CN111315747A - Dihydropyrazolone pyrimidine compound and preparation method and application thereof - Google Patents
Dihydropyrazolone pyrimidine compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN111315747A CN111315747A CN201880072261.0A CN201880072261A CN111315747A CN 111315747 A CN111315747 A CN 111315747A CN 201880072261 A CN201880072261 A CN 201880072261A CN 111315747 A CN111315747 A CN 111315747A
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- Prior art keywords
- compound
- alkyl
- pharmaceutically acceptable
- group
- metabolite
- 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.)
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Links
- -1 pyrimidine compound Chemical class 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title abstract description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 228
- 101150040313 Wee1 gene Proteins 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 48
- 125000000623 heterocyclic group Chemical group 0.000 claims description 35
- 239000000651 prodrug Substances 0.000 claims description 33
- 229940002612 prodrug Drugs 0.000 claims description 33
- 239000002207 metabolite Substances 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000003386 piperidinyl group Chemical group 0.000 claims description 19
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 238000001990 intravenous administration Methods 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000005620 boronic acid group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- 238000001361 intraarterial administration Methods 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 238000004949 mass spectrometry Methods 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000000203 mixture Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 102000001253 Protein Kinase Human genes 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 108060006633 protein kinase Proteins 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000007363 ring formation reaction Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 229950009557 adavosertib Drugs 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 description 6
- JKBQCALHIQOSTC-UHFFFAOYSA-N 6-methylsulfanyl-2-prop-2-enyl-1h-pyrazolo[3,4-d]pyrimidin-3-one Chemical compound CSC1=NC=C2C(=O)N(CC=C)NC2=N1 JKBQCALHIQOSTC-UHFFFAOYSA-N 0.000 description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
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- 125000004429 atom Chemical group 0.000 description 6
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- 239000003054 catalyst Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
- KDLLVCAIZGRRAY-UHFFFAOYSA-N 4-N,4-N-dimethyl-1-N-phenylpiperidine-1,4-diamine Chemical compound CN(C1CCN(CC1)NC1=CC=CC=C1)C KDLLVCAIZGRRAY-UHFFFAOYSA-N 0.000 description 5
- DFARRYPPQVWWES-UHFFFAOYSA-N 6-[4-[4-(dimethylamino)piperidin-1-yl]anilino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-one Chemical compound CC(C)n1n(-c2cccc(n2)C(C)(C)O)c2nc(Nc3ccc(cc3)N3CCC(CC3)N(C)C)ncc2c1=O DFARRYPPQVWWES-UHFFFAOYSA-N 0.000 description 5
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 5
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- JJPGWMXCKDKAAH-UHFFFAOYSA-N 1-(4-amino-2-fluorophenyl)-n,n-dimethylpiperidin-4-amine Chemical compound C1CC(N(C)C)CCN1C1=CC=C(N)C=C1F JJPGWMXCKDKAAH-UHFFFAOYSA-N 0.000 description 3
- OXSDDDKLMCHNHF-UHFFFAOYSA-N 2-(6-bromopyridin-2-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(Br)=N1 OXSDDDKLMCHNHF-UHFFFAOYSA-N 0.000 description 3
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- BIKAXNVBMQFCNT-UHFFFAOYSA-N 4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)aniline Chemical compound C1C2CN(C)CC2CN1C1=CC=C(N)C=C1 BIKAXNVBMQFCNT-UHFFFAOYSA-N 0.000 description 3
- IXDYRENQELLJKX-UHFFFAOYSA-N 6-methylsulfanyl-2-propan-2-yl-1h-pyrazolo[3,4-d]pyrimidin-3-one Chemical compound CSC1=NC=C2C(=O)N(C(C)C)NC2=N1 IXDYRENQELLJKX-UHFFFAOYSA-N 0.000 description 3
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- ZTBNRSAVTCMMFO-UHFFFAOYSA-N 1-(2-fluoro-4-nitrophenyl)-n,n-dimethylpiperidin-4-amine Chemical compound C1CC(N(C)C)CCN1C1=CC=C([N+]([O-])=O)C=C1F ZTBNRSAVTCMMFO-UHFFFAOYSA-N 0.000 description 2
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- ZRFMJMFYMQAUDO-UHFFFAOYSA-N 2-(3-bromophenyl)propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(Br)=C1 ZRFMJMFYMQAUDO-UHFFFAOYSA-N 0.000 description 2
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- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000000499 gel Substances 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
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- YXFSJHIKSHCRDI-UHFFFAOYSA-N iodomethane;magnesium Chemical compound [Mg].IC YXFSJHIKSHCRDI-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 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
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- KMFJVYMFCAIRAN-UHFFFAOYSA-N methyl 3-bromobenzoate Chemical compound COC(=O)C1=CC=CC(Br)=C1 KMFJVYMFCAIRAN-UHFFFAOYSA-N 0.000 description 1
- SGNCOKUHMXLGAH-UHFFFAOYSA-N methyl 6-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(Br)=N1 SGNCOKUHMXLGAH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000006618 mitotic catastrophe Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000005012 myelin Anatomy 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
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-M orotate Chemical compound [O-]C(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-M 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 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
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to a dihydropyrazolone pyrimidine compound, a preparation method and application thereof. In particular, the application relates to a compound shown in a formula I, a pharmaceutical composition and a pharmaceutical preparation containing the compound, a preparation method of the compound and application of the compound in preparing a medicine for preventing or treating diseases related to Wee1 protein.
Description
The application relates to a dihydropyrazolone pyrimidine compound, a preparation method and application thereof.
The cell cycle is a highly regulated and controlled process, tightly regulated by a complex network formed by a series of protein, metabolic and microenvironment interactions, aimed at proliferating cells only in accordance with specific stimuli and appropriate conditions (S.Diaz-Moralli, M.Tarrago-Castellarnau, A.Miranda, M.Cascante, Pharmacology & Therapeutics,2013,138: 255-one 271). The standard cell cycle undergoes a G1 phase, an S phase (DNA synthesis phase), a G2 phase, and an M phase (cell division phase) in this order. There are several cycle-block checkpoints during G1-S transition, S phase, G2-M transition, etc., to maintain genome integrity and provide time for repair of damaged DNA prior to entry into mitosis. In response to DNA damage, cell cycle checkpoints can be activated at stages G1/S, S and G2/M and induce cell cycle arrest until repair is complete; if repair is unsuccessful, cell senescence or apoptosis will be driven (R.Visconti, M.R.Della, D.Grieco, Journal of Experimental & Clinical Cancer Research,2016,35: 153).
The Wee1 protein kinase is a member of the serine/threonine protein kinase family, is a key element of the G2/M checkpoint of the cell cycle, and plays a key role in the scheduling of cell division (c.j. matheson, d.s. backkos, p.reigan, Trends in pharmaceutical Sciences,2016,37: 872). Entry into mitosis from the G2/M checkpoint is dependent on the phosphorylation state of CDK1 (also known as CDC2) and the binding state of cyclin B. Before mitosis, Wee1 phosphorylates the Tyr15 site of CDK1, and then myelin transcription factor (MYT1) phosphorylates the Thr14 site of CDK1, maintaining the inactive state of CDK1, inhibiting the cell from entering M phase. Wee1 is therefore a negative regulator of cell entry from G2 into M.
Thus, inhibiting Wee1 kinase activity to remove the function of the G2/M checkpoint is a potential strategy to drive tumor cells into an unplanned mitosis, thereby undergoing mitotic catastrophe leading to cell death. This way, in which cells are forced into mitosis without complete DNA replication, is highly toxic to cells and represents a novel mechanism for inducing tumor cell death. Therefore, the Wee1 inhibitor has good application prospect as a medicine. Patent WO2007126128 reports that certain compounds exhibit activity as Wee1 protein kinase inhibitors.
In order to meet the drug requirements of better tumor treatment effect, safer or low side effect, the application provides a novel structure Wee1 protein kinase inhibitor, and finds that the compound with the structure shows excellent Wee1 protein inhibition effect and drug effect duration.
Disclosure of Invention
One aspect of the present application provides a dihydropyrazolone pyrimidine compound having Wee1 protein kinase inhibitory activity, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, the compound having the structure of formula I below:
wherein,
x is selected from CH and N;
R1selected from hydroxy-C1-6Alkyl radical-、C1-6alkoxy-C1-6Alkyl-and cyano-C3-6Cycloalkyl-;
R2selected from 7-10 membered fused heterocyclyl, said 7-10 membered fused heterocyclyl being optionally substituted by one or more C1-6Alkyl substituted, each C1-6The alkyl groups may be the same or different; or R2Selected from piperidinyl, said piperidinyl being optionally substituted by one or more-NR5R6Substitution; r5、R6Each independently selected from C1-6An alkyl group;
R3is selected from C1-6Alkyl and C2-6An alkenyl group;
R4selected from hydrogen and halogen.
