CN117088849A - 用于治疗或预防冠状病毒感染的3cl蛋白酶小分子抑制剂及其用途 - Google Patents
用于治疗或预防冠状病毒感染的3cl蛋白酶小分子抑制剂及其用途 Download PDFInfo
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- CN117088849A CN117088849A CN202210512720.0A CN202210512720A CN117088849A CN 117088849 A CN117088849 A CN 117088849A CN 202210512720 A CN202210512720 A CN 202210512720A CN 117088849 A CN117088849 A CN 117088849A
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- 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
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229940049920 malate Drugs 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
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- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- KJOMYNHMBRNCNY-UHFFFAOYSA-N pentane-1,1-diamine Chemical compound CCCCC(N)N KJOMYNHMBRNCNY-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical compound CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- HBEFYGYBMKPNSZ-UHFFFAOYSA-N s-phenyl chloromethanethioate Chemical compound ClC(=O)SC1=CC=CC=C1 HBEFYGYBMKPNSZ-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 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
- 210000002966 serum Anatomy 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical class O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/14—Antivirals for RNA viruses
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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Abstract
本申请涉及用于治疗或预防冠状病毒感染的3CL蛋白酶小分子抑制剂及其用途。具体地，本申请涉及式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，及其在制备用于治疗或预防冠状病毒感染或由冠状病毒引起的疾病或症状的药物中的用途。
Description
技术领域
本申请涉及生物医药领域，尤其涉及用于治疗或预防冠状病毒感染的3CL蛋白酶小分子抑制剂及其用途。
背景技术
新型冠状病毒(SARS-CoV-2)是目前已知的RNA病毒中基因组最大的一种正链RNA病毒。研究发现，新型冠状病毒主要通过人体呼吸道黏膜系统侵染细胞，进入细胞后，病毒基因被蛋白酶切割以开始翻译和复制所需蛋白。3CL蛋白酶识别特异性的酶切位点，将多聚蛋白前体剪切为多个非结构蛋白，对病毒的生命周期至关重要，是极好的抗病毒药物靶点。许多上市的抗病毒药物针对如HIV、HCV的3CL蛋白酶。其中，HIV 3CL蛋白酶的抑制剂洛匹那韦(lopinavir)和利托那韦(ritonavir)在体外与新型冠状病毒的3CL蛋白酶有一定相互作用，但在临床测试中被证明对新型冠状病毒感染的患者没有正向作用。因此，特异性针对新型冠状病毒的3CL蛋白酶的强抑制剂显得尤为重要。
发明内容
在第一方面，本申请提供了式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，
其中，
环A选自五元或六元杂脂环或杂芳环；
环B为存在的或不存在的；
其中，1)当环B存在时，环B选自任选地被卤素、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氨基或硝基取代的五元或六元脂族环、芳族环、杂脂环或杂芳环，并且环A任选地被卤素或C1-C3烷基取代；
2)当环B不存在时，环A任选地被R1NH-取代，其中R1选自H、卤素、C1-C3烷基、R2C(＝O)、R2S(＝O)2或叔丁氧羰基，其中R2选自H、任选地被羟基或卤素取代的C1-C3烷基或C3-C4环烷基、或任选地被卤素或C1-C3烷基取代的氨基；
P1选自任选地被卤素、C1-C3烷基、氨基、氰基或C1-C3卤代烷基取代的其中R3选自H、卤素、C1-C3烷基、氰基或吡唑基；并且
