TW201841896A - 作為pd—l1抑制劑的雜環類化合物 - Google Patents

作為pd—l1抑制劑的雜環類化合物 Download PDF

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Publication number: TW201841896A
Authority: TW; Taiwan
Prior art keywords: compound; formula; tert; amino; mmol
Prior art date: 2017-04-26

Application number

TW107114012A

Other languages

English (en)

Chinese (zh)

Inventor

王勇

趙立文

劉欣

尹偉

劉笑

于琪

Original Assignee

大陸商南京聖和藥業股份有限公司

Priority date (The priority date 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 date listed.)

2017-04-26

Filing date

2018-04-25

Publication date

2018-12-01

2018-04-25 Application filed by 大陸商南京聖和藥業股份有限公司 filed Critical 大陸商南京聖和藥業股份有限公司

2018-12-01 Publication of TW201841896A publication Critical patent/TW201841896A/zh

Links

239000012271 PD-L1 inhibitor Substances 0.000 title abstract description 3
150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 3
229940121656 pd-l1 inhibitor Drugs 0.000 title abstract description 3
150000001875 compounds Chemical class 0.000 claims abstract description 182
238000002360 preparation method Methods 0.000 claims abstract description 182
150000003839 salts Chemical class 0.000 claims abstract description 48
239000012453 solvate Substances 0.000 claims abstract description 46
229940002612 prodrug Drugs 0.000 claims abstract description 44
239000000651 prodrug Substances 0.000 claims abstract description 44
206010028980 Neoplasm Diseases 0.000 claims abstract description 39
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
208000035473 Communicable disease Diseases 0.000 claims abstract description 6
-1 amine compound Chemical class 0.000 claims description 112
229910052760 oxygen Inorganic materials 0.000 claims description 43
239000013078 crystal Substances 0.000 claims description 42
229910052717 sulfur Inorganic materials 0.000 claims description 41
150000001413 amino acids Chemical class 0.000 claims description 33
238000000034 method Methods 0.000 claims description 28
125000006239 protecting group Chemical group 0.000 claims description 28
229910052727 yttrium Inorganic materials 0.000 claims description 24
125000000217 alkyl group Chemical group 0.000 claims description 20
229910052757 nitrogen Inorganic materials 0.000 claims description 20
229910052799 carbon Inorganic materials 0.000 claims description 15
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
229910052739 hydrogen Inorganic materials 0.000 claims description 10
201000011510 cancer Diseases 0.000 claims description 8
230000008569 process Effects 0.000 claims description 7
239000003814 drug Substances 0.000 claims description 5
238000006460 hydrolysis reaction Methods 0.000 claims description 5
230000002378 acidificating effect Effects 0.000 claims description 4
208000015181 infectious disease Diseases 0.000 claims description 4
238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
239000000203 mixture Substances 0.000 abstract description 59
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 209
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 175
238000006243 chemical reaction Methods 0.000 description 94
235000019439 ethyl acetate Nutrition 0.000 description 83
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
239000000243 solution Substances 0.000 description 59
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 56
230000002829 reductive effect Effects 0.000 description 55
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
239000007787 solid Substances 0.000 description 49
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 44
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 35
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 33
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 32
239000012074 organic phase Substances 0.000 description 31
239000003208 petroleum Substances 0.000 description 27
229940024606 amino acid Drugs 0.000 description 26
235000001014 amino acid Nutrition 0.000 description 26
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 26
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 23
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
239000002904 solvent Substances 0.000 description 22
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
239000007858 starting material Substances 0.000 description 20
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 19
125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 17
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 17
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 17
238000000746 purification Methods 0.000 description 17
229960001153 serine Drugs 0.000 description 17
239000011734 sodium Substances 0.000 description 17
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
239000011541 reaction mixture Substances 0.000 description 16
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 15
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
239000011630 iodine Substances 0.000 description 15
229910052740 iodine Inorganic materials 0.000 description 15
239000008346 aqueous phase Substances 0.000 description 14
238000004440 column chromatography Methods 0.000 description 14
DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 14
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 13
125000004432 carbon atom Chemical group C* 0.000 description 13
238000002474 experimental method Methods 0.000 description 13
239000007788 liquid Substances 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 12
125000003277 amino group Chemical group 0.000 description 12
TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 12
238000001990 intravenous administration Methods 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
239000012267 brine Substances 0.000 description 11
238000004821 distillation Methods 0.000 description 11
239000010410 layer Substances 0.000 description 11