In some preferred embodiments, the compounds have the following structure of formula I-1:
wherein, X, R1、R2、R3And R4The definition is shown in the general formula I.
In some preferred embodiments, the compounds have the following structure of formula I-2:
wherein R is1And R2The definition is shown in the general formula I.
Another aspect of the present application provides a process for preparing a compound of formula (I):
in the formula, Hal1Is halogen (e.g., F, Cl or Br); hal2Is halogen (e.g., Cl, Br, or I), a boronic acid group, or a boronic ester group; r1、R2、R3、R4And X have the same meanings as in the above formula I.
In some embodiments, the present application also provides a method of preparing a compound of formula I-2:
in the formula, Hal1Is halogen (e.g., F, Cl or Br); hal2Is halogen (e.g., Cl, Br, or I), a boronic acid group, or a boronic ester group; PG is a protecting group selected from benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, preferably tert-butoxycarbonyl; r1And R2The definition of (a) is the same as that of the above general formula I-2.
Another aspect of the present application provides a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
Another aspect of the present application provides a method of making the pharmaceutical composition, the method comprising combining the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, with one or more pharmaceutically acceptable carriers.
Another aspect of the present application provides a pharmaceutical formulation comprising the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition.
Another aspect of the present application provides a use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, the pharmaceutical composition or the pharmaceutical preparation for the manufacture of a medicament for the prevention or treatment of a Wee1 protein kinase-associated disease, preferably, the disease is cancer.
Another aspect of the present application provides the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition for use in the treatment of a Wee1 protein kinase-associated disease, preferably the disease is cancer.
Another aspect of the present application provides a method for preventing or treating a Wee1 protein kinase related disease, the method comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition; preferably, the disease is cancer.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C1-6Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halo (when the group is referred to as" haloalkyl ", e.g., CF)3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl or-CH2CH2CF3Etc.).
As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic ring, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalinyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, for example 3 to 6, carbon atoms. For example, the term "C3-6Cycloalkyl "refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) having 3 to 6 ring carbon atoms, optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.
As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.
The term "alkoxy," as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. C1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy, and the like.
As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic group, e.g., having 2, 3,4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., 1,2, 3, or 4) members selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) heteroatoms such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianylThe term "fused heterocyclyl" refers to polycyclic heterocyclyl groups in which each ring shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups.
The term "substituted" means that one or more (e.g., 1,2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted with …", the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.
If a substituent is described as "independently selected from" a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
As used herein, the term "one or more" means 1 or more than 1, such as 2, 3,4, 5 or 10, under reasonable conditions.
Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
When a bond of a substituent is shown through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)2H、3H) (ii) a Isotopes of carbon (e.g. of11C、13C and14C) (ii) a Isotopes of chlorine (e.g. of chlorine)37Cl); isotopes of fluorine (e.g. of fluorine)18F) (ii) a Isotopes of iodine (e.g. of iodine)123I and125I) (ii) a Isotopes of nitrogen (e.g. of13N and15n); isotopes of oxygen (e.g. of15O、17O and18o); isotopes of phosphorus (e.g. of phosphorus)32P); and isotopes of sulfur (e.g. of35S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in drug and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e. tritium3H) And carbon-14 (i.e.14C) Are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g. of the type11C、18F、15O and13n) can be used to examine substrate receptor occupancy in Positron Emission Tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed previously. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D2O, acetone-d6Or DMSO-d6。
The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, dihydropyrimidine groups may exist in solution in equilibrium with the following tautomeric forms. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
Solid lines may be used hereinSolid wedge shapeOr virtual wedge shapeCarbon-carbon bonds of the compounds are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, solid and dotted wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds are describedIt is intended that the compounds may exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present application encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
It will also be appreciated that certain compounds of the present application may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the present application" or "the compound," it is also intended to encompass the various derivative forms of the compound described above.
Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts thereof.
Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.
Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, sodium salts, tromethamine salts and other similar salts.
For a review of suitable Salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.
The compounds of the present application may be present in the form of solvates, preferably hydrates, wherein the compounds of the present application comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
The present application also includes metabolites of the compounds, i.e., substances formed in vivo upon administration of the compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present application includes metabolites of the compounds, including compounds made by the method of contacting the compounds with a mammal for a time sufficient to produce a metabolite thereof.
The present application further includes prodrugs of the compounds which are certain derivatives of the compounds which may themselves have little or no pharmacological activity which may be converted to the compounds having the desired activity by, for example, hydrolytic cleavage when administered into or onto the body. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987(E.B.Roche editions, American Pharmaceutical Association). Such Prodrugs can be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of drugs", h. bundgaard (Elsevier,1985) ") for the appropriate functional groups present in the compounds of the present application.
The application also encompasses such compounds containing protecting groups. In any process for the preparation of said compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of said compounds. This can be achieved by conventional protecting Groups, for example, as described in Protective Groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "about" means within. + -. 10%, preferably within. + -. 5%, more preferably within. + -. 2% of the stated value.
Compound (I)
It is an object of the present application to provide a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, having the structure of formula I:
wherein,
x is selected from CH and N;
R1selected from hydroxy-C1-6Alkyl-, C1-6alkoxy-C1-6Alkyl-and cyano-C3-6Cycloalkyl-;
R2selected from 7-10 membered fused heterocyclyl, said 7-10 membered fused heterocyclyl being optionally substituted by one or more C1-6Alkyl substituted, each C1-6The alkyl groups may be the same or different; or R2Selected from piperidinyl, said piperidinyl being optionally substituted by one or more-NR5R6Substitution; r5、R6Each independently selected from C1-6An alkyl group;
R3is selected from C1-6Alkyl and C2-6An alkenyl group;
R4selected from hydrogen and halogen.
In some preferred embodiments, the compounds have the structure shown in formula I-1,
wherein, X, R1、R2、R3And R4The definition is shown in the general formula I.
In some embodiments, X in formula I or formula I-1 is CH.
In some embodiments, X in formula I or formula I-1 is N.
In some embodiments, R in formula I or formula I-11Selected from hydroxy-C1-4Alkyl-, C1-3alkoxy-C1-4Alkyl-and cyano-C3-6Cycloalkyl-. In some preferred embodiments, R1Selected from the group consisting of 2-hydroxypropan-2-yl, 2-methoxyprop-2-yl and 1-cyanocyclopropyl-1-yl.
In some embodiments, R in formula I or formula I-12Selected from 7-10 membered bicyclic fused heterocyclic group, said 7-10 membered bicyclic fused heterocyclic group optionally substituted with one or more C1-6Alkyl (e.g. C)1-4Alkyl radical, C1-2Alkyl) substituted. In some embodiments, R2Selected from 8-membered fused heterocyclic groups, said 8-membered fused heterocyclic group being substituted by a C1-6Alkyl (e.g. C)1-4Alkyl radical, C1-2Alkyl) substituted. In some preferred embodiments, R2Selected from 8-membered bicyclic fused heterocyclic group, said 8-membered bicyclic fused heterocyclic group being substituted by a C1-6Alkyl (e.g. C)1-4Alkyl radical, C1-2Alkyl) substituted. In some preferred embodiments, R2Is selected fromIn some preferred embodiments, R2Is 5-methyl hexahydro-pyrrolo [3,4-c]Pyrrol-2 (1H) -yl.
In some embodiments, R in formula I or formula I-12Being piperidinyl, said piperidinyl being substituted by one or more-NR5R6Substituted, R5、R6Each independently selected from C1-4An alkyl group. In some preferred embodiments, R2Being piperidinyl, said piperidinyl being substituted by one or more-NR5R6Substituted, R5、R6Each independently selected from C1-2An alkyl group. In some preferred embodiments, R2Is composed ofR5、R6Each independently selected from C1-6Alkyl (e.g. C)1-4Alkyl radical, C1-2Alkyl groups). In some preferred embodiments, R2Is 4-dimethylaminopiperidin-1-yl.
In some embodiments, R in formula I or formula I-13Is selected from C1-4Alkyl and C2-4An alkenyl group. In some preferred embodiments, R3Selected from allyl and isopropyl.
In some embodiments, R in formula I or formula I-14Selected from hydrogen, fluorine, chlorine and bromine. In some embodiments, R4Selected from hydrogen and fluorine. In some embodiments, R4Is hydrogen. In some embodiments, R4Is fluorine.
In some embodiments, the compounds have the structure shown in formula I-2,
wherein R is1And R2The definition is defined in the general formula I.
In some embodiments, R1Selected from hydroxy-C1-6Alkyl-, C1-6alkoxy-C1-6Alkyl-and cyano-C3-6Cycloalkyl-.
