CN113880813A - 2-aminopyrimidine heterocyclic compound and application thereof - Google Patents
2-aminopyrimidine heterocyclic compound and application thereof Download PDFInfo
- Publication number
- CN113880813A CN113880813A CN202010615654.0A CN202010615654A CN113880813A CN 113880813 A CN113880813 A CN 113880813A CN 202010615654 A CN202010615654 A CN 202010615654A CN 113880813 A CN113880813 A CN 113880813A
- Authority
- CN
- China
- Prior art keywords
- substituted
- alkyl
- membered
- unsubstituted
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 2-aminopyrimidine heterocyclic compound Chemical class 0.000 title claims abstract description 38
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims abstract description 15
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 claims abstract description 15
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 claims abstract description 15
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims abstract description 9
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 123
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 230000000694 effects Effects 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 16
- 102000003903 Cyclin-dependent kinases Human genes 0.000 claims description 15
- 108090000266 Cyclin-dependent kinases Proteins 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 208000032612 Glial tumor Diseases 0.000 claims description 7
- 206010018338 Glioma Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims 2
- 150000002391 heterocyclic compounds Chemical class 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 description 43
- 238000003786 synthesis reaction Methods 0.000 description 43
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- 238000000034 method Methods 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000003921 oil Substances 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 13
- 238000001308 synthesis method Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229950001573 abemaciclib Drugs 0.000 description 12
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 108091007914 CDKs Proteins 0.000 description 4
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QBVOAZVDLKSGLR-UHFFFAOYSA-N 3-fluoro-4-piperidin-1-ylaniline Chemical compound FC1=CC(N)=CC=C1N1CCCCC1 QBVOAZVDLKSGLR-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 201000007983 brain glioma Diseases 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- PDUSWJORWQPNRP-UHFFFAOYSA-N n-propan-2-ylacetamide Chemical compound CC(C)NC(C)=O PDUSWJORWQPNRP-UHFFFAOYSA-N 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- MVYNWBRDGGKNCS-UHFFFAOYSA-N 1-(2-fluoro-4-nitrophenyl)piperidine Chemical compound FC1=CC([N+](=O)[O-])=CC=C1N1CCCCC1 MVYNWBRDGGKNCS-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- WMASLRCNNKMRFP-UHFFFAOYSA-N 1-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(F)=C1 WMASLRCNNKMRFP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 108050006400 Cyclin Proteins 0.000 description 2
- 102000016736 Cyclin Human genes 0.000 description 2
- 102000003910 Cyclin D Human genes 0.000 description 2
- 108090000259 Cyclin D Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LJFQSBXZAZWUKC-UHFFFAOYSA-N FC1(C(C=CC(=C1)C)S(=O)(=O)OC)C1=CC=C(C=C1)[N+](=O)[O-] Chemical compound FC1(C(C=CC(=C1)C)S(=O)(=O)OC)C1=CC=C(C=C1)[N+](=O)[O-] LJFQSBXZAZWUKC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000005005 aminopyrimidines Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 2
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 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 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- MMWFMFZFCKADEL-UHFFFAOYSA-N 2-fluoro-4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1F MMWFMFZFCKADEL-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- HKGNZXXYXCKJHO-UHFFFAOYSA-N 315228-19-4 Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1F HKGNZXXYXCKJHO-UHFFFAOYSA-N 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- BFQSQUAVMNHOEF-UHFFFAOYSA-N 4-bromo-2,6-difluoroaniline Chemical compound NC1=C(F)C=C(Br)C=C1F BFQSQUAVMNHOEF-UHFFFAOYSA-N 0.000 description 1
- KDTVWEHAAISPNW-UHFFFAOYSA-N 4-methylthiomorpholine Chemical compound CN1CCSCC1 KDTVWEHAAISPNW-UHFFFAOYSA-N 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100383153 Caenorhabditis elegans cdk-9 gene Proteins 0.000 description 1
- 102000002435 Cyclin T Human genes 0.000 description 1
- 108010068106 Cyclin T Proteins 0.000 description 1
- 108010025461 Cyclin-Dependent Kinase 9 Proteins 0.000 description 1
- 102000013702 Cyclin-Dependent Kinase 9 Human genes 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000005059 dormancy Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- AXMODJGMGVEOES-UHFFFAOYSA-N formaldehyde;morpholine Chemical compound O=C.C1COCCN1 AXMODJGMGVEOES-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XGXNTJHZPBRBHJ-UHFFFAOYSA-N n-phenylpyrimidin-2-amine Chemical class N=1C=CC=NC=1NC1=CC=CC=C1 XGXNTJHZPBRBHJ-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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229950003687 ribociclib Drugs 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
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 1
- 238000003210 sulforhodamine B staining Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002626 targeted therapy Methods 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a 2-aminopyrimidine heterocyclic compound with a structure shown in a general formula I and application thereof, belongs to kinase CDK4, CDK6 and/or CDK9 inhibitors, can be widely used for treating various cancers, and has great clinical application value.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a 2-aminopyrimidine heterocyclic compound and application thereof. In particular to a pyrimidine derivative and a pharmaceutically acceptable salt, ester or solvate thereof, belonging to a Cyclin Dependent Kinase (CDK) inhibitor, and a preparation method and a pharmaceutical application of the compound in preventing or treating diseases related to CDK.
Background
Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine(Thr) kinase, an important signal transduction molecule in cells, and a CDK-cyclin complex formed by cyclins, are involved in the growth, proliferation, dormancy or apoptosis of cells. Wherein CDK4/6(cyclin-dependent kinase 4/6) regulates cell trafficking by binding to cyclin D (cyclin D)1The phase is switched to the S phase. Cell cycle runaway is an important factor in the development and progression of cancer, and CDK4/6 is a key factor in cell cycle runaway. Whereas CDK9 binding to cyclin T has been shown to be involved in cellular transcriptional regulation, inhibitors of CDK9 are believed to be useful in the treatment of a variety of cancers.
CDK binds to cyclins to form heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which in turn initiate events required for cell cycle transcription and progression. Since uncontrolled cellular proliferation is a hallmark of cancer, and most cancer cells exhibit dysregulation of CDKs, inhibition of CDKs has become a possible therapy for a wide variety of cancers, with selective inhibitors of CDK4/6 currently being viewed as a promising class of potential anti-cancer or anti-inflammatory agents, due to the important role of both CDK4/6 in regulating cellular proliferation and the toxic effects associated with inhibiting other members of the CDK family.