239000000047 product Substances 0.000 description 11
125000001424 substituent group Chemical group 0.000 description 11
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 10
229940126062 Compound A Drugs 0.000 description 9
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 9
241000699670 Mus sp. Species 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
125000000753 cycloalkyl group Chemical group 0.000 description 9
229910052736 halogen Inorganic materials 0.000 description 9
150000002367 halogens Chemical group 0.000 description 9
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
239000012230 colorless oil Substances 0.000 description 8
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 8
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 8
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
102000008096 B7-H1 Antigen Human genes 0.000 description 7
108010074708 B7-H1 Antigen Proteins 0.000 description 7
206010009944 Colon cancer Diseases 0.000 description 7
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
210000001744 T-lymphocyte Anatomy 0.000 description 7
230000003197 catalytic effect Effects 0.000 description 7
239000012043 crude product Substances 0.000 description 7
125000002768 hydroxyalkyl group Chemical group 0.000 description 7
239000011259 mixed solution Substances 0.000 description 7
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
238000003756 stirring Methods 0.000 description 7
125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
KJYAFJQCGPUXJY-UMSFTDKQSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-(tritylamino)butanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KJYAFJQCGPUXJY-UMSFTDKQSA-N 0.000 description 6
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
125000004429 atom Chemical group 0.000 description 6
208000029742 colonic neoplasm Diseases 0.000 description 6
OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 6
239000000706 filtrate Substances 0.000 description 6
239000005457 ice water Substances 0.000 description 6
229920006395 saturated elastomer Polymers 0.000 description 6
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 5
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
125000004093 cyano group Chemical group *C#N 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
239000012065 filter cake Substances 0.000 description 5
238000001914 filtration Methods 0.000 description 5
239000012046 mixed solvent Substances 0.000 description 5
239000012044 organic layer Substances 0.000 description 5
229910000027 potassium carbonate Inorganic materials 0.000 description 5
238000010992 reflux Methods 0.000 description 5
238000010898 silica gel chromatography Methods 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
102100040678 Programmed cell death protein 1 Human genes 0.000 description 4
101710089372 Programmed cell death protein 1 Proteins 0.000 description 4
206010039491 Sarcoma Diseases 0.000 description 4
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
235000004279 alanine Nutrition 0.000 description 4
230000000259 anti-tumor effect Effects 0.000 description 4
230000037396 body weight Effects 0.000 description 4
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
TXWOGHSRPAYOML-UHFFFAOYSA-M cyclobutanecarboxylate Chemical compound [O-]C(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-M 0.000 description 4
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
230000000694 effects Effects 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
230000000670 limiting effect Effects 0.000 description 4
XNEMDNLBFBUFGI-UHFFFAOYSA-N methyl 4-[(2-methylpropan-2-yl)oxycarbonylamino]oxane-4-carboxylate Chemical compound CC(C)(C)OC(=O)NC1(C(=O)OC)CCOCC1 XNEMDNLBFBUFGI-UHFFFAOYSA-N 0.000 description 4
AZFBPYNPITWILD-UHFFFAOYSA-N methyl 4-aminooxane-4-carboxylate Chemical compound COC(=O)C1(N)CCOCC1 AZFBPYNPITWILD-UHFFFAOYSA-N 0.000 description 4
239000003921 oil Substances 0.000 description 4
239000002504 physiological saline solution Substances 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
238000000926 separation method Methods 0.000 description 4
239000001632 sodium acetate Substances 0.000 description 4
235000017281 sodium acetate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
238000012360 testing method Methods 0.000 description 4
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 3
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LKRXXARJBFBMCE-BDAKNGLRSA-N (2s,3r)-3-[(2-methylpropan-2-yl)oxy]-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)O[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C LKRXXARJBFBMCE-BDAKNGLRSA-N 0.000 description 3
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
SPPDKPRJPFTBEV-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxycarbonylamino]oxane-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1(C(O)=O)CCOCC1 SPPDKPRJPFTBEV-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
239000007821 HATU Substances 0.000 description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
239000002253 acid Substances 0.000 description 3
125000005189 alkyl hydroxy group Chemical group 0.000 description 3
SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
125000000539 amino acid group Chemical group 0.000 description 3
235000011114 ammonium hydroxide Nutrition 0.000 description 3
BPHBGLDLMNWKAA-UHFFFAOYSA-N benzyl 1-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxocyclobutane-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)NC1(CC(C1)=O)C(=O)OCC1=CC=CC=C1 BPHBGLDLMNWKAA-UHFFFAOYSA-N 0.000 description 3
125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
239000000460 chlorine Substances 0.000 description 3
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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TW107114012A 2017-04-26 2018-04-25 作為pd—l1抑制劑的雜環類化合物 TW201841896A (zh)

