NZ592761A - 6-Morpholino-purine derivatives - Google Patents

Info

Publication number

NZ592761A

NZ592761A NZ592761A NZ59276109A NZ592761A NZ 592761 A NZ592761 A NZ 592761A NZ 592761 A NZ592761 A NZ 592761A NZ 59276109 A NZ59276109 A NZ 59276109A NZ 592761 A NZ592761 A NZ 592761A

Authority

NZ

New Zealand

Prior art keywords

group

substituents selected

compound

salt

alkylamino

Prior art date

2008-10-14

Links

• Espacenet
• Global Dossier
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• MEOMXKNIFWDDGZ-UHFFFAOYSA-N 6-morpholin-4-yl-9h-purine Chemical class C1COCCN1C1=NC=NC2=C1N=CN2 MEOMXKNIFWDDGZ-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 405
• 125000001424 substituent group Chemical group 0.000 claims abstract description 276
• 150000003839 salts Chemical class 0.000 claims abstract description 86
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 43
• 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 7
• 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 6
• 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
• 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
• 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
• 206010060862 Prostate cancer Diseases 0.000 claims abstract description 6
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 6
• 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 6
• 201000001441 melanoma Diseases 0.000 claims abstract description 6
• 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims abstract description 5
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 5
• 239000003937 drug carrier Substances 0.000 claims abstract description 5
• 201000005202 lung cancer Diseases 0.000 claims abstract description 5
• 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
• 206010014733 Endometrial cancer Diseases 0.000 claims abstract 2
• 206010014759 Endometrial neoplasm Diseases 0.000 claims abstract 2
• 238000013519 translation Methods 0.000 claims description 282
• 125000003282 alkyl amino group Chemical group 0.000 claims description 101
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 91
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 45
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 45
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 43
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• 108091007960 PI3Ks Proteins 0.000 claims description 37
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims description 37
• 125000003277 amino group Chemical group 0.000 claims description 35
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
• 125000005843 halogen group Chemical group 0.000 claims description 33
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 29
• 125000001072 heteroaryl group Chemical group 0.000 claims description 27
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 25
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 25
• 125000003118 aryl group Chemical group 0.000 claims description 23
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 22
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 22
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 20
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• 125000004043 oxo group Chemical group O=* 0.000 claims description 15
• QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 14
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 12
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 12
• 239000003112 inhibitor Substances 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 230000035772 mutation Effects 0.000 claims description 9
• 230000026731 phosphorylation Effects 0.000 claims description 9
• 238000006366 phosphorylation reaction Methods 0.000 claims description 9
• 125000004429 atom Chemical group 0.000 claims description 8
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 8
• AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 7
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
• 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 6
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 6
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 6
• 125000002393 azetidinyl group Chemical group 0.000 claims description 6
• 230000000694 effects Effects 0.000 claims description 6
• 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
• 229910019142 PO4 Inorganic materials 0.000 claims description 5
• 125000002947 alkylene group Chemical group 0.000 claims description 5
• 230000002018 overexpression Effects 0.000 claims description 5
• 101710173511 Tensin homolog Proteins 0.000 claims description 4
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
• 239000010452 phosphate Substances 0.000 claims description 4
• 102000005912 ran GTP Binding Protein Human genes 0.000 claims description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
• 229910052739 hydrogen Chemical group 0.000 claims description 2
• 239000001257 hydrogen Chemical group 0.000 claims description 2
• 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims 8
• 101100243951 Caenorhabditis elegans pie-1 gene Proteins 0.000 claims 1
• 101100086490 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) rbd-2 gene Proteins 0.000 claims 1
• 102100032543 Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN Human genes 0.000 claims 1
• ZARHKMRIVDUEMH-UHFFFAOYSA-N 5-[9-(cyclopropylmethyl)-8-(4-methylsulfonylpiperazin-1-yl)-6-morpholin-4-ylpurin-2-yl]pyrimidin-2-amine Chemical compound C1CN(S(=O)(=O)C)CCN1C1=NC2=C(N3CCOCC3)N=C(C=3C=NC(N)=NC=3)N=C2N1CC1CC1 ZARHKMRIVDUEMH-UHFFFAOYSA-N 0.000 abstract description 4
• RHQXYBYIDZQMDN-UHFFFAOYSA-N 5-[9-(2-methylpropyl)-8-(4-methylsulfonylpiperazin-1-yl)-6-morpholin-4-ylpurin-2-yl]pyrimidin-2-amine Chemical compound N1=C2N(CC(C)C)C(N3CCN(CC3)S(C)(=O)=O)=NC2=C(N2CCOCC2)N=C1C1=CN=C(N)N=C1 RHQXYBYIDZQMDN-UHFFFAOYSA-N 0.000 abstract description 3
• SOJJMSYMCLIQCZ-CYBMUJFWSA-N 1-[(2r)-4-[2-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)purin-8-yl]-2-methylpiperazin-1-yl]ethanone Chemical compound C1CN(C(C)=O)[C@H](C)CN1C1=NC2=C(N3CCOCC3)N=C(C=3C=NC(N)=NC=3)N=C2N1CC(F)(F)F SOJJMSYMCLIQCZ-CYBMUJFWSA-N 0.000 abstract description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 318
• 239000000203 mixture Substances 0.000 description 280
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 269
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 194
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 190