The cancer targeted therapy is an effective treatment scheme, has strong specificity and small toxic and side effects, basically does not damage normal tissues, and can more effectively provide further reference for the selection of clinical treatment schemes. With the deepening of pharmacological and molecular biological researches, the research and application of targeted drugs have made breakthrough progress, the research and development of new therapeutic target drugs have become a focus of attention of people, the cancer therapy is led to step into the personalized and precise era, and the good news is brought to more cancer patients. Compared with a plurality of existing antitumor drugs, the CDK small molecule inhibitor has more potential advantages when being applied to targeted anticancer treatment, and the risk of secondary tumor development can be reduced.
Most of CDK small molecule inhibitors disclosed in the prior art are CDK4/6 inhibitors, for example, the CDK4/6 inhibitors which are approved to be on the market are: palbociclib (pyroxene, approved by FDA at month 2 in 2015 and approved by CFDA at month 9 in 2018), Ribociclib (norway, approved by FDA at month 3 in 2017 and not yet approved by CFDA), Abemaciclib (gift, approved by FDA at month 10 in 2017 and not yet approved by CFDA). However, no CDK9 inhibitor has been approved for sale.
Through retrieval, patent documents related to Abemaciclib and structural modification and reconstruction around Abemaciclib specifically include:
the patent document with publication number WO 2010075074a1 (chinese family CN 102264725a) discloses a compound of structural formula 1, which is characterized in that: with frenum substituents R attached to amino groups of aminopyrimidines4The nitrogen-containing aromatic heterocycle of (1).
Patent publication No. CN 105294683a discloses a compound of structural formula 2, which is characterized by the following structural features: linked with amino in aminopyrimidine, is a B ring which is a para-substituted (disubstituted) benzene ring or a nitrogen-containing aromatic heterocycle.
the patent document with publication number WO 2016014904a1 (chinese family CN 106687454a) discloses compounds of structural formula 3 and structural formula 4, which are characterized by the following structural features: linked to the amino group of the aminopyrimidine, is a pyrimidine.
In the aforementioned patent documents, only the activity inhibition data (IC) of some compounds on CDK4 and CDK6 at the enzymatic or cellular level are disclosed50Value), no inhibition of activity was shown for CDK 9.
In addition, a related phenylaminopyrimidine derivative is also searchedThe patent of (1), namely the patent document with publication number WO 2018019204a1 (chinese family is CN 108602802a), discloses a compound of structural formula 5, which is characterized in that: with frenum substituents Y and R bound to amino groups of aminopyrimidines2The benzene ring of (2).
Wherein Y is H or selected from the following structures: (double bond or triple bond structure with unsaturated bond). However, this patent is an improvement over the third generation EGFR inhibitor AZD9291, whose activity test data indicate efficacy against EGFR and wild-type EGFR, and no knowledge of whether CDK4, CDK6, or CDK9 is effective.
In conclusion, how to develop a novel CDK inhibitor, which has better activity inhibition effect on CDK4, CDK6 or CDK9 than Abemaciclib, is even effective on specific tumor diseases such as lung cancer, brain glioma and breast cancer, and on the basis of the activity inhibition effect, the development of the chinese innovative medicine with independent intellectual property rights is a technical problem which needs to be solved urgently by the technical personnel in the field.
Disclosure of Invention
The invention aims to solve the technical problem of providing a 2-aminopyrimidine heterocyclic compound with a brand-new structure, which can inhibit the kinase activity of CDK4, CDK6 or CDK9 and has obvious antitumor activity.
In order to solve the technical problems, the invention adopts the following technical scheme:
a2-aminopyrimidine heterocyclic compound is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m-;
Ring A is substituted by one or more substituents R8Substituted 3-to 10-membered cycloalkyl, substituted by one or more substituents R8Substituted 3-10 membered heterocycloalkyl, substituted by one or more substituents R8Substituted 5-12 membered aryl, or substituted by one or more substituents R8Substituted 5-12 membered heteroaryl, but excluding piperazine;
R1and R2Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl or halo C1-C6An alkoxy group;
R3、R4and R7Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy, carboxy, cyano, amino, C1-C6Alkylamino, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;
R5、R6and R11Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, amino, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
R9And R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl is selected from hydrogen, C1-C6Alkyl, hydroxy or amino;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6.
Preferably, the compound is represented by formula II or a pharmaceutically acceptable salt thereof:
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m;
R3And R4Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, amino, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered arylThe substituent on the 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6.
Preferably, halogen is F or Cl; the 3-10 membered heterocyclic group and the 5-12 membered heteroaryl group contain one or more heteroatoms, and the heteroatoms are N, O, S.
A2-aminopyrimidine heterocyclic compound is selected from compounds with the following structures or pharmaceutically acceptable salts thereof, wherein the compounds are numbered from BT-B-1 to BT-B-16:
the term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" of the present invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compound" of the present invention also includes tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.
The solvent compound of the compound is selected from hydrate, ethanol compound, methanol compound, acetone compound, diethyl ether compound or isopropanol compound.
The invention also includes all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
Compounds containing the foregoing general structure, the terms used herein have the following meanings:
the term "hydroxy" refers to-OH.
The term "carboxyl" refers to-COOH.
The term "carbonyl" refers to-CO.
The term "cyano" refers to — CN.
The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "alkyl" denotes a straight or branched chain saturated aliphatic hydrocarbon radical consisting of carbon and hydrogen atoms, such as C1-C20Alkyl, preferably C1-C6Alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl, isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, and the like.
The term "alkoxy" refers to a straight or branched chain alkyl group attached through an oxygen atom, such as C1-C6Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), n-hexoxy, 2-methylhexoxy, and the like.
The term "amino" refers to the group-NH2。
The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as C1-C6Alkylamino groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.
The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic alkyl group consisting of carbon and hydrogen atoms, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; when polycyclic, they may be fused, bridged or spiro. In one aspect, typical monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocycloalkyl" refers to a saturated cyclic group having heteroatoms, the group containing 1 or more heteroatoms independently selected from N, O, S, the remainder being carbon-containing groups of a stable 3-to 10-membered saturated heterocyclic ring system. Unless otherwise specifically indicated in the specification, a heterocycloalkyl group may be a monocyclic, bicyclic, or polycyclic ring system; when polycyclic, they may be fused, bridged or spiro. In one aspect, typical 4-6 membered monocyclic heterocycloalkyl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to And the like. In one aspect, typical 7-10 membered bicyclic heterocycloalkyl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to And the like.
