55 2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-5-methoxy- 2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol
This compound was similarly prepared following Example 49 by substituting 7-azaindole for 1 -methyl- 1H-indole in Method A. Mass: (M + 1), 470.
Example 56 2-((4-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4- ylamino)phenyl)amino)ethan- 1 -ol
This compound was similarly prepared following Example 49 by substituting 1H-indol for 1 -methyl-1H-indole in Method A. Mass: (M + 1), 469.
Example 57 2-((4-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5- methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol
This compound was similarly prepared following Example 49 by substituting 5-fluoro-1- m ethyl- 1H-indole for 1 -methyl-1H-indole in Method A. Mass: (M + 1), 501.
Example 58 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-l -methyl-1H- indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-ynamide
This compound was similarly prepared following Example 54 by substituting 5-fluoro-1- m ethyl- 1H-indole for 1 -methyl- 1H-indole in Method A, and changing Method D to an EDC catalyzed coupling reaction with but-2-ynoic acid. Mass: (M + 1), 530.
Example 59 (E)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-1-methyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide
This compound was similarly prepared similar following Example 58 by changing Method D to a EDC catalyzed coupling reaction with crotonic acid. Mass: (M + 1), 532.
Example 60 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- (pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol
This compound was similarly prepared following Example 53 by changing Method D to Buchwald approach with a 4-chloropyrimidine. Mass: (M + 1),483.
Example 61 (E)-N-(5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- hydroxyethyl)(methyl)amino)-4-methoxyphenyl)but-2-enamide
This compound was similarly prepared following Example 59 by substituting 2- (methylamino)ethan-1-ol instead for N1, N1 -dimethylethane- 1,2-diamine as SN Ar reaction reagent before the reduction step (Method C). Mass: (M + 1), 504.
Example 62 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro- 4-methoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 1 by substituting 7-azaindole for1H- indole in Method A and substituting morpholine for dimethylamine in Method E. Mass: (M + 1), 504.
Example 63(E)- N-(5-((4-(1H-pyrrolo[2,3-/»]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro- 4-methoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 62 by substituting 4-chloro-2- m ethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5 -nitroaniline in Method B. Mass: (M + 1), 520.
Example 64(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-methylphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 62 by substituting 2-methoxy-
4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 500.
Example 65(E)-N-( 3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 62 by substituting 2-methoxy -
5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 486, Example 66 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro- 4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 62 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 502.
Example 67 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro- 4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 63 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 519.
Example 68 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-methylphenyl)-4-(piperidin- 1 -yl)but-2-enamide
This compound was similarly prepared following Example 64 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 498.
Example 69(E)-N-( 3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide
This compound was similarly prepared following Example 65 by substituting piperidine for morpholine in Method E. Mass: (M + 1), 484.
Example 70 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4- dimethoxyphenyl)-4-(piperidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 66 by substituting 2,4- dimethoxy-5 -nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 514.
Example 71 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro- 4-methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 62 by substituting dimethylamine for morpholine in Method E. Mass: (M + 1), 462.
Example 72(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4- dimethoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 62 by substituting by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M + 1), 517.
Example 73 (E)-N-(5- ((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 71 by adding addition a SN Ar winh methylamine before the reduction step (Method C). Mass: (M + 1), 473.
Example 74(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-(methylamino)phenyl)-4-(piperidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 66 by adding addition a SN Ar step with methylamine before the reduction step (Method C). Mass: (M + 1), 514.
Example 75 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4- methoxy-2-(methylamino)phenyl)-4-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)but-2-enamide This compound was similarly prepared following Example 73 by substituting 5- azaspiro[2.4]heptan-7-ol for dimethylamineine Method E. Mass: (M + 1), 542.
Example 76(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2- (dimethylamino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 71 by adding addition a SN Ar step with dimethylamine before the reduction step (Method C). Mass: (M + 1), 488.
Example 77(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2- (dimethylamino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide
This compound was similarly prepared following Example 76 substituting piperidine for dimethylamineine Method E. Mass: (M + 1), 528.
Example 78(E)-N-( 5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-amino- 4-methoxyphenyl)-4-morpholinobut-2-enamide
This compound was similarly prepared following Example 62 by adding addition a SN Ar step with ammonium before the reduction step (Method C) and the -NH2 group was then protected via -Boc. Other steps were accomplished via routine protocol and the -Boc group was removed with an additional step with TFA after Method E. Mass: (M + 1), 502.