In some embodiments, R2Selected from 7-10 membered fused heterocyclyl, said 7-10 membered fused heterocyclyl being optionally substituted by one or more C1-6Alkyl substituted, each C1-6The alkyl groups may be the same or different; or R2Selected from piperidinyl, said piperidinyl being substituted by one or more-NR5R6Substituted, R5、R6Each independently selected from C1-6An alkyl group.
In some embodiments, R1Selected from hydroxy-C1-4Alkyl-, C1-3alkoxy-C1-4Alkyl-and cyano-C3-6Cycloalkyl-; preferably, R1Selected from the group consisting of 2-hydroxypropan-2-yl, 2-methoxyprop-2-yl and 1-cyanocyclopropyl-1-yl.
In some embodiments, R2Selected from 8-membered fused heterocyclic groups, said 8-membered fused heterocyclic group being substituted by a C1-6Alkyl substitution;
preferably, R2Selected from 8-membered bicyclic fused heterocyclic group, said 8-membered bicyclic fused heterocyclic group being substituted by a C1-6Alkyl (e.g. C)1-4Alkyl radical, C1-2Alkyl) substitution;
More preferably, R2Is 5-methyl hexahydro-pyrrolo [3,4-c]Pyrrol-2 (1H) -yl.
In some embodiments, R2Is selected fromR5、R6Each independently selected from C1-6Alkyl (e.g. C)1-4Alkyl radical, C1-2Alkyl groups); preferably, R2Is 4-dimethylaminopiperidin-1-yl.
In some embodiments, the compounds have the structure of formula I-2 above,
wherein R is1Selected from hydroxy-C1-6Alkyl-, C1-6alkoxy-C1-6Alkyl-and cyano-C3-6Cycloalkyl-;
R2selected from 7-10 membered fused heterocyclyl, said 7-10 membered fused heterocyclyl being optionally substituted by one or more C1-6Alkyl substituted, each C1-6The alkyl groups may be the same or different; or R2Selected from piperidinyl, said piperidinyl being substituted by one or more-NR5R6Substituted, R5、R6Each independently selected from C1-6An alkyl group.
In some embodiments, the compounds have the structure of formula I-2 above,
wherein R is1Selected from hydroxy-C1-4Alkyl-, C1-3alkoxy-C1-4Alkyl-and cyano-C3-6Cycloalkyl-; preferably, R1Selected from 2-hydroxyprop-2-yl, 2-methoxyprop-2-yl and 1-cyanocyclopropyl-1-yl;
R2selected from 8-membered fused heterocyclic groups, said 8-membered fused heterocyclic group being substituted by a C1-6Alkyl substitution; preferably, R2Is selected fromPreferably, R2Is 5-methyl hexahydropyrrole [3,4-c]Pyrrol-2 (1H) -yl;
or, R2Is selected fromR5、R6Each independently selected from C1-6An alkyl group; preferably, R2Is 4-dimethylaminopiperidin-1-yl.
In some embodiments, the compound has the following structure:
preparation method
It is another object of the present application to provide a process for preparing a compound of formula (I):
in the formula, Hal1Is halogen (e.g., F, Cl or Br); hal2Is halogen (e.g., Cl, Br, or I), a boronic acid group, or a boronic ester group; r1、R2、R3、R4And X have the same meaning as in formula I above.
(1) Reacting compound IN-1 with a hydrazine compound to obtain compound IN-2;
in some embodiments: compound IN-1 can be reacted with an alkylhydrazine compound to give compound IN-2, preferably IN a suitable organic solvent. The organic solvent may be selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dioxane, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of a suitable organic base. The organic base can be selected from triethylamine, pyridine, 4-dimethylaminopyridine and diisopropylethylamine, and preferably is diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably from 50 to 70 ℃. The reaction is preferably carried out for a suitable time, for example 6 to 16 hours.
In other embodiments: the compound IN-1 can also be reacted with hydrazine hydrate firstly and then subjected to reduction reaction with aldehyde compounds to obtain the compound IN-2. The reaction with hydrazine hydrate is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dioxane, and any combination thereof, preferably ethanol. The reaction is preferably carried out at a suitable temperature, preferably from 0 to 25 ℃. The reaction is preferably carried out for a suitable time, for example 1 to 6 hours. The reduction reaction with the aldehyde compound is preferably carried out in a suitable organic solvent and in the presence of a reducing agent. The solvent can be selected from methanol, ethanol, dichloromethane, chloroform, acetonitrile, preferably methanol. The reducing agent may be selected from sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like, preferably sodium cyanoborohydride. The reaction temperature is preferably 0 to 25 ℃ in general, and the reaction time is preferably 1 to 3 hours in general.
(2) Cyclizing the compound IN-2 to obtain a compound IN-3;
the cyclization reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from methanol, ethanol, tetrahydrofuran, dioxane and any combination thereof, preferably ethanol. The base used for the cyclization can be selected from inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate, and sodium hydroxide is preferred. The cyclization reaction temperature is preferably room temperature (20 to 30 ℃ C.) in general, and the cyclization reaction time is preferably 0.5 to 2 hours in general.
(3) Reacting compound IN-3 with compound IN-4 to give compound IN-5;
the compound IN-3 is subjected to a coupling reaction with the compound IN-4 to obtain the compound IN-5. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a copper salt catalyst, preferably cuprous iodide, cupric acetate, and the like. The base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, 2-bipyridine, potassium phosphate, preferably potassium carbonate. The ligand of the coupling reaction is selected from trans-N, N ' -dimethyl-1, 2-cyclohexanediamine and N, N ' -dimethylethylenediamine, preferably trans-N, N ' -dimethyl-1, 2-cyclohexanediamine. The solvent for the coupling reaction is selected from benzene, toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, etc. or a mixed solvent thereof, and dioxane and dimethylformamide are preferred. The coupling reaction temperature is preferably from 80 to 110 ℃ in general. The reaction time is preferably 4 to 6 hours in general.
(4) Oxidizing the compound IN-5 to obtain a compound IN-6;
the oxidation reaction may preferably be carried out in a suitable organic solvent and in the presence of an oxidizing agent. The solvent may be selected from benzene, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide and the like, preferably acetonitrile. The oxidant can be selected from m-chloroperoxybenzoic acid, potassium peroxymonosulfate complex salt and the like, and potassium peroxymonosulfate complex salt is preferred. The reaction temperature is usually preferably room temperature (20 to 30 ℃ C.), and the reaction time is usually preferably 0.5 to 3 hours.
(5) Reacting compound IN-6 with compound IN-7 to give a compound of formula I;
the reaction is preferably carried out in an inert solvent including toluene, benzene, chloroform, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc., or a mixed solvent thereof, preferably toluene. The reaction is preferably carried out in the presence of a suitable organic base which may be selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably diisopropylethylamine. The reaction temperature is preferably 60 to 120 ℃ and the reaction time is preferably 4 to 12 hours.
It is a further object of the present application to provide a process for preparing a compound of formula I-2:
in the formula, Hal1Is halogen (e.g., F, Cl or Br); hal2Is halogen (e.g., Cl, Br, or I), a boronic acid group, or a boronic ester group; PG is a protecting group selected from benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, preferably tert-butoxycarbonyl; r1And R2The definition of (a) is the same as that of the above general formula I-2.
(1) Reacting compound IN-1 with compound IN-8 to give compound IN-9;
the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dioxane, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of a suitable organic base. The organic base can be selected from triethylamine, pyridine, 4-dimethylaminopyridine and diisopropylethylamine, and preferably is diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably from 50 to 70 ℃. The reaction is preferably carried out for a suitable time, for example 6 to 16 hours.
(2) Removing the protecting group PG from the compound IN-9 to obtain a compound IN-10;
this reaction for removing the protecting group PG can be applied to a hydrolysis reaction method of a carboxylic ester well known in the field of organic chemistry, and in an embodiment in which the protecting group PG is a t-butoxycarbonyl group, the reaction is preferably carried out by an acid hydrolysis reaction of an ester in the presence of an acid. The acid may be an inorganic acid or a suitable organic acid including, but not limited to, hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid; the reaction solvent can be selected from dioxane, dichloromethane, ethyl acetate or their mixture, acid can also be used as reaction solvent, preferably trifluoroacetic acid. The reaction temperature is usually preferably 40 to 70 ℃. The reaction time is preferably 1 to 3 hours in general.
(3) Cyclizing compound IN-10 to give compound IN-11;
the cyclization reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from methanol, ethanol, tetrahydrofuran, dioxane and any combination thereof, preferably ethanol. The base used in the cyclization reaction can be selected from inorganic bases such as sodium hydroxide, potassium hydroxide and potassium carbonate, and sodium hydroxide is preferred. The cyclization reaction temperature is preferably room temperature (20 to 30 ℃ C.) in general, and the cyclization reaction time is preferably 0.5 to 2 hours in general.