The term "aryl" refers to an all-carbon aromatic group having a fully conjugated pi-electron system, which may be a single ring or a fused ring, generally having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to an aromatic group containing a heteroatom, which may be a single ring or a fused ring, preferably containing 1-4 5-12 membered heteroaryl groups independently selected from N, O, S, including but not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, indolyl, and the like. In thatIn one embodiment, typical 5-6 membered monocyclic heteroaryl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to And the like.
The term "halo C1-C6Alkyl group "," halogeno C1-C6Alkoxy "means a group in which one or more (especially 1 to 3) hydrogen atoms are replaced by halogen atoms, in particular fluorine or chlorine atoms.
In the present invention, the terms "comprising" and "comprises" are open-ended and not closed-ended, i.e. comprise what is indicated in the present invention, but do not exclude other aspects.
In the present invention, when a substituent is not specifically indicated in the listed groups, such a group means only unsubstituted. For example when "C1-C6When an alkyl group is "without the limitation of" substituted or unsubstituted ", it means only" C1-C6Alkyl "by itself or unsubstituted C1-C6Alkyl groups ".
Linking substituents are described herein and when the structure clearly requires a linking group, the markush variables listed for that group are to be understood as linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
In some specific structures, when an alkyl group is expressly indicated as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo C1-C6C in alkyl1-C6Alkyl is understood to mean C1-C6An alkylene group.
The present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions can be referred to those conventional in the art unless otherwise indicated.
It will be understood by those skilled in the art that the "used in describing the structural formulae of the groups in the present invention means that the corresponding group is attached to other fragments, groups in the compound through the site, according to the convention used in the art.
The above preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The invention also provides a preparation method of the 2-aminopyrimidine heterocyclic compound, which comprises the following steps: under the protection of nitrogen, respectively adding the intermediate A, the intermediate B, an alkali reagent and a palladium catalyst into a reaction solvent, and carrying out coupling reaction to obtain a final product with a structure shown in a formula I. The reaction formula is as follows:
the invention also provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt or the solvate thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
"pharmaceutical composition" as used herein, refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier generally accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate delivery of the drug to an organism.
The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with, and facilitates the administration of, an active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is acceptable for human or animal (e.g., livestock) use as permitted by the drug administration. For example, including but not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
The pharmaceutical composition can be prepared into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powder, granules, paste, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
The route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granules, if necessary with the addition of small amounts of excipients, to form tablets or tablet cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).
The invention also provides the use of a compound or pharmaceutical composition as hereinbefore described in the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by Cyclin Dependent Kinase (CDK) activity.
Preferably, the pharmaceutical use is for the prevention or treatment of a disease associated with altered CDK4, CDK6 or CDK9 activity.
More preferably, the pharmaceutical use is for preventing or treating cancer, including but not limited to breast cancer, lung cancer, intestinal cancer, small cell lung cancer, melanoma, glioma, lymphoma, prostate cancer, rectal cancer, pancreatic cancer, liver cancer, stomach cancer, bladder cancer, ovarian cancer, mantle cell lymphoma, acute myelogenous leukemia or chronic myelogenous leukemia.
Compared with the prior art, the 2-aminopyrimidine heterocyclic compound is scientifically and reasonably designed based on a target, and a series of compounds with novel structures are obtained through substituent modification of groups; and a series of compounds with anti-tumor activity are optimally screened by combining the evaluation of in vitro and in vivo experiments, the compounds can be effective on CDK4 or CDK6, part of the compounds show better activity in cancers such as lung cancer, breast cancer, glioma and the like, are better than the CDK inhibitor of Abemaciclib, have great clinical application value on the prevention or treatment of the cancers, and have considerable market potential.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Example 1 compound BT-B-1: n- (3-fluoro-4-piperidin-methyl) phenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-B-1 is as follows:
intermediate A1(322mg,1mmol), intermediate B1(208mg,1mmol), cesium carbonate (651mg,2mmol), 4, 5-bisDiphenylphosphine-9, 9-Dimethylxanthene (Xantphos,116mg,0.2mmol) was dissolved in 1, 4-dioxane (10mL), and tris (dibenzylideneacetone) dipalladium (Pd) was added under nitrogen protection2(dba)3183mg,0.2mmol), reaction at 90 ℃ for 3 hours until completion, cooling the reaction solution to room temperature, pouring into 10mL of water, extracting with ethyl acetate three times (30 mL. times.3), combining the organic phases, washing the organic phase with saturated brine (50mL), drying over anhydrous sodium sulfate, filtering, spinning off and purifying the solid with a silica gel column (DCM: CH)3OH ═ 20:1) to give the target compound BT-B-1(257mg, 52%) as a yellow solid.
MS(m/z):495.3[M+H]+。
1HNMR(400MHz,DMSO-d6)δppm 9.98(s,1H),8.68(d,J=3.6Hz,1H),8.24(s,1H),7.78(dd,J=12.8,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.27(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.42(s,2H),2.65(s,3H),2.33(m,4H),1.62(d,J=6.8Hz,6H),1.48(m,4H),1.37(m,2H)。
The synthetic route of intermediate a1 is as follows:
step 1: synthesis of isopropyl acetamide (3)
Isopropylamine (1,59.1g,1mol), triethylamine (101.2g,1mol) were dissolved in dichloromethane (DCM,300mL) and acetic anhydride (2,102.1g,1mol) was added dropwise at-10 ℃ and after addition, the mixture was allowed to warm to room temperature to react, after which the reaction was completed, the solvent was distilled off under reduced pressure, ethyl acetate (500mL) and potassium carbonate (200g) were added, the mixture was stirred for 3 hours, filtered under suction, and the solvent was distilled off under reduced pressure to give an oil, i.e., Compound 3(93.2g, 92.1%).
MS(m/z):102.1[M+H]+。
Step 2: synthesis of N' - (4-bromo-2-6-difluorophenyl) -N-isopropylacetamidine (5)
Dissolving 4-bromo-2, 6-difluoroaniline (4,20.56g,98.9mmol) and isopropylacetamide (3,20g,197.7mmol) in toluene (150mL), cooling to-10 deg.C, and adding dropwise phosphorus oxychloride (POCl) under nitrogen protection322.7g,148.3mmol), triethylamine (15.0g,148.3mmol) is added dropwise, the mixture is moved into an oil bath pot after the addition, and the mixture is heated and refluxed for reaction for 3 hours at 115 ℃. After the reaction solution was cooled to room temperature, it was poured into a saturated aqueous sodium bicarbonate solution (3000mL), ethyl acetate was added, liquid separation was performed after thorough mixing, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (200mL), dried over anhydrous sodium sulfate, filtered, concentrated and then washed with petroleum ether (100mL) for 1 hour, filtered, and the filter cake was dried to obtain a solid, i.e., Compound 5(24.2g, 84.1%).