Example 79 (E)-N-(5-((5-cyano-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was similarly prepared following Example 2 by substituting 2,4- dichloropyrimidine for 2,4-dichloropyrimidine-5-carbonitrile. Mass: (M+l), 500.
Example 80 (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid
This compound was similarly prepared following Example 79 by with a subsequently acid hydrolysis process. Mass: (M+l), 519.
Example 81 ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate
This compound was similarly prepared following Example 80 by a subsequently EDC esterification process with ethanol. Mass: (M+l), 547.
Example 82 (E)-N-(5-((5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide
This compound was prepared following Example 1, by substituting 2,4-dichloro-5- methylpyrimidine for 2,4-dichloropyrimidine-5-carbonitrile in Method A. Mass: (M + 1), 486.
Example 83 (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylic acid
This compound was similarly prepared following Example 82 by with a subsequently acid hydrolysis process. Mass: (M+l), 505.
Example 84 ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2- methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate
This compound was similarly prepared following Example 83 by a subsequently EDC esterification process with ethanol. Mass: (M+l), 533.
Claims
R is selected from H, halogen, halogen-lower alkyl, -CN, carboxylic acid, carboxylic ester or carboxylic amide;
X is selected from direct bond, -O-, -S-, or -N(R')-;
R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl, hydroxyl, lower alkoxy, amino, hydroxyl alkylamino, aryl or heterocyclyl;
Q’ is a heterocyclyl, selected from pyrimidinyl and pyridinyl:
Y is selected from H, or -NR’R’. R’R’ can form an aliphatic, heterocyclic ring; or a pharmaceutically acceptable salt thereof.
R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, carboxylic lower alkyl ester or carboxylic lower alkyl amide with nitrogen mono or dual substituted; preferably selected from Cl, Br and carboxylic acid.
X is selected from -O-, or -N(R')-; preferably -NH-;
R’ is selected from H, halogen, halogeno-lower alkyl, lower alkyl; preferably lower alkoxy or a halogen.
Q’ is selected from pyrimidinyl and pyridinyl:
Y is selected from H, or -NR’R’, R’R’ can form a aliphatic, heterocyclic ring; preferably the -NR’R’ group is selected from substituted or unsubstituted N,N- dimethyl amino (-NMe2), pyrrolidine, morpholine, piperidine and piperazine or a pharmaceutically acceptable salt thereof.
Formula I
X is -NH-;
R is selected from H, fluorine, chlorine, bromine, methyl or trifluoromethyl;
4. A compound described in Claim 1 that is selected from:
5. A compound according to Claim 1 that is selected from:
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide;
(E)-4- (dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)- 4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(17Aindol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-4- (dimethylamino)-N-(2-fluoro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)- 4-methoxyphenyl)but-2-enamide;
(E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)- 4-(dimethylamino)but-2-enamide;
(E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-
4-(dimethylamino)but-2-enamide;
(E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-
(dimethylamino)but-2-enamide;
(E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-
(methylamino)phenyl)-4-morpholinobut-2-enamide;
(E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)-2-(methylamino)phenyl)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-
4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4- dimethoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2- methylphenyl)-4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4- (dimethylamino)but-2-enamide;
(E)-4-(dimethylamino)-N-(4-methoxy-2-methyl-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin- 2-yl)amino)phenyl)but-2-enamide;
(E)-4-(dimethylamino)-N-(4-methoxy-3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)but-2-enamide;
(E)-N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide;
(E)-N- (2-chloro-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4- (dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)- 4-(piperazin- 1 -yl)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4- morpholinobut-2-enamide;
(E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2- morpholinophenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (methylamino)phenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4- morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)- 4-(piperidin-1-yl)but-2-enamide;
(E)-N-( 5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)- 4-(4-methylpiperazin-1-yl)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)- 4-morpholinobut-2-enamide;
(E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(piperidin-1-yl)but-2-enamide;
(E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide;
(E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(piperazin- 1 -yl)but-2-enamide;
(E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide;
(E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-morpholinobut-2-enamide;
(E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide;
(E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(piperazin- 1 -yl)but-2-enamide;
(E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-morpholinobut-2-enamide;
(E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide;
(E)-4-(dimethylamino)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide;
(E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide;
(E)-N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4- (dimethylamino)but-2-enamide;
(E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)- 4-morpholinobut-2-enamide;
(E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)- 4-(pyrrolidin-1-yl)but-2-enamide;