P2选自任选地被卤素取代的C1-C5烷基、C3-C6环烷基或苯基。
在本发明的另一个实施方式中，
环A选自五元或六元杂脂环或杂芳环且包含1或2个选自O、S或N的杂原子，优选为吡咯、咪唑、吡唑、吡啶、嘧啶、吡嗪、哒嗪、氮杂环戊烷或氮杂环己烷；并且
环B当存在时选自五元或六元脂族环、芳族环、杂脂环或杂芳环且所述杂脂环或杂芳环包含1或2选自O、S或N的杂原子，优选为环戊烷、环己烷、苯、吡咯、咪唑、吡唑、吡啶、嘧啶、吡嗪、哒嗪、氮杂环戊烷或氮杂环己烷。
在本发明的另一个实施方式中，
1)当环B存在时，环B任选地被氟、氯、溴、甲基、乙基、丙基、二氟甲基、三氟甲基、甲氧基、乙氧基或硝基取代，并且环A任选地被氟、氯、溴、甲基、乙基或丙基取代；并且
2)当环B不存在时，环A任选地被R1NH-取代，其中R1选自H、氟、氯、溴、甲基、乙基、丙基、R2C(＝O)、R2S(＝O)2或叔丁氧羰基，其中R2选自H、任选地被羟基、氟、氯或溴取代的甲基、乙基、丙基、环丙基或环丁基、或任选地被氟、氯、溴、甲基、乙基或丙基取代的氨基。
在本发明的一个优选实施方式中，
P1选自任选地被氟、氯、溴、甲基或乙基取代的 其中R3选自氢、氰基或吡唑基。
在本发明的一个优选实施方式中，
P2选自任选地被氟、氯或溴取代的异丙基、环己基、苯基，优选地选自
为了简明起见，后文所述“式(I)化合物”或“本申请的化合物”也可以涵盖式(I)化合物的任意同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物。
术语“光学异构体”意指，当化合物具有一个或更多个手性中心时，每个手性中心可以存在R构型或S构型，由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如，通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指，当化合物中存在双键时，该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解：互变异构体之间可以互相转变，在某一状态下可能会达到一种平衡状态而共存。
除非另有指明，本文提到“式(I)化合物”或“本发明的化合物”时也涵盖该化合物中任一个原子被其同位素原子代替而得到的同位素标记化合物。本发明包括式(I)化合物的所有药学上可接受的同位素标记化合物，其中，一个或者多个原子被具有与通常在自然界中所发现的原子相同原子序数但是不同原子质量或者质量数的原子所替换。
适用于包含在本发明的化合物中的同位素的实例包括氢的同位素，诸如2H(D)和3H(T)，碳的同位素，诸如11C、13C和14C，氯的同位素，诸如36Cl，氟的同位素，诸如18F，碘的同位素，诸如123I和125I，氮的同位素，诸如13N和15N，氧的同位素，诸如15O、17O和18O，以及硫的同位素，诸如35S。
式(I)的同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂以类似于在本文所附的实例和制备中所描述的方法，来进行制备。
式(I)化合物可以药学上可接受的盐的形式存在，比如，式(I)化合物的酸加成盐和/或碱加成盐。除非另有指明，否则本文所用的“药学上可接受的盐”包括可出现于式(I)化合物内的酸加成盐或碱加成盐。
式(I)化合物的药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于：乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于：铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。关于合适的盐的综述，参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahland Wermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。一般而言，式(I)化合物无论以溶剂化形式存在或以未溶剂化形式存在，其都包括在本发明的范围内。
本发明的某些化合物可以不同晶型或不定型形式存在，无论以何种形式存在，式(I)化合物都包括在本发明的范围内。
为了避免歧义，下面对本文中所使用的术语给出定义。除非另有说明，本文所用术语的含义如下。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地，该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
“前体药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本发明化合物的衍生物。
“代谢物”是指在细胞或有机体优选人中源自本发明任意化合物的所有分子。
术语“氰基”是指-CN。
在本文中使用时，术语“被取代”是指基团中的一个或多个(优选1至5个，更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时，术语“独立地”是指当取代基的个数超过一个时，这些取代基可以相同也可以不同。
在本文中使用时，术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如，一个基团“任选地被取代”表示：该基团可以是未被取代的，也可以是被取代的。
在本文中使用时，术语“杂原子”代表氧(O)、氮(N)、或S(O)m(其中m可以是0、1或2，即硫原子S、或亚砜基SO、或磺酰基S(O)2)。