MS(m/z):291.0[M+H]+。
And step 3: synthesis of 1-isopropyl-2-methyl-4-fluoro-6-bromo-1H-benzo [ d ] imidazole (6)
Compound 5(24.2g,83.1mmol) was dissolved in N, N-dimethylformamide (DMF,120mL), potassium tert-butoxide (10.3g,91.4mmol) was added at 0 deg.C, and the mixture was heated to 110 deg.C under nitrogen for 2 hours. The reaction was cooled to room temperature and poured into water (700mL), extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated and washed with petroleum ether (100mL) slurry for 1 hour, filtered and the filter cake dried to give compound 6(20.0g, 88.9%) as a solid.
MS(m/z):271.0[M+H]+。
And 4, step 4: synthesis of 1-isopropyl-2-methyl-4-fluoro-6-boronic acid pinacol ester-1H-benzo [ d ] imidazole (8)
Compound 6(9.7g,35.8mmol), pinacol ester bisboronic acid (7, B)2(pin)213.6g,53.7mmol), Tricyclohexylphosphine (PCy)31.71g,6.1mmol) and potassium acetate (10.5g,107.2mmol) were dissolved in dimethyl sulfoxide (DMSO, 100mL), and palladium acetate (Pd (OAc) was added under nitrogen protection20.80g,3.6mmol), and the temperature is raised to 80 ℃ for reaction for 4 hours. Cooling the reaction solution to room temperature, pouring the reaction solution into water (300mL), extracting with ethyl acetate, combining organic phases, washing the organic phases with saturated saline (100mL), drying the organic phases with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by using a silica gel column (PE/EA is 4:1) to obtain the compoundTo solid, compound 8(7.64g, 67%).
MS(m/z):319.2[M+H]+。
And 5: synthesis of 1-isopropyl-2-methyl-4-fluoro-6- (2-chloro-5-fluoropyrimidin-4-yl) -1H-benzo [ d ] imidazole (A1)
2, 4-dichloro-5-fluoropyrimidine (9,3.23g,19.36mmol), sodium carbonate (3.66g,34.57mmol) were dissolved in 1, 4-dioxane/water (18mL/4.5mL), and bis-triphenylphosphine palladium dichloride (Pd (PPh) was added under nitrogen protection3)2Cl20.29g, 0.42mmol), and a solution of Compound 8(4.4g,13.83mmol) in 1, 4-dioxane (22.5mL) was added dropwise at 80 ℃ and reacted at 80 ℃ for 5 hours. The reaction was cooled to room temperature, poured into ice water (100mL), and a white solid precipitated, filtered to give a residue, and slurried with isopropanol to give compound a1(3.5g, 78.5%).
MS(m/z):323.1[M+H]+。
The synthetic route of intermediate B1 is as follows:
step 1 Synthesis of 2-fluoro-4-nitrobenzol (11)
2-fluoro-4-nitrobenzoic acid (10,9.25g,50mmol) was dissolved in tetrahydrofuran (30mL), cooled to-15 deg.C, stirred for 10 min and BH was added slowly3The THF solution (1mol/L,150mL,150mmol) was transferred to room temperature for 2 hours after completion of the dropwise addition. After completion of the reaction, the reaction solution was quenched by slowly pouring methanol (50mL) and the organic phase was concentrated to give compound 11(7.7g, 90%) as a white solid.
MS(m/z):170.2[M-H]-。
Step 2: synthesis of methyl 2-fluoro-4-nitrophenyl-4-methylbenzenesulfonate (12)
Compound 11(3.42g,20mmol) was dissolved in dichloromethane (20mL), triethylamine (4.04g,40mmol) and 4-methylbenzenesulfonyl chloride (5.72g,30mmol) were added, and the reaction was carried out at room temperature under nitrogen for 2 hours. After completion of the reaction, 5mL of water was added to the reaction mixture, and the organic phase was separated, dried over saturated brine and anhydrous sodium sulfate, and concentrated to give compound 12(5.85g, 90%) as a yellow oil.
MS(m/z):326.3[M+H]+。
And step 3: synthesis of 1- (2-fluoro-4-nitrophenyl) piperidine (13)
Compound 12(1.63g,5mmol) was dissolved in acetonitrile (10mL), triethylamine (757mg,7.5mmol) and piperidine (639mg,7.5mmol) were added, and the mixture was reacted at room temperature under nitrogen atmosphere overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, the reaction mixture was washed with water (10mL), extracted three times (20 mL. times.3) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate with saturated brine, and the organic phase was concentrated to give compound 13(1.1g, 92%) as a yellow oil.
MS(m/z):239.2[M+H]+。
And 4, step 4: synthesis of 1- (2-fluoro-4-aminophenyl) piperidine (B1)
Compound 13(952mg,4mmol) was dissolved in a mixed solvent of 12mL of ethanol and 4mL of water, and ammonium chloride (384mg,7.2mmol) and reduced iron powder (1.57g,28mmol) were added thereto, and the mixture was heated to 80 ℃ to react for 2 hours. After the reaction is completed, the system is cooled, filtered, and the filter residue is washed by ethanol. The filtrate was concentrated and saturated potassium carbonate solution was added to adjust the pH to alkaline. Extraction was carried out three times with ethyl acetate (20 mL. times.3), the organic phases were combined, saturated brine and anhydrous sodium sulfate were added to dry, and the organic phase was concentrated to give compound B1(724mg, 87%) as a yellow oil.
MS(m/z):209.2[M+H]+。
Example 2 compound BT-B-2: n- (4- ((4-dimethylamino) piperidin-1-yl) methyl) -3-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-B-2 is as follows:
with reference to the synthesis of BT-B-1 of example 1, a yellow solid, the target compound BT-B-2, was obtained.
MS(m/z):538.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.69(d,J=4.0Hz,1H),8.23(d,J=0.8Hz,1H),7.79(dd,J=12.8,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.47(dd,J=8.8,2.4Hz,1H),7.27(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.43(s,2H),2.85(m,2H),2.65(s,3H),2.16(s,6H),2.03(m,1H),1.93(m,2H),1.69(m,2H),1.62(d,J=6.8Hz,6H),1.35(m,2H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B2 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B2 as a yellow oil.
MS(m/z):252.3[M+H]+。
Example 3 compound BT-B-3: n- (3-fluoro-4- (morpholin-1-ylmethyl) phenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-B-3 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-3, can be obtained.