(4) Reacting compound IN-11 with compound IN-12 to give compound IN-13;
the compound IN-11 is subjected to a coupling reaction with the compound IN-12 to obtain the compound IN-13. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. The metal catalyst is a copper salt catalyst, preferably cuprous iodide, copper acetate, or the like. The base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, 2-bipyridine, potassium phosphate, preferably potassium carbonate. The ligand of the coupling reaction is selected from trans-N, N ' -dimethyl-1, 2-cyclohexanediamine and N, N ' -dimethylethylenediamine, preferably trans-N, N ' -dimethyl-1, 2-cyclohexanediamine. The solvent for the coupling reaction is selected from benzene, toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, etc. or a mixed solvent thereof, and dioxane and dimethylformamide are preferred. The coupling reaction temperature is preferably 80 to 110 ℃. The reaction time is preferably 4 to 6 hours.
(5) Oxidizing the compound IN-13 to obtain a compound IN-14;
the oxidation reaction may preferably be carried out in a suitable organic solvent and in the presence of an oxidizing agent. The solvent may be selected from benzene, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide and the like, preferably acetonitrile. The oxidant can be selected from m-chloroperoxybenzoic acid, potassium peroxymonosulfate complex salt and the like, and potassium peroxymonosulfate complex salt is preferred. The reaction temperature is usually preferably room temperature (20 to 30 ℃ C.), and the reaction time is usually preferably 0.5 to 3 hours.
(6) Reacting compound IN-14 with compound IN-15 to give a compound of formula I-2;
the reaction is preferably carried out in an inert solvent selected from toluene, benzene, chloroform, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc., or a mixed solvent thereof, preferably toluene. The reaction is preferably carried out in the presence of a suitable organic base which may be selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably diisopropylethylamine. The reaction temperature is preferably 60 to 120 ℃ and the reaction time is usually preferably 4 to 12 hours.
In preparing compounds of formula I or formula I-2, it may be desirable to protect remote functional groups (e.g., hydroxyl or amino groups) of the intermediate. The need for such protection may vary with the nature of the distal functional group and the conditions of the preparation method. For a summary of protecting Groups and their use, see t.w. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
Pharmaceutical composition and pharmaceutical preparation
It is another object of the present application to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
By "pharmaceutically acceptable carrier" herein is meant a diluent, adjuvant, excipient, or vehicle that is administered with the therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical composition may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
For these routes of administration, the pharmaceutical composition may be administered in a suitable dosage form. Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
The amount or dose of the compound in the pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150 mg.
It is another object of the present application to provide a process for preparing the pharmaceutical composition, the process comprising combining the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof with one or more pharmaceutically acceptable carriers.
It is another object of the present application to provide a pharmaceutical formulation comprising said compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or a mixture thereof, or said pharmaceutical composition.
Methods of treatment and uses
Another object of the present application is to provide a use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition for the preparation of a medicament for the prevention or treatment of Wee1 protein kinase-associated diseases. In some embodiments, the Wee1 protein kinase related disease is cancer.
Another object of the present application is to provide the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition for use in the prevention or treatment of Wee1 protein kinase-associated diseases. In some embodiments, the Wee1 protein kinase related disease is cancer.
It is another object of the present application to provide a method for preventing or treating a Wee1 protein kinase-associated disease, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition. In some embodiments, the Wee1 protein-related disease is cancer.
In some embodiments, the cancer includes, but is not limited to, head and neck cancer, ovarian cancer, colorectal cancer, bladder cancer, breast cancer, non-small cell lung cancer, and endometrial cancer.
The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.
The amount of the compound administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.
As used herein, unless otherwise specified, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.
As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. Herein, "non-human animal" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Examples
In order to make the objects and technical solutions of the present invention clearer, the present invention is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.
The abbreviations herein have the following meanings:
abbreviations | Means of |
TLC | Thin layer chromatography |
LC-MS | Liquid chromatography-mass spectrometry |
DIPEA | N, N-diisopropylethylamine |
CD 3OD | Deuterated methanol |
CDCl 3 | Deuterated chloroform |
DMSO-d 6 | Hexahydro-deuterated dimethyl sulfoxide |
TMS | Tetramethylsilane |
NMR | Nuclear magnetic resonance |
MS | Mass spectrometry |
s | Single peak (singlet) |
d | Double peak (doublet) |
t | Triple peak (triplet) |
q | Quartet (quartz) |
dd | Double two peak (double) |
m | Multiplet (multiplex) |
J | Coupling constant |
Hz | Hertz's scale |
The following fruitThe structures of the compounds described in the examples are given by1H-NMR or MS.1H-NMR measurement apparatus Using Bruker 400MHz NMR spectrometer, CD was used as a measurement solvent3OD、CDCl3Or DMSO-d6The internal standard substance is TMS, and all delta values are expressed in ppm. Mass Spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.
Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20cm) from Merck was used, and GF 254 (0.4-0.5 mm) was used for separation and purification by thin layer chromatography.
The reaction was monitored by Thin Layer Chromatography (TLC) or LC-MS using a developing system of: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, and volume ratio of solvent is regulated according to different polarities of the compounds or by adding triethylamine and the like.
The column chromatography generally uses 200-300 mesh silica gel as a carrier. The system of eluents comprises: the volume ratio of the solvent is adjusted according to different polarities of the compounds in a dichloromethane and methanol system and a petroleum ether and ethyl acetate system, and a small amount of triethylamine can also be added for adjustment.
Preparing a high performance liquid chromatograph, wherein the instrument model is as follows: agilent 1260, column: waters Xbridge Prep C18OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution.
Unless otherwise specified, the reaction temperatures of the examples are room temperature (20 ℃ C. to 30 ℃ C.).
Reagents used in this application are available from Acros Organics, Aldrich Chemical Company, Shanghai Teber Chemical science and technology, Inc., and the like.
Preparation of an intermediate:
intermediate preparation example 1: preparation of 2-allyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
The first step is as follows: preparation of ethyl 4- (2-allyl-2- (tert-butoxycarbonyl) hydrazino) -2- (methylthio) pyrimidine-5-carboxylate
Ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (20g,85.8mmol), tert-butyl 1-allylhydrazinecarbonate (15g,85.8mmol) and DIPEA (28g,215mmol) were added to tetrahydrofuran (200mL) and stirred under reflux for 18 hours. The reaction mixture was cooled, the reaction solvent was distilled off under reduced pressure, ether (100mL) was added to the residue, the precipitated solid was filtered, and the filtrate was concentrated to give the title compound of this step (31.7g, yield: 100%).
MS m/z(ESI):369.2[M+H]+。
The second step is that: preparation of ethyl 4- (2-allylhydrazino) -2- (methylthio) pyrimidine-5-carboxylate
To ethyl 4- (2-allyl-2- (tert-butoxycarbonyl) hydrazino) -2- (methylthio) pyrimidine-5-carboxylate (31.7g,85.8mmol) was added trifluoroacetic acid (60mL) while cooling on ice, and the mixture was stirred at room temperature for 1 hour, heated at 70 ℃ for 1 hour, and the reaction mixture was concentrated to give the title compound of this step (23g, yield: 100%).
MS m/z(ESI):269.1[M+H]+。
The third step: preparation of 2-allyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
Ethyl 4- (2-allylhydrazino) -2- (methylthio) pyrimidine-5-carboxylate (10g,38.2mmol) was dissolved in ethanol (70mL), and 6N aqueous sodium hydroxide (140mL) was added under ice bath, stirred at room temperature for 15 minutes, adjusted to pH 1 with concentrated hydrochloric acid, and the ethanol was distilled off under reduced pressure, filtered, and the resulting solid was washed with ether to obtain the title compound (16 g, yield: 83%) after drying.
MS m/z(ESI):223.1[M+H]+。
Intermediate preparation example 2: preparation of 2- (6-bromopyridin-2-yl) propan-2-ol
Methyl 6-bromopyridine-2-carboxylate (5g,23.1mmol) was dissolved in ether (100mL), magnesium methyliodide (17mL,50.8mmol) was added under nitrogen protection, the mixture was stirred at room temperature for 0.5 hour, water and 2N hydrochloric acid were added to the reaction mixture, ethyl acetate was extracted 3 times, the organic layers were combined and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave the title compound (5g, yield: 100%).
MS m/z(ESI):216.0[M+H]+。
Intermediate preparation example 3: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
The first step is as follows: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (2g,9.0mmol), 2- (6-bromopyridin-2-yl) propan-2-ol (2.5g,11.7mmol), cuprous iodide (1.7g,9.0mmol), potassium carbonate (1.7g,12.6mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (1.4g,9.9mmol) were added to dioxane (35mL) and reacted at 95 ℃ for 4 hours, after cooling to room temperature, aqueous ammonia was added, ethyl acetate was extracted 3 times, the organic phases were combined and concentrated, and the residue was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3/1) to give the title compound of this step (2.6g, yield: 81%).