在本文中使用时，术语“烷基”是指饱和的脂族烃，包括直链及支链。在一些实施方式中，烷基基团具有1-8个、或1-6个、或1-3个碳原子。例如，术语“C1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C1-8烷基”在其定义中包括术语“C1-6烷基”、“C1-C3烷基”和“C1-C4烷基”。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。
在本文中使用时，术语“n元环烷基或脂族环”是指具有含n个碳原子的环状烷基。
在本文中使用时，术语“n元杂环烷基或杂脂环”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的环烷基，所述杂原子选自O、S及N。例如，3-7元杂环烷基包括但不限于氧杂环丁烷、硫杂环丁烷、氮杂环丁烷、四氢呋喃、四氢噻吩、吡咯烷、四氢吡喃、四氢噻喃、哌啶、吗啉、哌嗪、氧杂环庚烷、硫杂环庚烷、氮杂环庚烷。杂环烷基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“n元芳基或芳族环”是指具有含n个碳原子的芳环的芳基，优选为苯基。
在本文中使用时，术语“n元杂芳基或杂芳环”是指具有m个形成芳环的碳原子和(n-m)个形成芳环的杂原子的杂芳基，所述杂原子选自O、S及N。例如，5-7元杂芳基包括但不限于吡嗪、吡唑、吡咯、呋喃、噻吩、噻唑、吡啶。杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“卤代烷基”是指具有一或多个卤素取代基的烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。例如，术语“C1-6卤代烷基”是指具有一或多个卤素取代基的C1-6烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。另举一例，术语“C1-4卤代烷基”是指具有一或多个卤素取代基的C1-4烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；术语“C1-3卤代烷基”是指具有一或多个卤素取代基的C1-3烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；且术语“C1-2卤代烷基”是指具有一或多个卤素取代基的C1-2烷基基团(即，甲基或乙基)(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。再另举一例，术语“C1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括：CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl等。
本文中，与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举，而范围仅是作为一种简化的表示法。例如：“1-4个取代基”表示1、2、3或4个取代基；“3-8个环原子”表示3个、4个、5个、6个、7个或8个环原子。因此，与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围，且每一个子范围也视为被本文公开。
本申请化合物可按有机合成领域技术人员已知的多种方式制备。本领域技术人员可以参照本申请具体实施例的具体化合物的合成路线，对反应原料和反应条件进行适当调整而得到其它化合物的合成方法。
在第二方面，本申请提供了一种药物组合物，其包含式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，以及药学上可接受的载体。
药学上可接受的载体可以是有机或无机惰性载体材料，例如，合适的载体包括水、明胶、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇、凡士林、甘露醇、纤维素、纤维素衍生物、糖精钠、葡萄糖、蔗糖、碳酸镁、盐水、甘油、乙醇等。此外，药物组合物还可含有其他药物添加剂，例如调味剂、防腐剂、稳定剂、乳化剂、缓冲剂、稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂等。
本申请的药物组合物的剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、丸剂、栓剂、膜剂、贴片、气雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。本申请的药物组合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
在一些实施方式中，所述药物组合物的剂型选自片剂、颗粒剂、散剂、糖浆剂、吸入剂和注射剂。
用于口服的固体剂型可以包括胶囊、片剂、丸剂、粉末和颗粒。在这种固体剂型中，将活性化合物与至少一种惰性赋型剂(或载体)(例如，柠檬酸钠或磷酸二钙)混合，其中还可以包括：(a)填料或混合剂(例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸)；(b)粘结剂(例如，羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶)；(c)保湿剂(例如，丙三醇)；(d)崩解剂(例如，琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠)；(e)溶液阻滞剂(例如，石蜡)；(f)吸收促进剂(例如，季铵化合物)；(g)润湿剂(例如，十六烷醇和单硬脂酸丙三醇酯)；(h)吸附剂(例如，高岭土和斑脱土)和(i)润滑剂(例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