MS(m/z):497.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.68(d,J=3.6Hz,1H),8.23(s,1H),7.81(dd,J=13.2Hz,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.48(dd,J=8.4Hz,2.0Hz,1H),7.29(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.56(t,J=4.4Hz,4H),3.46(s,2H),2.65(s,3H),2.37(t,J=4.4Hz,4H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B3 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B3 as a yellow oil.
MS(m/z):211.2[M+H]+。
Example 4 compound BT-B-4: n- (4- ((4, 4-difluoropiperidin-1-yl) methyl) -3-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-B-4 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-4, can be obtained.
MS(m/z):531.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.02(s,1H),8.69(d,J=3.6Hz,1H),8.23(d,J=1.6Hz,1H),7.82(dd,J=13.2,2.4Hz,1H),7.66(d,J=12.8Hz,1H),7.48(dd,J=8.4,2.0Hz,1H),7.30(t,J=8.4Hz,1H),4.85(p,J=7.2Hz,1H),3.56(s,2H),2.65(s,3H),2.51(m,4H),1.95(m,4H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B4 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B4 as a yellow oil.
MS(m/z):245.2[M+H]+。
Example 5 compound BT-B-5: n- (1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-4-yl) acetamide
The synthesis route of the compound BT-B-5 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, the target compound BT-B-5 can be obtained as a yellow solid.
MS(m/z):552.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.68(d,J=3.6Hz,1H),8.24(d,J=1.2Hz,1H),7.80(dd,J=12.8,2.0Hz,1H),7.74(d,J=7.6Hz,1H),7.66(d,J=12.4Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.27(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.48(m,1H),3.44(s,2H),2.76(m,2H),2.65(s,3H),2.01(m,2H),1.77(s,3H),1.69(m,2H),1.62(d,J=6.8Hz,6H),1.34(m,2H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B5 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B5 as a yellow oil.
MS(m/z):266.3[M+H]+。
Example 6 Compound BT-B-6: 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- (3-fluoro-4- (pyrrolidin-1-ylmethyl) phenyl) pyrimidin-2-amine
The synthesis route of the compound BT-B-6 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-6, can be obtained.
MS(m/z):481.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 9.99(s,1H),8.69(d,J=4.0Hz,1H),8.23(d,J=1.2Hz,1H),7.80(dd,J=13.2,2.0Hz,1H),7.66(d,J=12.4Hz,1H),7.46(dd,J=8.4,2.0Hz,1H),7.29(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.56(s,2H),2.65(s,3H),2.44(m,4H),1.67(m,4H),1.62(d,J=7.2Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B6 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B6 as a yellow oil.
MS(m/z):195.2[M+H]+。
Example 7 compound BT-B-7: 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- (3-fluoro-4- (methylthiomorpholine) phenyl) pyrimidin-2-amine
The synthesis route of the compound BT-B-7 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-7, can be obtained.
MS(m/z):513.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.69(d,J=3.6Hz,1H),8.23(d,J=1.2Hz,1H),7.81(dd,J=13.2,2.4Hz,1H),7.66(d,J=12.4Hz,1H),7.48(dd,J=8.0,2.0Hz,1H),7.28(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.50(s,2H),2.61(m,11H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B7 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B7 as a yellow oil.
MS(m/z):227.2[M+H]+。
Example 8 Compound BT-B-8: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-3-ol
The synthesis route of the compound BT-B-8 is as follows:
with reference to the synthesis of BT-B-1 of example 1, a yellow solid, the target compound BT-B-8, was obtained.
MS(m/z):511.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.69(d,J=3.6Hz,1H),8.24(d,J=1.2Hz,1H),7.79(dd,J=12.8,2.0Hz 1H),7.66(d,J=12.0Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.27(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),4.57(d,J=5.2Hz,1H),3.44(m,3H),3.07-3.00(m,2H),2.79(m,1H),2.65(m,5H),1.86(m,1H),1.71(m,2H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B8 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B8 as a yellow oil.
MS(m/z):225.2[M+H]+。
Example 9 compound BT-B-9: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-4-ol
The synthesis route of the compound BT-B-9 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-9, can be obtained.
MS(m/z):511.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.69(d,J=3.6Hz,1H),8.24(d,J=1.6Hz,1H),7.80(d,J=2.4Hz,1H),7.66(d,J=12.0Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.27(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),4.53(d,J=4.4Hz,1H),3.44(s,3H),2.65(m,5H),2.05(m,2H),1.68(m,2H),1.62(d,J=6.8Hz,6H),1.37(m,2H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B9 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B9 as a yellow oil.
MS(m/z):225.2[M+H]+。
Example 10 compound BT-B-10: 2- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amine) phenyl) -1-morpholineacetyl-1-one
The synthesis route of the compound BT-B-10 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, the target compound BT-B-10 was obtained as a yellow solid.
MS(m/z):525.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 9.98(s,1H),8.68(d,J=3.6Hz,1H),8.22(d,J=1.2Hz,1H),7.81(dd,J=13.2,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.45(dd,J=8.4,2.0Hz,1H),7.16(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.68(s,2H),3.61-3.53(m,6H),3.47-3.45(m,2H),2.65(s,3H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B10 is as follows:
step 1 Synthesis of 2- (2-fluoro-4-nitrophenyl) -1-morpholinoethyl-1-one (22)
2-fluoro-4-nitrophenylacetic acid (10,1.99g,10mmol) was dissolved in 30mL of DMF and CDI (1.64g,10mmol) was added slowly and reacted at 70 ℃ for 2 hours under nitrogen. After completion of the reaction, the temperature was lowered to room temperature, morpholine (0.96g,11mmol) was slowly added, and the reaction was carried out at 40 ℃ for 2 hours. After completion of the reaction, water (50mL) was poured into the reaction mixture, ethyl acetate was added thereto and extracted three times (20mL × 3), the organic phases were combined, saturated brine and anhydrous sodium sulfate were added thereto and dried, and the organic phase was concentrated to obtain a dark brown oil, i.e., compound 22(2.28g, 85%).
MS(m/z):269.2[M-H]-。
Step 2: synthesis of 2- (2-fluoro-4-aminophenyl) -1-morpholinoethyl-1-one (B10)
Compound 22(1.34g,5mmol) was dissolved in a mixed solvent of 12mL of ethanol and 4mL of water, ammonium chloride (481mg,9.0mmol) and reduced iron powder (1.96g,35mmol) were added, and the mixture was heated to 80 ℃ to react for 2 hours. After the reaction is completed, the system is cooled, filtered, and the filter residue is washed by ethanol. The filtrate was concentrated and saturated potassium carbonate solution was added to adjust the pH to alkaline. The combined organic phases were extracted three times with ethyl acetate (20 mL. times.3), dried with saturated brine, anhydrous sodium sulfate and concentrated to give compound B10(1.10g, 93%) as a yellow oil.