MS m/z(ESI):358.1[M+H]+。
The second step is that: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (200mg,0.56mmol) was dissolved in acetonitrile (5mL) and water (5mL), potassium hydrogen peroxymonosulfate complex salt (282mg,1.68mmol) was added, stirred at room temperature for 2 hours, water was added, extracted 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (200mg, yield: 96%).
MS m/z(ESI):374.1[M+H]+。
Intermediate preparation example 4: preparation of 1- (6-bromopyridin-2-yl) cyclopropylcarbonitrile
The first step is as follows: preparation of 2- (6-bromopyridin-2-yl) acetonitrile
Acetonitrile (1.5mL,28.7mmol) was dissolved in tetrahydrofuran (20mL), n-butyllithium (11.2mL,27.9mmol) was added dropwise at-78 ℃ and stirred for 30 minutes, a solution of 2, 6-dibromopyridine (2g,8.4mmol) in tetrahydrofuran (30mL) was added, stirring was continued for 45 minutes, the reaction was gradually raised to room temperature, water and ethyl acetate were added and the organic phase was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 3/1) to obtain the title compound of this step (1.28g, yield: 77%).
MS m/z(ESI):197.0[M+H]+。
The second step is that: preparation of 1- (6-bromopyridin-2-yl) cyclopropylcarbonitrile
2- (6-bromopyridin-2-yl) acetonitrile (500mg,2.54mmol), 1, 2-dibromoethane (716mg,3.81mmol), tetrabutylammonium hydrogensulfate (164mg,0.51mmol) were dissolved in toluene (5mL), 50% aqueous sodium hydroxide solution (2.5mL) was added, stirring was performed at room temperature for 1 hour, the reaction mixture was extracted with water and ethyl acetate, the organic phase was combined and washed with water and saturated brine in this order, and the residue obtained by concentrating the organic phase was purified by preparative thin-layer chromatography (eluent: petroleum ether/ethyl acetate: 1/1) to give the title compound (300mg, yield: 53%).
MS m/z(ESI):223.0[M+H]+。
Intermediate preparation example 5: preparation of 2-bromo-6- (2-methoxyprop-2-yl) pyridine
2- (6-Bromopyridin-2-yl) propan-2-ol (500mg,2.3mmol) and iodomethane (980mg,6.9mmol) were dissolved in tetrahydrofuran (15mL), sodium hydride (276mg,6.9mmol) was added, the mixture was stirred at room temperature overnight, the reaction solution was extracted with water and ethyl acetate, the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (377mg, 71%).
MS m/z(ESI):230.0[M+H]+。
Intermediate preparation example 6: preparation of 4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -phenylamine
The first step is as follows: preparation of 5- (4-nitrophenyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carbonic acid tert-butyl ester
1-fluoro-4-nitrobenzene (312.4mg,2.2mmol) was dissolved in acetonitrile (10mL), followed by the addition of hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carbonic acid tert-butyl ester (500mg,2.4mmol) and DIPEA (455.8mg,3.5mmol) followed by heating under reflux and stirring for 5 hours. The reaction solution was cooled, filtered with suction, and dried to obtain the title compound (620mg, yield: 79.0%) of this step.
MS m/z(ESI):334.2[M+H]+。
The second step is that: preparation of 2- (4-nitrophenyl) hexahydropyrrolo [3,4-c ] pyrrole hydrochloride
5- (4-Nitrophenyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carbonic acid tert-butyl ester (620mg,1.9mmol) was dissolved in 4N hydrochloric acid in 1,4 dioxane (20mL), stirred at room temperature for 2 hours, and the reaction solution was concentrated to obtain the title compound of this step (560mg, yield: 100%).
MS m/z(ESI):234.1[M+H]+。
The third step: preparation of 2-methyl-5- (4-nitrophenyl) hexahydropyrrolo [3,4-c ] pyrrole
2- (4-Nitrophenyl) hexahydropyrrolo [3,4-c ] pyrrole hydrochloride (560mg,2.4mmol) and 40% aqueous formaldehyde (2.6g,36.0mmol) were dissolved in dichloromethane (20mL), and after addition of sodium borohydride acetate (1.5g,7.2mmol), stirring was carried out at room temperature for 1 hour, water was added, extraction was carried out 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (600mg, yield: 100%) of this step.
MS m/z(ESI):248.1[M+H]+。
The fourth step: preparation of 4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -phenylamine
2-methyl-5- (4-nitrophenyl) hexahydropyrrolo [3,4-c ] pyrrole (600mg,2.4mmol) was dissolved in methanol (10mL), raney nickel and hydrazine hydrate (606.6mg,12.1mmol) were sequentially added, the mixture was stirred at room temperature for 2 hours, the reaction solution was filtered through celite, methanol was distilled off under reduced pressure, water and dichloromethane were added and extracted 3 times, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (342mg, yield: 65%).
MS m/z(ESI):218.2[M+H]+。
Intermediate preparation example 7: preparation of 2-isopropyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
The first step is as follows: preparation of ethyl 4-hydrazino-2- (methylthio) pyrimidine-5-carboxylate
Ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5g,21.5mmol) was dissolved in ethanol (150mL), cooled to 0 ℃ in an ice bath, hydrazine hydrate (3.2g) was added, the reaction mixture was stirred at 0 ℃ for 1 hour, then evaporated to dryness under reduced pressure, the residue was added to methyl t-butyl ether (100mL), stirred for 30 minutes and filtered, and the filter cake was dried under vacuum to give the title compound of this step (4.3g, yield: 88%).
MS m/z(ESI):229.1[M+H]+。
The second step is that: preparation of ethyl 2- (methylthio) -4- (2- (prop-2-ylidene) hydrazino) pyrimidine-5-carboxylate
Ethyl 4-hydrazino-2- (methylthio) pyrimidine-5-carboxylate (4.3g,18.8mmol) was placed in a 150mL single-necked flask, acetone (100mL) was added, the temperature was raised to 70 ℃ and stirred overnight, and the reaction solution was concentrated to give the title compound of this step (5.1g, yield: 100%).
MS m/z(ESI):269.1[M+H]+。
The third step: preparation of ethyl 4- (2-isopropylhydrazino) -2- (methylthio) pyrimidine-5-carboxylate
Ethyl 2- (methylthio) -4- (2- (prop-2-ylidene) hydrazino) pyrimidine-5-carboxylate (5.1g,18.8mmol) was dissolved in methanol (100mL), cooled to 0 ℃ in an ice bath, sodium cyanoborohydride (1.8g,28.2mmol) and concentrated hydrochloric acid (0.1mL) were added, and after stirring for 2 hours while maintaining 0 ℃, a saturated aqueous sodium bicarbonate solution (50mL) was added to the reaction solution, followed by stirring for 10 minutes, ethyl acetate extraction 3 times, merging of the organic phases, drying over anhydrous sodium sulfate, filtration, and evaporation of the filtrate under reduced pressure to dryness to obtain the title compound of this step (4.9g, yield: 96%).
MS m/z(ESI):271.1[M+H]+。
The fourth step: preparation of 2-isopropyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
Ethyl 4- (2-isopropylhydrazino) -2- (methylthio) pyrimidine-5-carboxylate (4.9g,18.1mmol) was dissolved in methanol (400mL), 5N aqueous sodium hydroxide solution (100mL) was added, stirring was carried out at room temperature overnight, the reaction solution was evaporated under reduced pressure to remove methanol, the remaining aqueous phase was extracted twice with ethyl acetate, the aqueous phase was adjusted to pH 2 with 5N diluted hydrochloric acid, extracted 5 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to dryness to give the title compound (1.3g, yield: 31%).
MS m/z(ESI):225.1[M+H]+。
Intermediate preparation example 8: preparation of 1- (4-amino-2-fluorophenyl) -N, N-dimethylpiperidin-4-amine
The first step is as follows: preparation of 1- (4-nitro-2-fluorophenyl) -N, N-dimethylpiperidin-4-amine
1, 2-difluoro-4-nitrobenzene (1g,6.28mmol), N-dimethylpiperidin-4-amine (0.96g,7.55mmol) and potassium carbonate (1.72g,12.5mmol) were added to acetonitrile (10mL) and reacted at 50 ℃ for 16 hours, the reaction solution was cooled and poured into water, filtered and the solid was dried to obtain the title compound of this step (1.2g, yield: 71.4%).
MS m/z(ESI):268.2[M+H]+。
The second step is that: preparation of 1- (4-amino-2-fluorophenyl) -N, N-dimethylpiperidin-4-amine
1- (4-Nitro-2-fluorophenyl) -N, N-dimethylpiperidin-4-amine (200mg,0.75mmol) was dissolved in methanol (5mL), a catalytic amount of Raney nickel was added thereto, hydrazine hydrate (1mL) was added dropwise, the mixture was stirred at room temperature for 2 hours, and the mixture was filtered through a small pad of celite to obtain the title compound (170mg, yield: 96%) after the filtrate was concentrated.