• 230000002829 reductive effect Effects 0.000 description 190
• 239000007787 solid Substances 0.000 description 177
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 174
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 166
• 239000002904 solvent Substances 0.000 description 147
• 238000005160 1H NMR spectroscopy Methods 0.000 description 144
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 137
• 239000000243 solution Substances 0.000 description 133
• 239000011541 reaction mixture Substances 0.000 description 128
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 118
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 117
• 239000012044 organic layer Substances 0.000 description 112
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 104
• 101150041968 CDC13 gene Proteins 0.000 description 100
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 100
• 238000010898 silica gel chromatography Methods 0.000 description 87
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 86
• 235000019341 magnesium sulphate Nutrition 0.000 description 86
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 66
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
• 229920006395 saturated elastomer Polymers 0.000 description 62
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 59
• 235000017557 sodium bicarbonate Nutrition 0.000 description 59
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 55
• 239000000706 filtrate Substances 0.000 description 54
• 238000006243 chemical reaction Methods 0.000 description 51
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 50
• -1 CCI-779 Chemical class 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
• 238000001914 filtration Methods 0.000 description 44
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 38
• 238000000034 method Methods 0.000 description 38
• 239000010410 layer Substances 0.000 description 36
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 35
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 34
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 33
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 33
• 238000001816 cooling Methods 0.000 description 33
• 235000019253 formic acid Nutrition 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• 238000005481 NMR spectroscopy Methods 0.000 description 31
• 238000002953 preparative HPLC Methods 0.000 description 30
• 102000038030 PI3Ks Human genes 0.000 description 29
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 28
• JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 28
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 28
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 26
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 26
• 239000000725 suspension Substances 0.000 description 25
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 24
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
• 125000006239 protecting group Chemical group 0.000 description 19
• 238000006467 substitution reaction Methods 0.000 description 19
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 16
• ZHLLXTBYDKZEFM-UHFFFAOYSA-N 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-ylpurin-2-yl]-4-methylpyrimidin-2-amine Chemical compound CC1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(Cl)N2CC3CC3)C2=N1 ZHLLXTBYDKZEFM-UHFFFAOYSA-N 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• 239000002246 antineoplastic agent Substances 0.000 description 14
• 201000011510 cancer Diseases 0.000 description 13
• 230000002401 inhibitory effect Effects 0.000 description 13
• 238000010992 reflux Methods 0.000 description 13
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 12
• BXEMEYQLLIFSLY-UHFFFAOYSA-N 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-ylpurin-2-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(Cl)N2CC3CC3)C2=N1 BXEMEYQLLIFSLY-UHFFFAOYSA-N 0.000 description 12
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 12
• 239000000654 additive Substances 0.000 description 12
• 239000012298 atmosphere Substances 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 238000009472 formulation Methods 0.000 description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 12
• 230000002411 adverse Effects 0.000 description 11
• 125000000217 alkyl group Chemical group 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• DOJFQBCTEHGPBN-UHFFFAOYSA-N 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)purin-2-yl]pyrimidin-2-amine Chemical compound C1=NC(N)=NC=C1C1=NC(N2CCOCC2)=C(N=C(Cl)N2CC(F)(F)F)C2=N1 DOJFQBCTEHGPBN-UHFFFAOYSA-N 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 150000001412 amines Chemical class 0.000 description 10
• 230000000259 anti-tumor effect Effects 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 9
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• 230000035484 reaction time Effects 0.000 description 9
• JOMNTHCQHJPVAZ-YFKPBYRVSA-N (2s)-2-methylpiperazine Chemical compound C[C@H]1CNCCN1 JOMNTHCQHJPVAZ-YFKPBYRVSA-N 0.000 description 8
• ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 description 8
• 239000004480 active ingredient Substances 0.000 description 8
• 238000005804 alkylation reaction Methods 0.000 description 8
• 239000002585 base Substances 0.000 description 8
• 238000005859 coupling reaction Methods 0.000 description 8
• 239000012046 mixed solvent Substances 0.000 description 8
• JOMNTHCQHJPVAZ-RXMQYKEDSA-N (2r)-2-methylpiperazine Chemical compound C[C@@H]1CNCCN1 JOMNTHCQHJPVAZ-RXMQYKEDSA-N 0.000 description 7
• IFNWESYYDINUHV-OLQVQODUSA-N (2s,6r)-2,6-dimethylpiperazine Chemical compound C[C@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-OLQVQODUSA-N 0.000 description 7
• ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 7
• GVYLZZWPZPJRQZ-OAHLLOKOSA-N 5-[8-[(3r)-3-methylpiperazin-1-yl]-9-(2-methylpropyl)-6-morpholin-4-ylpurin-2-yl]pyrimidin-2-amine Chemical compound N1=C2N(CC(C)C)C(N3C[C@@H](C)NCC3)=NC2=C(N2CCOCC2)N=C1C1=CN=C(N)N=C1 GVYLZZWPZPJRQZ-OAHLLOKOSA-N 0.000 description 7
• 230000007730 Akt signaling Effects 0.000 description 7
• 150000001721 carbon Chemical group 0.000 description 7
• 229940125904 compound 1 Drugs 0.000 description 7
• 230000032050 esterification Effects 0.000 description 7
• 238000005886 esterification reaction Methods 0.000 description 7
• 229940098779 methanesulfonic acid Drugs 0.000 description 7
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
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