MS(m/z):239.3[M+H]+。
Example 11 Compound BT-B-11: 7- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) -7-azaspiro [3.5] non-2-one
The synthesis route of the compound BT-B-11 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-11, can be obtained.
MS(m/z):549.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.69(d,J=3.6Hz,1H),8.23(d,J=1.2Hz,1H),7.80(dd,J=12.8,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.29(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.46(s,2H),2.74(m,4H),2.65(s,3H),2.35(m,4H),1.66(t,J=5.6Hz,4H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B11 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B11 as a yellow oil.
MS(m/z):263.2[M+H]+。
Example 12 compound BT-B-12: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidin-4-one
The synthesis route of the compound BT-B-12 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-12, can be obtained.
MS(m/z):509.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.03(s,1H),8.70(d,J=4.0Hz,1H),8.23(d,J=1.2Hz,1H),7.84(dd,J=13.2,2.0Hz,1H),7.67(d,J=12.0Hz,1H),7.50(dd,J=8.4,2.0Hz,1H),7.36(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.63(s,2H),2.71(t,J=6.0Hz,4H),2.65(s,3H),2.35(t,J=6.0Hz,4H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B12 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B12 as a yellow oil.
MS(m/z):223.2[M+H]+。
Example 13 Compound BT-B-13: n- (4- ((3, 3-difluoroazapyridin-1-yl) methyl) -3-fluorophenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-B-13 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-13, can be obtained.
MS(m/z):503.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),8.70(d,J=3.6Hz,1H),8.22(d,J=1.2Hz,1H),7.85(dd,J=13.2,2.4Hz,1H),7.66(d,J=12.0Hz,1H),7.48(dd,J=8.4,2.0Hz,1H),7.31(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.70(s,2H),3.61(t,J=12.4Hz,4H),2.65(s,3H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B13 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B13 as a yellow oil.
MS(m/z):217.1[M+H]+。
Example 14 Compound BT-B-14: (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) phenyl) (morpholine) methanone
The synthesis route of the compound BT-B-14 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-14, can be obtained.
MS(m/z):511.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.26(s,1H),8.73(d,J=3.6Hz,1H),8.22(d,J=1.2Hz,1H),7.98(dd,J=13.2,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.55(dd,J=8.4,2.0Hz,1H),7.35(t,J=8.0Hz,1H),4.85(p,J=6.8Hz,1H),3.64(m,4H),3.55(m,2H),3.30(s,2H),2.65(s,3H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B14 is as follows:
referring to the synthesis of B10 of example 10, only step 1 will beBy replacement withThe rest of the procedure was the same as B10 in example 10, to give compound B14 as a yellow oil.
MS(m/z):225.2[M+H]+。
Example 15 Compound BT-B-15: 1- (2-fluoro-4- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) benzyl) piperidine-4-carboxamide
The synthesis route of the compound BT-B-15 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-15, can be obtained.
MS(m/z):538.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.69(d,J=4.0Hz,1H),8.24(d,J=1.2Hz,1H),7.80(dd,J=13.2,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.47(dd,J=8.3,2.2Hz,1H),7.28(t,J=8.5Hz,1H),7.20(s,1H),6.72(s,1H),4.85(p,J=6.8Hz,1H),3.44(s,2H),3.06-3.00(m,1H),2.82(d,J=11.2Hz,2H),2.65(s,3H),1.97-1.88(m,2H),1.62(d,J=6.8Hz,6H),1.66-1.49(m,4H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B15 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B15 as a yellow oil.
MS(m/z):252.2[M+H]+。
Example 16 compound BT-B-16: n- (3-fluoro-4- ((4-methyl-1, 4-diazepan-1-yl) methyl) phenyl) -5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-amine
The synthesis route of the compound BT-B-16 is as follows:
with reference to the synthesis method of BT-B-1 of example 1, a yellow solid, i.e., the target compound BT-B-16, can be obtained.
MS(m/z):524.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.68(d,J=3.6Hz,1H),8.24(d,J=1.2Hz,1H),7.78(dd,J=13.2,2.0Hz,1H),7.66(d,J=12.0Hz,1H),7.48(dd,J=8.4,2.0Hz,1H),7.32(t,J=8.4Hz,1H),4.85(p,J=6.8Hz,1H),3.58(s,2H),2.59(m,11H),2.23(s,3H),1.70(p,J=6.0Hz,2H),1.62(d,J=6.8Hz,6H)。
The synthetic route and the synthetic procedure of the intermediate A1 are the same as those of A1 in example 1, and are not repeated herein.
The synthetic route of intermediate B16 is as follows:
referring to the synthesis of B1 of example 1, only step 3 will beBy replacement withThe remaining procedure was as in B1 of example 1 to give compound B16 as a yellow oil.
MS(m/z):238.3[M+H]+。
Inhibition of CDK4 and CDK6 kinases by the compounds of example 17
The compound of the invention is dissolved in DMSO to prepare a stock solution with the concentration of 1000. mu.M. mu.L of the stock solution was diluted stepwise with a proportion of 60. mu.L DMSO to 10 concentrations of compound. 100 μ L of DMSO was added to two empty wells as a no compound control and a no enzyme control. Prepare an intermediate plate, add 10. mu.L of sample solution of different concentrations to the intermediate plate, add 90. mu.L of kinase buffer, mix well with shaking. The appropriate amounts of CDK4, CDK6, and CDK9 kinase were diluted 2.5 times the final concentration with buffer, and the fluorescently labeled peptide and ATP were diluted 2.5 times the final concentration with 1 × kinase buffer, respectively.
To a 384 well plate, 10. mu.L of diluted kinase and 5. mu.L of sample solution at different concentrations were added, and the no compound control and no enzyme control groups were replaced with 10% DMSO, respectively. After 1 hour of incubation at room temperature, 10. mu.L of the diluted fluorescent-labeled peptide and ATP were added to the reaction system, and the mixture was incubated at room temperature for 30 minutes. Termination of additionAssay buffer 25. mu.L. The fluorescence intensity (emission wavelength: 445nm and 520nm, excitation wavelength: 400nm) was measured with a microplate reader, and IC was calculated with Graphpad Prism V5.0 software50The value is obtained.
Inhibitory activity of compounds of the invention against CDK4 and CDK6 kinases, the results are given in the table below.