MS m/z(ESI):238.2[M+H]+。
Compound preparation example:
example 1: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- ((4- (4-dimethylaminopiperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (compound 1)
2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (58mg,0.16mmol) was dissolved in toluene (5mL), followed by addition of (4-dimethylaminopiperidin-1-yl) aniline (68mg,0.32mmol) and DIPEA (82.6mg,0.64mmol), heating to 80 ℃ for 4 hours, concentration of the reaction solution, and purification of the residue by preparative high performance liquid chromatography gave the title compound (29mg, yield: 34%).
MS m/z(ESI):529.3[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.84(s,1H),7.87(t,J=8.0Hz,1H),7.74(d,J=8.0 Hz,1H),7.48(d,J=8.4Hz,2H),7.36(d,J=7.6Hz,1H),6.92(d,J=8.8Hz,2H),5.73-5.67(m,1H),5.05(dd,J=10.0,1.2Hz,1H),4.94(dd,J=17.2,1.2Hz,1H),4.74(d,J=6.0Hz,2H),3.74(d,J=12.4Hz,2H),2.83-2.71(m,5H),2.56(s,7H),2.09(d,J=12.0Hz,2H),1.83-1.80(m,2H),1.59(s,6H)。
Example 2: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- ((4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (Compound 2)
2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (50mg,0.13mmol) was dissolved in toluene (5mL), and 4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -aniline (58mg,0.27mmol) and DIPEA (67.1mg,0.52mmol) were sequentially added, heated to 80 ℃ for 4 hours, and the reaction was concentrated, and the residue was purified by preparative high performance liquid chromatography to give the title compound (9mg, yield: 14%).
MS m/z(ESI):527.3[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.83(s,1H),7.87(t,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.46(d,J=7.6Hz,2H),7.35(d,J=7.2Hz,1H),6.72(d,J=8.8Hz,2H),5.70(d,J=6.8Hz,1H),5.35(t,J=4.8Hz,1H),5.05(d,J=9.2Hz,1H),4.94(d,J=18.0Hz,1H),4.73(d,J=6.4Hz,2H),3.75(s,3H),3.44(d,J=10.0Hz,2H),3.35(s,2H),3.17(s,2H),2.79(s,5H),1.59(s,6H)。
Example 3: preparation of 2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6- ((4- (4-dimethylaminopiperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (compound 3)
The first step is as follows: preparation of 2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6-methylsulfanyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (280mg,1.26mmol), 2-bromo-6- (1-cyanocycloprop-1-yl) pyridine (366mg,1.64mmol), cuprous iodide (239mg,1.26mmol), potassium carbonate (243mg,1.76mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (197mg,1.39mmol) were added to dioxane (8mL), reacted at 95 ℃ for 4 hours, cooled to room temperature, followed by addition of aqueous ammonia, extraction with ethyl acetate 3 times, organic phase combination and concentration, and the residue was chromatographed on a silica gel column (eluent: petroleum ether/ethyl acetate: 3/1) to give the title compound of this step (289mg, yield: 63%).
The second step is that: preparation of 2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6-methylsulfinyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6-methylsulfanyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (289mg,0.8mmol) was dissolved in acetonitrile (5mL) and water (5mL), potassium monopersulfate complex salt (400mg,2.4mmol) was added, stirred at room temperature for 2 hours, water was added, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (292mg, yield: 96%).
The third step: preparation of 2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6- ((4- (4-dimethylaminopiperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6-methylsulfinyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (62mg,0.16mmol) was dissolved in toluene (5mL), followed by addition of (4-dimethylaminopiperidin-1-yl) aniline (72mg,0.33mmol) and DIPEA (84mg,0.65mmol), heating to 80 ℃ for 4 hours, concentration of the reaction solution, and purification of the residue by preparative high performance liquid chromatography gave the title compound (30mg, yield: 35%).
MS m/z(ESI):527.3[M+H]+
1H-NMR(400MHz,CDCl3)δ:7.95(s,1H),7.35(t,J=15.2Hz,1H),7.08(dd,J=15.2,3.2Hz,1H),7.03-7.00(m,1H),6.99-6.97(m,1H),6.78-6.76(m,1H),6.75-6.73(m,1H),6.25(dd,J=14.8,3.2Hz,1H),5.96-5.79(m,1H),5.24-5.16(m,1H),5.16-5.12(m,1H),4.95(s,1H),3.56-3.46(m,2H),3.44-3.32(m,2H),3.16-3.05(m,2H),2.26(s,6H),1.95-1.82(m,2H),1.74-1.57(m,5H),1.51-1.39(m,2H)。
Example 4: preparation of 2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6- ((4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (Compound 4)
2-allyl-1- (6- (1-cyanocycloprop-1-yl) pyridin-2-yl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (80mg,0.21mmol) was dissolved in toluene (5mL), 4- (5-methylhexahydropyrrole [3,4-c ] pyrrol-2 (1H) -yl) -aniline (91.4mg,0.42mmol) and DIPEA (108.5mg,0.84mmol) were sequentially added, heated to 80 ℃ for 4 hours, the reaction solution was concentrated, and the residue was purified by preparative HPLC to give the title compound (32mg, yield: 28.6%).
MS m/z(ESI):534.6[M+H]+
1H-NMR(400MHz,CDCl3)δ:7.95(s,1H),7.35(t,J=7.2Hz,1H),7.08(dd,J=7.2,1.6Hz,1H),7.00(d,J=7.2Hz,2H),6.76(d,J=7.2Hz,2H),6.25(dd,J=7.2,1.6Hz,1H),5.92-5.82(m,1H),5.20-5.14(m,2H),4.89(s,1H),4.89(s,1H),3.67-3.64(m,2H),3.51(d,J=6.0Hz,1H),3.47(d,J=6.4Hz,1H),2.96-2.85(m,4H),2.18(s,3H),2.14-2.08(m,2H),1.84-1.77(m,2H),1.74-1.67(m,2H),1.48-1.42(m,2H)。
Example 5: preparation of 2-allyl-1- (6- (2-methoxypropan-2-yl) pyridin-2-yl) -6- ((4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (Compound 5)
The first step is as follows: preparation of 2-allyl-1- (6- (2-methoxyprop-2-yl) pyridin-2-yl) -6-methylsulfanyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (140mg,0.63mmol), 2-bromo-6- (2-methoxyprop-2-yl) pyridine (188.6mg,0.82mmol), cuprous iodide (119.5mg,0.63mmol), potassium carbonate (121.5mg,0.88mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (98.5mg,0.70mmol) were added to dioxane (8mL) to react at 95 ℃ for 4 hours, after cooling to room temperature, aqueous ammonia was added, ethyl acetate was extracted 3 times, the organic phase was combined and concentrated, and the residue was chromatographed on a silica gel column (eluent: petroleum ether/ethyl acetate: 3/1) to give the title compound of this step (166mg, yield: 71%).
The second step is that: preparation of 2-allyl-1- (6- (2-methoxyprop-2-yl) pyridin-2-yl) -6-methylsulfinyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (6- (2-methoxyprop-2-yl) pyridin-2-yl) -6-methylsulfanyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (150mg,0.4mmol) was dissolved in acetonitrile (5mL) and water (5mL), potassium hydrogen peroxymonosulfate complex salt (203.7mg,1.2mmol) was added, stirred at room temperature for 2 hours, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (152mg, yield: 98%).
The third step: preparation of 2-allyl-1- (6- (2-methoxyprop-2-yl) pyridin-2-yl) -6- ((4- (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (6- (2-methoxyprop-2-yl) pyridin-2-yl) -6-methylsulfinyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (75mg,0.19mmol) was dissolved in toluene (5mL), 4- (5-methylhexahydropyrrole [3,4-c ] pyrrol-2 (1H) -yl) aniline (84mg,0.39mmol) and DIPEA (100mg,0.77mmol) were added in this order, the mixture was heated to 80 ℃ for 4 hours, and the reaction mixture was concentrated to prepare the title compound (34mg, yield: 33%) which was purified by high performance liquid chromatography.
MS m/z(ESI):541.7[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.81(s,1H),7.87-7.75(m,2H),7.50-7.36(m,3H),6.68(d,J=8.8Hz,2H),5.72-5.61(m,1H),4.99(d,J=9.6Hz,1H),4.92-4.80(m,3H),3.34-3.21(m,8H),3.13(s,2H),2.85(s,4H),2.53(s,3H),1.56(s,6H)。
Example 6: preparation of 2-allyl-1- (6- (2-methoxypropan-2-yl) pyridin-2-yl) -6- ((4- (4-dimethylaminopiperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (compound 6)
2-allyl-1- (6- (2-methoxyprop-2-yl) pyridin-2-yl) -6-methylsulfinyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (75mg,0.19mmol) was dissolved in toluene (5mL), followed by addition of (4-dimethylaminopiperidin-1-yl) aniline (85mg,0.39mmol) and DIPEA (100mg,0.77mmol), heating to 80 ℃ for reaction at 4 hours, and concentration of the reaction mixture to afford the title compound (35mg, yield: 34%) by HPLC purification.