2-((5-methoxy-4-((4-(1 -methyl- 1H-pyrrolo[2,3-b]pyridin-3 -yl)pyrimidin-2-yl)amino)-2- (pyridin-2 -ylamino)phenyl)amino)ethan- 1 -ol ; N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;
N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)acrylamide;
N1 -(2-(dimethylamino)ethyl)-5-methoxy-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)- N2 -(pyrimidin-4-yl)benzene-1,2,4-triamine;
2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(pyridin-2- ylamino)phenyl)amino)ethan- 1 -ol;
N1 -(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)-N2-(pyri din-2 -yl)benzene- 1 ,2,4-triamine;
2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-
4-ylamino)phenyl)amino)ethan-1-ol;
2-((4-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4- ylamino)phenyl)amino)ethan-1-ol;
2-((4-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2- (pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-ynamide;
(E)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-l -methyl- 1H-indol-3- yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide;
2-((5-methoxy-4-((4-(l -methyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(pyrimidin-4- ylamino)phenyl)amino)ethan-1-ol;
(E)-N-(5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- hydroxyethyl)(methyl)amino)-4-methoxyphenyl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4- methoxyphenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2- methylphenyl)-4-morpholinobut-2-enamide;
(E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4- methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2- methylphenyl)-4-(piperidin-1-yl)but-2-enamide;
(E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- (piperidin-1-yl)but-2-enamide;
(E)-N-(5-((1H-pyrrolo[2,3-b]pyridin-1-yl) pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)- 4-(piperidin- 1 -yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)- 4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (methylamino)phenyl)-4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-
(methylamino)phenyl)-4-(piperidin- 1 -yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (methylamino)phenyl)-4-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4- methoxyphenyl)-4-(piperidin- 1 -yl)but-2-enamide;
(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-amino-4- methoxyphenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((5-cyano-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1- methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid; ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-
(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate
(E)-N-(5-((5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-
(dimethylamino)but-2-enamide
(E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1H- indol-3-yl)pyrimidine-5-carboxylic acid ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4- (1H-indol-3-yl)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt thereof.
6. A compound according to Claim 1 that is selected from:
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4- (dimethylamino)but-2-enamide;
(E)-4-(dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)- 4-(dimethylamino)but-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-4- methoxyphenyl)-4-(dimethylamino)but-2-enamide;
(E)-4-(dimethylamino)-N-(2-fluoro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-
4-methoxyphenyl)but-2-enamide;
(E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)- 4-(dimethylamino)but-2-enamide;
(E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-
4-(dimethylamino)but-2-enamide;
(E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)-4-morpholinobut-2-enamide;
(E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4- (dimethylamino)but-2-enamide;
(E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-
(methylamino)phenyl)-4-morpholinobut-2-enamide; (E)-4-(dimethylamino)-N-(4-methoxy-
5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)but-2- enamide; or a pharmaceutically acceptable salt thereof.
7. A process that synthesizes the compound of Formula I that described in Claim 1, by following synthesis procedures in Scheme 1 or Scheme 2:
Formula I
Wherein R, R’, R”, X, Q and Q’ are as defined previously.
8. A pharmaceutical composition that comprises as an active ingredient a compound as defined in any one of Claims 1-6 or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate of the compound and a pharmaceutically acceptable carrier.
9. A compound adapted for use in the method of treatment of EGFR mutants including L858R, T790M in a subject by administering an effective amount of said compound as in any of Claim 1-6.
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Citations (4)
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CN104761585A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Substituted aminopyrimidine working as inhibitor of EGFR epidermal growth factor receptor |
WO2017205459A1 (en) * | 2016-05-26 | 2017-11-30 | Kalyra Pharmaceuticals, Inc. | Egfr inhibitor compounds |
US20180162832A1 (en) * | 2011-07-27 | 2018-06-14 | Astrazeneca Ab | 2-(2,4,5-substituted-anilino)pyrimidine compounds |
WO2021111462A1 (en) * | 2019-12-02 | 2021-06-10 | Natco Pharma Limited | An improved process for the preparation of osimertinib mesylate |
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US20180162832A1 (en) * | 2011-07-27 | 2018-06-14 | Astrazeneca Ab | 2-(2,4,5-substituted-anilino)pyrimidine compounds |
CN104761585A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Substituted aminopyrimidine working as inhibitor of EGFR epidermal growth factor receptor |
WO2017205459A1 (en) * | 2016-05-26 | 2017-11-30 | Kalyra Pharmaceuticals, Inc. | Egfr inhibitor compounds |
WO2021111462A1 (en) * | 2019-12-02 | 2021-06-10 | Natco Pharma Limited | An improved process for the preparation of osimertinib mesylate |
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