Inhibition of CDK4 and CDK6 Activity by Compounds of the invention
Compound (I) | CDK4 kinase IC50(nM) | CDK6 kinase IC50(nM) |
Abemaciclib | 2.6 | 18 |
BT-B-1 | 0.79 | 1.8 |
BT-B-3 | 1.5 | 7.4 |
BT-B-4 | 3.8 | ND |
BT-B-5 | 1.3 | 3.5 |
BT-B-6 | 1.1 | 2.0 |
BT-B-7 | 2.2 | 21 |
Note: ND means not measured.
From the above table, it can be seen that the compound of the present invention has a strong inhibitory effect on the kinase activity of one or more of CDK4 and CDK6 kinases, and the inhibitory effect is better than that of positive control Abemaciclib.
EXAMPLE 18 SRB assay for inhibition of cancer cell proliferation by Compounds
Measuring proliferation inhibition activity of tested compound and positive control drug Abemaciclib on human breast cancer cell MCF-7, human brain glioma cell U87-MG and human brain glioma cell A172 by using sulforhodamine B (SRB) cell proliferation and toxicity detection kit, wherein IC is used for the activity50The values are represented.
The experimental scheme is as follows: taking cells in logarithmic growth phase, and preparing into 2 × 10 cells by conventional digestion4The cell suspension/mL, was inoculated into a 96-well plate at 100. mu.L/well, and then placed at 37 ℃ in 5% CO2And culturing in a saturated humidity incubator for 12 hours, and adding the tested compounds with different concentration gradients. Placing at 37 ℃ and 5% CO2Culturing in an incubator with saturated humidity for 72 hours; the test compound OD was determined by the SRB method, following strictly the SRB kit instructions, and IC was calculated using GraphPad Prim5.0 software50Values, results are given in the table below.
Inhibition of various cancer cells by the compounds of the Invention (IC)50 nM)
Compound (I) | Breast cancer cell MCF-7 | Glioma cell U87-MG | Glioma cell A172 |
Abemaciclib | 180.90 | 612.70 | 251.80 |
BT-B-1 | <50 | <10 | <10 |
BT-B-2 | <50 | <1 | <1 |
BT-B-3 | <50 | <50 | <10 |
BT-B-4 | <50 | <500 | <10 |
BT-B-5 | <10 | <100 | <10 |
BT-B-6 | <10 | <10 | <10 |
BT-B-7 | <50 | <300 | <10 |
BT-B-8 | <10 | <10 | <1 |
BT-B-9 | <50 | <10 | <10 |
BT-B-10 | <50 | <100 | <50 |
BT-B-11 | <10 | <10 | <10 |
BT-B-12 | <10 | <10 | <1 |
BT-B-13 | <50 | <10 | <10 |
BT-B-14 | <50 | <50 | <10 |
BT-B-15 | <10 | <1 | <1 |
BT-B-16 | <50 | <10 | <1 |
As can be seen from the above table, the compound has a strong inhibition effect on the proliferation of one or more of breast cancer cells MCF-7, glioma cells U87-MG and glioma cells A172, and the inhibition effect is better than that of positive control drug Abemaciclib.
EXAMPLE 19 CCK-8 assay of inhibition of proliferation of Small cell Lung cancer cells by Compounds
The Cell Counting Kit-8(CCK-8) Cell proliferation and toxicity detection Kit is adopted to measure the proliferation inhibition activity of the tested compound and the positive control drug Abemaciclib on the human small Cell lung cancer Cell H69, and the IC is used for the activity50The values are represented.
The experimental scheme is as follows: taking a certain amount of cells, inoculating to 96-well culture plate with each well at 100 μ L, and placing at 37 deg.C with 5% CO2And culturing in a saturated humidity incubator for 12 hours, and adding the tested compounds with different concentration gradients. Placing at 37 ℃ and 5% CO2Culturing in an incubator with saturated humidity for 72 hours; addingAdding 10 μ L CCK-8 solution, incubating for 2 hr, measuring OD value at 450nm wavelength with microplate reader, and calculating IC with GraphPad Prim5.0 software50Values, results are given in the table below.
Inhibitory Effect (IC) of the Compound of the present invention on Small cell Lung cancer cell line H6950 nM)
As can be seen from the table, the compound of the invention has strong inhibition effect on cell proliferation in small cell lung cancer cells H69, and the inhibition effect is better than that of positive control drug Abemaciclib.
Claims (9)
1. A2-aminopyrimidine heterocyclic compound is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m-;
Ring A is substituted by one or more substituents R8Substituted 3-to 10-membered cycloalkyl, substituted by one or more substituents R8Substituted 3-10 membered heterocycloalkyl, substituted by one or more substituents R8Substituted 5-12 membered aryl, or substituted by one or more substituents R8Substituted 5-12 membered heteroaryl, but excluding piperazine;
R1and R2Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl or halo C1-C6An alkoxy group;
R3、R4and R7Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, hydroxy, carboxy, cyano, amino, C1-C6Alkylamino, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;
R5、R6and R11Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, substituted or unsubstituted 5-to 12-membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, amino, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
R9And R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6.
2. The heterocyclic compound of 2-aminopyrimidine according to claim 1, which is a compound of formula ii or a pharmaceutically acceptable salt thereof:
wherein W is selected from a single bond and C1-C6Alkyl, - (CH)2)nO(CH2)m-、-(CH2)nCO(CH2)m-、-(CH2)nNH(CH2)m-or- (CH)2)nNHCO(CH2)m;
R3And R4Each independently selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkyl group;
R5and R6Each independently selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, cyano, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl,Substituted or unsubstituted 5-12 membered heteroaryl, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
And, R5And R6Not hydrogen at the same time;
R8selected from hydrogen, halogen, C1-C6Alkyl, halo C1-C6Alkyl, halo C1-C6Alkoxy, hydroxy, carboxy, amino, - (CH)2)nOR9、-(CH2)nCOR9、-(CH2)nCOOR9、-(CH2)nCONHR9、-(CH2)nCONR9R10、-(CH2)nNHR9Or- (CH)2)nNR9R10;
R9、R10Each independently selected from C1-C6Alkyl, amino, substituted or unsubstituted 3-to 10-membered cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted 5-to 12-membered aryl, or substituted or unsubstituted 5-to 12-membered heteroaryl;
the substituent on the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-12 membered aryl and 5-12 membered heteroaryl is selected from hydrogen and C1-C6Alkyl, hydroxy or amino;
m and n are each independently selected from 0,1, 2, 3, 4,5 or 6.