MS m/z(ESI):543.3[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.83(s,1H),7.85(t,J=7.6Hz,1H),7.77(d,J=7.6Hz,1H),7.48(d,J=8.0Hz,3H),6.93(d,J=9.2Hz,2H),5.72-5.61(m,1H),4.99(d,J=9.6Hz,1H),4.91-4.82(m,3H),3.73(d,J=12.4Hz,2H),3.22(s,3H),2.79-2.72(m,4H),2.54(s,6H),2.08(d,J=12.0Hz,2H),1.86-1.74(m,2H),1.56(s,6H)。
Example 7: preparation of 6- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -2-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (Compound 7)
The first step is as follows: preparation of 1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -2-isopropyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-isopropyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (300mg,1.34mmol) and 2-hydroxypropyl-6-bromopyridine (347mg,1.61mmol) were dissolved in 1, 4-dioxane (50mL), cuprous iodide (255mg,1.34mmol), potassium carbonate (277mg,2.01mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (285mg,2.01mmol) were added, and after completion, the temperature was raised to 95 ℃ and the mixture was stirred overnight, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3/1-1/1) to obtain the title compound (350mg, yield: 72%) of this step.
MS m/z(ESI):360.1[M+H]+。
The second step is that: preparation of 6- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -2-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -2-isopropyl-6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (180mg,0.50mmol) was dissolved in toluene (12mL), m-chloroperoxybenzoic acid (104mg,0.60mmol) was added, and after stirring at room temperature for two hours, diisopropylethylamine (258mg,2.00mmol) and (4-dimethylaminopiperidin-1-yl) aniline (220mg,1.00mmol) were added, and after completion of addition, the temperature was raised to 80 ℃ and stirring was continued overnight, the reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the title compound (165mg, yield: 62.1%).
MS m/z(ESI):531.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ:10.12(s,1H),8.75(s,1H),8.07(t,J=7.2Hz,1H),7.71(d,J=8.0Hz,1H),7.65(d,J=7.6Hz,1H),7.54(s,2H),6.90(d,J=9.2Hz,2H),5.33(s,1H),4.18-4.11(m,1H),3.64(d,J=12.4Hz,2H),2.64-2.58(m,2H),2.19(s,6H),2.18-2.14(m,1H),1.84-1.81(m,2H),1.52-1.48(m,2H),1.44(s,6H),1.37(s,3H),1.36(s,3H)。
Example 8: 2-allyl-6- ((4- (4- (dimethylamino) piperidin-1-yl) -3-fluorophenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (compound 8)
Dissolving 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (sulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (100mg,0.27mmol) and 1- (4-amino-2-fluorophenyl) -N, N-dimethylpiperidin-4-amine (80mg,0.32mmol) in 1, 4-dioxane (5mL), dropwise adding trifluoroacetic acid (0.5mL), heating to 95 ℃ for reaction for 2 hours, cooling to room temperature, pouring the reaction solution into water, extracting impurities with ethyl acetate, adjusting the pH of the aqueous phase to 8-9 with potassium carbonate, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtration and concentration of the filtrate were carried out, and the residue was purified by preparative high performance liquid chromatography to give the title compound (48mg, yield: 32.8%).
MS m/z(ESI):547.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ:8.88(s,1H),8.02(t,J=8.0Hz,1H),7.76-7.71(m,2H),7.64(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.37-7.34(m,1H),7.03-6.98(t,J=5.2Hz,1H),5.70-5.63(m,1H),5.35(s,1H),5.01-4.98(m,1H),4.84-4.80(m,1H),4.68(d,J=5.2Hz,1H),2.65-2.59(t,J=10.8Hz,2H),2.21(s,6H),1.84(d,J=10.8Hz,2H),1.57-1.52(m,2H),1.44(s,6H)。
Example 9: preparation of 2-allyl-6- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -1- (3- (2-hydroxypropan-2-yl) phenyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (compound 9)
The first step is as follows: preparation of 3- (1-hydroxy-1-methylethyl) bromobenzene
Adding methyl 3-bromobenzoate (1g,4.65mmol) into diethyl ether (20mL) under the protection of nitrogen, cooling in an ice-water bath, dropwise adding a diethyl ether solution of methyl magnesium iodide (4mL,3mol/L,12mmol), and naturally heating to room temperature for reaction for 12 hours after dropwise adding. The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound of this step (820mg, yield: 82%).
MS m/z(ESI):245.0[M+H]+。
The second step is that: preparation of 3- (1-hydroxy-1-methylethyl) phenylboronic acid
Under nitrogen protection, 3- (1-hydroxy-1-methylethyl) bromobenzene (500mg,2.32mmol) was added to tetrahydrofuran (10mL), a N-hexane solution of N-butyllithium (3mL,2mol/L,6mmol) was slowly added dropwise at-60 deg.C, stirring was carried out at-60 deg.C for 1 hour, trimethyl borate (480mg,4.62mmol) was added dropwise, reaction was carried out at room temperature for 12 hours, water (20mL) was slowly added dropwise, extraction was carried out with ethyl acetate, the aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid, extraction was carried out with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound of this step (220mg, yield: 52.6%).
MS m/z(ESI):181.0[M+H]+。
The third step: preparation of 2-allyl-1- (3- (2-hydroxypropan-2-yl) phenyl) -6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-6- (methylthio) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (200mg,0.56mmol), copper acetate (160mg,0.8mmol) and 3- (1-hydroxy-1-methylethyl) phenylboronic acid (200mg,1.12mmol) were sequentially added to chloroform (3mL), pyridine (0.4mL) was added dropwise at room temperature for reaction for 48 hours, 30% aqueous ammonia was added to the reaction, stirring was carried out for 30 minutes, ethyl acetate extraction was carried out, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel thin chromatography to give the title compound of this step (30mg, yield 15%).
MS m/z(ESI):357.1[M+H]+。
The fourth step: preparation of 2-allyl-1- (3- (2-hydroxypropan-2-yl) phenyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (3- (2-hydroxypropan-2-yl) phenyl) -6- (methylthio) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (30mg,0.084mmol) was added to a mixed solvent of acetonitrile (2mL) and water (2mL), oxone complex salt (34mg,0.2mmol) was added thereto, the mixture was stirred at room temperature for 2 hours, the reaction mixture was diluted with 10mL of water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (20mg, yield 63.6%) of this step
MS m/z(ESI):373.1[M+H]+。
The fifth step: preparation of 2-allyl-6- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -1- (3- (2-hydroxypropan-2-yl) phenyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one
2-allyl-1- (3- (2-hydroxypropan-2-yl) phenyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (20mg,0.053mmol) and (4-dimethylaminopiperidin-1-yl) aniline (13mg,0.059mmol) were added to 1, 4-dioxane (10mL), trifluoroacetic acid (0.1mL) was added dropwise, the mixture was heated to 90 ℃ to react for 4 hours, the reaction was cooled to room temperature, the reaction solution was poured into water, ethyl acetate was used to extract impurities, the aqueous phase was adjusted to pH 8 to 9 with potassium carbonate, ethyl acetate was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by preparative high performance liquid chromatography to give the title compound (5mg, yield 18%).
MS m/z(ESI):528.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ:8.80(s,1H),7.55-7.48(m,5H),7.29-7.27(m,1H),6.85(d,J=8.8Hz,2H),5.70-5.62(m,1H),5.18(s,1H),5.08(d,J=9.2Hz,1H),4.27(br,2H),3.61(d,J=12.0Hz,2H),2.59(d,J=8.0Hz,2H),2.20(s,6H),2.20-2.15(m,3H),2.02-1.97(m,2H),1.83-1.80(m,2H),1.46(s,6H)。
Pharmacological testing
Experimental example 1: inhibition assay of Wee1 kinase:
to test the inhibitory effect of the compounds on the in vitro activity of Wee1 kinase, the experimental procedure was as follows:
1) after pre-incubation of Wee1 protein (Carna Biosciences) with different concentrations of test compounds for 15 min at room temperature, the reaction was initiated by adding substrate (Poly (Lys, Tyr), Sigma) and 10ATP according to the kit instructions and reacted for 90 min at 30 ℃.
2) An equal volume of ADP-Glo reagent (Promega) was added to the reaction system, and the reaction was terminated by incubation at room temperature for 40 minutes.