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US11130740B2 (en)	2017-04-25	2021-09-28	Arbutus Biopharma Corporation	Substituted 2,3-dihydro-1H-indene analogs and methods using same
AU2018306619B2 (en)	2017-07-28	2022-06-02	Chemocentryx, Inc.	Immunomodulator compounds
KR102670486B1 (ko)	2017-08-08	2024-05-28	케모센트릭스, 인크.	마크로사이클릭 면역조절제
CN111712494A (zh)	2018-02-13	2020-09-25	吉利德科学公司	Pd-1/pd-l1抑制剂
EP3755311A4 (fr)	2018-02-22	2021-11-10	ChemoCentryx, Inc.	Indane-amines utiles en tant qu'antagonistes de pd-l1
US12083118B2 (en)	2018-03-29	2024-09-10	Arbutus Biopharma Corporation	Substituted 1,1′-biphenyl compounds, analogues thereof, and methods using same
EP4600247A3 (fr)	2018-04-19	2025-11-19	Gilead Sciences, Inc.	Inhibiteurs de pd-1/pd-l1
KR20230159715A (ko)	2018-07-13	2023-11-21	길리애드 사이언시즈, 인코포레이티드	Pd-1/pd-l1 억제제
AU2019366355B2 (en)	2018-10-24	2022-10-13	Gilead Sciences, Inc.	PD-1/PD-L1 inhibitors
TW202024042A (zh) *	2018-10-25	2020-07-01	大陸商南京聖和藥業股份有限公司	1,3,4-噁二唑-2-環丁基類化合物及其製備方法和應用
MX2021013819A (es)	2019-05-15	2022-02-10	Chemocentryx Inc	Compuestos de triarilo para el tratamiento de enfermedades asociadas a pd-l1.
BR112021023750A2 (pt)	2019-06-20	2022-01-11	Chemocentryx Inc	Compostos para tratamento de doenças pd-l1
MX2022000318A (es)	2019-07-10	2022-02-10	Chemocentryx Inc	Indanos como inhibidores de pd-l1.
CN114585359B (zh)	2019-10-16	2025-08-12	凯莫森特里克斯股份有限公司	用于治疗pd-l1疾病的杂芳基联苯酰胺
MX2022004450A (es)	2019-10-16	2022-05-03	Chemocentryx Inc	Aminas de heteroaril-bifenilo para el tratamiento de enfermedades pd-l1.

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JP6521977B2 (ja) *	2013-09-06	2019-05-29	オーリジーンディスカバリーテクノロジーズリミテッドＡｕｒｉｇｅｎｅＤｉｓｃｏｖｅｒｙＴｅｃｈｎｏｌｏｇｉｅｓＬｉｍｉｔｅｄ	免疫調節剤としての１，２，４−オキサジアゾール誘導体
JP2016532711A (ja) *	2013-09-06	2016-10-20	オーリジーンディスカバリーテクノロジーズリミテッドＡｕｒｉｇｅｎｅＤｉｓｃｏｖｅｒｙＴｅｃｈｎｏｌｏｇｉｅｓＬｉｍｉｔｅｄ	免疫調節剤としての１，３，４−オキサジアゾール及び１，３，４−チアジアゾールの誘導体
SMT202200163T1 (it) *	2015-03-10	2022-05-12	Aurigene Discovery Tech Ltd	Composti di 1,2,4-0ssadiazolo e tiadiazolo come immunomodulatori

2018
- 2018-04-25 CN CN201810375602.3A patent/CN108794422B/zh active Active
- 2018-04-25 TW TW107114012A patent/TW201841896A/zh unknown
- 2018-04-25 WO PCT/CN2018/084352 patent/WO2018196768A1/fr not_active Ceased

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WO2018196768A1 (fr)	2018-11-01
CN108794422B (zh)	2022-07-01
CN108794422A (zh)	2018-11-13

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