3. The heterocyclic compound of 2-aminopyrimidine according to claim 1 or 2 wherein the halogen is F or Cl; the 3-10-membered heterocyclic group and the 5-12-membered heteroaryl group contain one or more heteroatoms, and the heteroatoms are N, O, S.
5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the prevention or treatment of a disease mediated by cyclin dependent kinase activity.
7. The use according to claim 6 wherein the cyclin dependent kinase activity-mediated disorder is a disorder associated with altered CDK4, CDK6 or CDK9 activity.
8. The use according to claim 7, wherein the disease is cancer.
9. The use according to claim 8, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, intestinal cancer, small cell lung cancer, melanoma, glioma, lymphoma, prostate cancer, rectal cancer, pancreatic cancer, liver cancer, stomach cancer, bladder cancer, ovarian cancer, mantle cell lymphoma, acute myelogenous leukemia and chronic myelogenous leukemia.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010615654.0A CN113880813B (en) | 2020-07-01 | 2020-07-01 | 2-Aminopyrimidine heterocyclic compound and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010615654.0A CN113880813B (en) | 2020-07-01 | 2020-07-01 | 2-Aminopyrimidine heterocyclic compound and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113880813A true CN113880813A (en) | 2022-01-04 |
CN113880813B CN113880813B (en) | 2024-05-28 |
Family
ID=79011857
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010615654.0A Active CN113880813B (en) | 2020-07-01 | 2020-07-01 | 2-Aminopyrimidine heterocyclic compound and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113880813B (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102007124A (en) * | 2008-02-15 | 2011-04-06 | 里格尔制药公司 | Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases |
US20130310340A1 (en) * | 2012-05-16 | 2013-11-21 | Rigel Pharmaceuticals, Inc. | Method of treating muscular degradation |
WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
WO2018019204A1 (en) * | 2016-07-26 | 2018-02-01 | 深圳市塔吉瑞生物医药有限公司 | Amino pyrimidine compound for inhibiting protein tyrosine kinase activity |
CN107827875A (en) * | 2017-09-25 | 2018-03-23 | 文韬创新药物研究(北京)有限责任公司 | A kind of application of benzimidazoles derivative as the inhibitor of Cyclin dependent kinase 4/6 |
WO2018140730A1 (en) * | 2017-01-27 | 2018-08-02 | Signalrx Pharmaceuticals, Inc. | Thienopyranones and furanopyranones as kinase, bromodomain, and checkpoint inhibitors |
-
2020
- 2020-07-01 CN CN202010615654.0A patent/CN113880813B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102007124A (en) * | 2008-02-15 | 2011-04-06 | 里格尔制药公司 | Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases |
US20130310340A1 (en) * | 2012-05-16 | 2013-11-21 | Rigel Pharmaceuticals, Inc. | Method of treating muscular degradation |
WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
WO2018019204A1 (en) * | 2016-07-26 | 2018-02-01 | 深圳市塔吉瑞生物医药有限公司 | Amino pyrimidine compound for inhibiting protein tyrosine kinase activity |
WO2018140730A1 (en) * | 2017-01-27 | 2018-08-02 | Signalrx Pharmaceuticals, Inc. | Thienopyranones and furanopyranones as kinase, bromodomain, and checkpoint inhibitors |
CN107827875A (en) * | 2017-09-25 | 2018-03-23 | 文韬创新药物研究(北京)有限责任公司 | A kind of application of benzimidazoles derivative as the inhibitor of Cyclin dependent kinase 4/6 |
Also Published As
Publication number | Publication date |
---|---|
CN113880813B (en) | 2024-05-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2671354T3 (en) | DNA-PK inhibitors | |
EP2167492B1 (en) | Novel amide derivative for inhibiting the growth of cancer cells | |
TWI527800B (en) | 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof | |
CN113544128A (en) | KRAS-G12C inhibitors | |
UA111754C2 (en) | SUBSTITUTED BENZILINDASOLS FOR THE APPLICATION OF BUB1-KINASE INHIBITORS FOR THE TREATMENT OF HYPERPROLIFERATIVE DISEASES | |
KR20200115583A (en) | 2H-indazole derivatives as CDK4 and CDK6 inhibitors and their therapeutic use | |
CN111377907B (en) | Polysubstituted phenylamino pyrimidine derivative and preparation method and application thereof | |
CN107827875B (en) | Application of benzimidazole derivative as cyclin-dependent kinase 4/6 inhibitor | |
CN103848829A (en) | Heteroaryl alkyne compounds and application thereof | |
BR112015027440B1 (en) | [1,2,4]TRIAZOL[4,3-A]PYRIDINE DERIVATIVE, ITS USES AND PREPARATION PROCESS, AND PHARMACEUTICAL COMPOSITION | |
CN113683616A (en) | KRAS G12C mutein inhibitors | |
CN112300082B (en) | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application | |
CN113045559B (en) | Diaryl urea PI3K alpha/mTOR double-target inhibitor and pharmaceutical composition and application thereof | |
CN114885607B (en) | Quinolinylphosphine oxide compounds, compositions and uses thereof | |
CN113880814B (en) | Pyrimidine amine compound and application thereof | |
CN113880816A (en) | Piperazine-containing aminopyrimidine derivative and application thereof | |
CN113966331B (en) | Triaryl ring compound containing urea structure and application thereof | |
CN113880813B (en) | 2-Aminopyrimidine heterocyclic compound and application thereof | |
CN105541792B (en) | Polycyclic class PI3K inhibitor | |
CN107540624B (en) | Heat shock protein inhibitor and preparation method and application thereof | |
CN116143806A (en) | Nitrogen-containing heterocyclic compound, preparation method and application | |
CN103864680A (en) | Chloroxoquinoline derivatives with anti-tumor activity | |
CA3188077A1 (en) | Egfr inhibitor, preparation method therefor and application thereof | |
CN109879887B (en) | Thieno [3,2-d ] pyrimidine derivative containing indole structure and application thereof | |
CN113087709A (en) | Pyrrolopyrimidine derivatives, and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information |
Address after: 311199, No. 159 Lvzhou Road, Linping Street, Linping District, Hangzhou City, Zhejiang Province Applicant after: HANGZHOU BIO-SINCERITY PHARMA-TECH Co.,Ltd. Address before: 311103 B203, building 1, 9 Zhenxing East Road, Yuhang Economic and Technological Development Zone, Yuhang District, Hangzhou City, Zhejiang Province Applicant before: HANGZHOU BIO-SINCERITY PHARMA-TECH Co.,Ltd. |
|
CB02 | Change of applicant information | ||
GR01 | Patent grant | ||
GR01 | Patent grant |