3) Kinase detection reagent was added and incubated for 30 minutes at room temperature. Detecting the self-luminescence signal of the product. The half maximal Inhibitory Concentration (IC) of the compound was calculated as the concentration of the remaining activity closest to 50% using the vehicle group (DMSO) as a negative control and the Buffer reaction Buffer group (containing no enzyme and compound) as a blank control50) The results are shown in table 1:
table 1 data for inhibition of Wee1 Activity by Compounds
As can be seen from the data in Table 1, the compound has obvious inhibition effect on Wee1 kinase.
Experimental example 2: rat Pharmacokinetic (PK) profile study
Male SD rats were given the Wee1 inhibitor AZD1775 and the test compound at the clinical trial stage by Intravenous (IV) and intragastric (PO) administration, respectively, and the pharmacokinetic profile of the test compound was examined. The dosages of IV and PO were 1mg/kg and 5mg/kg, respectively, with IV vehicle being 5% DMSO, 5% Solutol, 90% physiological saline, and PO vehicle being 0.5% MC. Blood was collected at various time points after IV and PO administration. EDTA-K is adopted for blood2Anticoagulated and centrifuged to obtain a plasma sample. Plasma samples were processed for precipitated protein and analyzed by LC-MS/MS.
Pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model, and the results are shown in tables 2 and 3.
TABLE 2 pharmacokinetic parameters of the Compounds in rats
The data in table 2 show that compound 2 of the present application has a bioavailability (F) in rats of 49.7% better than AZD1775, indicating that the compound of the present application has good drug exposure and bioavailability in rats and is suitable for oral administration.
TABLE 3 drug half-life comparison of Compounds in rats
Test object | Compound 1 | Compound 2 | AZD1775 |
Route of administration | Gavage stomach | Gavage stomach | Gavage stomach |
Sex | Male sex | Male sex | Male sex |
Dosage (mg/kg) | 5 | 5 | 5 |
T 1/2(h) | 4.37 | 3.79 | 1.73 |
The data in Table 3 show that Compound 1 and Compound 2, T of the present application are administered by gavage at a dose of 5mg/kg1/2The half-life period of the compound is improved by more than 1 time compared with that of the AZD1775 compound, the effect time of the medicine is longer, and the medicine has obvious advantages. Moreover, the compound can be administrated 1 time per day, so that the administration frequency can be reduced, and the compliance of patients can be improved.
Experimental example 3: mouse Pharmacokinetic (PK) profile study
Female Balb/c mice were given the Wee1 inhibitor AZD1775 and test compound in clinical trials via Intravenous (IV) and intragastric (PO) administration, respectively, and the pharmacokinetic profile of the test compound was examined. The dosages of IV and PO were 1mg/kg and 10mg/kg, respectively, with IV vehicle being 5% DMSO, 5% Solutol, 90% physiological saline, and PO vehicle being 0.5% MC. Blood was collected at various time points after IV and PO administration. EDTA-K is adopted for blood2Anticoagulated and centrifuged to obtain a plasma sample. Plasma samples were processed for precipitated protein and analyzed by LC-MS/MS.
Pharmacokinetic parameters were calculated using the WinNonlin 6.3 software using a non-compartmental model, and the results are shown in tables 4 and 5.
TABLE 4 pharmacokinetic parameters of Compounds in mice
The data in Table 4 show the AUC in mice for Compound 1 of the present application when administered 10mg/kg orallylast1770h ng/mL, better than the AUC of AZD1775 at the same doselastThe compounds of the present application are shown to have good drug exposure in mice and are suitable for oral administration.
TABLE 5 drug half-life comparison of Compounds in mice
The data in Table 5 show that Compound 1 of the present application, T, was administered intravenously and by gavage1/2The half-life period of the compound is 1.15 hours and 2.90 hours respectively, which shows that the half-life period of the compound is improved by more than 1 time compared with that of the compound AZD1775, the effect action time is longer, and the compound has obvious advantages. Moreover, the compound can be administrated 1 time per day, so that the administration frequency can be reduced, and the compliance of patients can be improved.
Claims (16)
- A compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, said compound having the structure of formula I:wherein,x is selected from CH and N;R1selected from hydroxy-C1-6Alkyl-, C1-6alkoxy-C1-6Alkyl-and cyano-C3-6Cycloalkyl-;R2selected from 7-10 membered fused heterocyclyl, said 7-10 membered fused heterocyclyl being optionally substituted by one or more C1-6Alkyl substitution; or R2Is piperidinyl, said piperidinyl group being optionally substituted by one or more-NR5R6Substitution; r5、R6Each independently selected from C1-6An alkyl group;R3is selected from C1-6Alkyl and C2-6An alkenyl group;R4selected from hydrogen and halogen.
- The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof,wherein R is1Selected from hydroxy-C1-4Alkyl-, C1-3alkoxy-C1-4Alkyl-and cyano-C3-6Cycloalkyl-;preferably, R1Selected from the group consisting of 2-hydroxypropan-2-yl, 2-methoxyprop-2-yl and 1-cyanocyclopropyl-1-yl.
- The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof,wherein R is2Selected from 7-10 membered bicyclic fused heterocyclic group, said 7-10 membered bicyclic fused heterocyclic group optionally substituted with one or more C1-6Alkyl substitution;preferably, R2Selected from 8-membered fused heterocyclic groups, said 8-membered fused heterocyclic group being substituted by a C1-6Alkyl substitution;preferably, R2Selected from 8-membered bicyclic fused heterocyclic group, said 8-membered bicyclic fused heterocyclic group being substituted by a C1-6Alkyl substitution;Preferably, R2Is 5-methyl-octahydro-pyrrolo [3,4-c]Pyrrol-2-yl.
- The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof,wherein R is2Being piperidinyl, said piperidinyl being substituted by one or more-NR5R6Substituted, R5、R6Each independently selected from C1-6An alkyl group;preferably, R2Being piperidinyl, said piperidinyl being substituted by one or more-NR5R6Substituted, R5、R6Each independently selected from C1-4An alkyl group;preferably, R2Is 4-dimethylaminopiperidin-1-yl.
- The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof,wherein R is3Is selected from C1-4Alkyl and C2-4An alkenyl group;preferably, R3Selected from allyl and isopropyl.
- The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof,wherein R is4Selected from hydrogen and fluorine.
- A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof,wherein R is1Selected from 2-hydroxyprop-2-yl, 2-methoxyprop-2-yl and 1-cyanocyclopropyl-1-yl;R2selected from 8-membered fused heterocyclic groups, said 8-membered fused heterocyclic group being substituted by a C1-6Alkyl substitution; preferably, R2Is 5-methyl hexahydropyrrole [3,4-c]Pyrrol-2 (1H) -yl; or R2Is selected fromR5、R6Each independently selected from C1-6An alkyl group; preferably, R2Is 4-dimethylaminopiperidin-1-yl.
- a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
- A pharmaceutical formulation comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 11; preferably, it is administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.
- Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite, or prodrug thereof, a pharmaceutical composition of claim 11, or a pharmaceutical formulation of claim 12, for the manufacture of a medicament for the prevention or treatment of a disease associated with the Wee1 protein; preferably, the Wee1 protein-related disease is cancer.
- The use of claim 13, wherein the cancer is selected from the group consisting of head and neck cancer, ovarian cancer, colorectal cancer, bladder cancer, breast cancer, non-small cell lung cancer, and endometrial cancer.
- A process for preparing a compound according to any one of claims 1 to 10, comprising the steps of:wherein HallIs halogen (e.g., F, Cl or Br); hal2Selected from halogen (e.g., Cl, Br or I), boronic acid groups or boronic ester groups; r1、R2、R3、R4And X is as defined in any one of claims 1 to 10;the reaction conditions for each step were as follows:(1) reacting compound IN-1 with a hydrazine compound to obtain compound IN-2;(2) cyclizing the compound IN-2 to obtain a compound IN-3;(3) reacting compound IN-3 with compound IN-4 to give compound IN-5;(4) oxidizing the compound IN-5 to obtain a compound IN-6;(5) reacting compound IN-6 with compound IN-7 to obtain the compound of formula I.
- A process for preparing the compound of claim 8, comprising the steps of:wherein Hal1Is halogen (e.g., F, Cl or Br); hal2Is halogen (e.g., Cl, Br, or I), a boronic acid group, or a boronic ester group; PG is a protecting group selected from benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl; r1And R2As defined in claim 8;the reaction conditions for each step were as follows:(1) reacting compound IN-1 with compound IN-8 to give compound IN-9;(2) removing the protecting group PG from the compound IN-9 to obtain a compound IN-10;(3) cyclizing compound IN-10 to give compound IN-11;(4) reacting compound IN-11 with compound IN-12 to give compound IN-13;(5) oxidizing the compound IN-13 to obtain a compound IN-14;(6) reacting compound IN-14 with compound IN-15 to give the compound of formula I-2.
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