适于肠胃外施用的制剂例如注射剂可以包括适于注射的水性和非水性等渗无菌溶液，以及水性和非水性无菌混悬剂。本文提供的肠胃外制剂任选地包含在单位剂量或多剂量密封容器(例如安瓿)中，并且可以储存在仅需要于即将使用前添加无菌液体载体(例如注射用水)的冷冻干燥(冻干)条件下。用于重构药物组合物(例如在注射前)的合适稀释剂的实例包括抑菌性注射用水、5％葡萄糖水溶液、磷酸盐缓冲盐水、林格氏(Ringer's)溶液、盐水、无菌水、去离子水及其组合。
喷雾剂可含有赋形剂，如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉剂，或这些物质的混合物。喷雾剂可另外含有常规推进剂，例如氯氟烃和挥发性未经取代的烃，例如丁烷和丙烷。吸入剂可包含赋形剂如乳糖，或是包含如聚环氧乙烷-9-月桂基醚，甘氨胆酸盐和脱氧胆酸盐的含水溶液，或是油性溶液以鼻滴剂或喷雾，或凝胶形式施用。
本申请的化合物在其药物组合物中的含量可以根据实际需要(例如剂型、施用方式、施用对象等)进行调整，例如为0.1-95重量％，例如1-95重量％，5-90重量％，10-80重量％等。
具体地，本申请的药物组合物中可以特别地包含0.01-10g(例如0.05g、0.1g、0.5g、1g或5g等)的本申请的化合物。
在第三方面，本申请提供了式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物在制备用于在有此需要的受试者中治疗或预防冠状病毒感染或由冠状病毒引起的疾病或症状的药物中的用途。式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物可以用于在有此需要的受试者中治疗或预防冠状病毒感染或由冠状病毒引起的疾病或症状。
本申请使用的术语“受试者”是指可潜在地从用式(I)化合物进行的治疗中受益的任何人类或非人类生物体。示例性受试者包括任何年龄的人类或哺乳动物。优选地，所述受试者是人。
本文使用的术语“治疗”包括在哺乳动物、尤其人类中治疗疾病或症状且包括：(a)抑制感染、疾病或症状，即遏制或延缓感染、疾病或症状的发展；(b)缓解感染、疾病或症状，即引起疾病或症状的消退，和/或(c)感染、疾病或症状的治愈。
本文使用的术语“预防”包括在哺乳动物、尤其人类中进行预防性疗法以旨在降低感染、疾病或症状发生的可能性。可以根据与一般群体相比感染或患有疾病或症状的风险增加为因素来选择接受预防性疗法的患者。“预防”可以包括对尚未呈现感染或临床病况的受试者进行处置，和预防相同或类似感染或临床病况的第二次出现。
本申请的发明人发现，本申请的化合物能够实现对冠状病毒感染的抑制，例如能够作为可逆的共价小分子抑制剂针对新冠病毒的3CL蛋白酶作用(即3CL蛋白酶抑制剂)，从而抑制冠状病毒的病毒复制。因此，本申请的化合物可以用于预防或治疗冠状病毒感染或由冠状病毒引起的疾病或症状。
在一些实施方式中，所述冠状病毒选自严重急性呼吸综合征冠状病毒(SARS-CoV)、新型冠状病毒(SARS-CoV-2)、中东呼吸综合征冠状病毒(MERS-CoV)、冠状病毒OC43(HCoV-OC43)、鼠肝炎冠状病毒(MHV)和与以上任一种冠状病毒的同源性大于85％且具备病毒活性的冠状病毒。在一些实施方式中，所述冠状病毒是新型冠状病毒(SARS-CoV-2)。
在一些实施方式中，由冠状病毒引起的疾病或症状包括由所述病毒引起的呼吸系统感染、急性呼吸综合征(SARS)、肺炎(包括重症肺炎)、肠胃炎(包括急性肠胃炎)、咳嗽、发热、寒战、呕吐、头痛、畏寒、呼吸急促、细胞因子风暴等。
在第四方面，本申请提供了一种治疗或预防冠状病毒感染或由冠状病毒引起的疾病或症状的方法，所述方法包括向有此需要的受试者施用治疗有效量的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物。
在一些实施方式中，本发明化合物可以通过口服、肠胃外、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、经肺、经呼吸道、经阴道、经直肠、腹膜内、病灶内、病灶周围等途径施用。
“治疗有效量”是指本申请化合物当单独或组合给药时有效治疗或预防冠状病毒感染或由冠状病毒引起的疾病或症状的量。
具体施用剂量将取决于施用途径、疾病的严重程度、患者的年龄和体重，以及主治医师在确定最适合特定患者的个体方案和剂量水平时通常考虑的其他因素。例如，本申请的化合物的日剂量可以特别地为0.001-150mg/kg体重(例如0.1mg/kg体重、1mg/kg体重、10mg/kg体重或100mg/kg体重等)。
具体的施用频率可以由相关领域的技术人员确定，例如为1天1次、2天1次、3天1次、4天1次、5天1次、6天1次、1天2次、1天3次等。
本领域技术人员能够理解，在本申请的一个方面中描述的定义和优选项同样适用于其他方面。本领域技术人员能够明了本申请各个方面的实施方式可以以各种方式组合，而不偏离本申请的主题和思想，这些组合也包括在本申请的范围内。
具体实施方式
本申请式(I)化合物可以用有机合成领域的技术人员所熟悉的多种方法合成。以下具体实施例中给出了一些示例性的式(I)化合物的合成方法，这些方法是合成化学领域所公知的。显然，参照本专利中的示例性方案，本领域技术人员可以适当调整反应物、反应条件和保护基团而容易地设计其他式(I)化合物的合成路线。
下面进一步结合实施例来阐述本发明；但这些实施例并不限制本发明的范围。除非另有声明，各实施例中所用的所有反应物均从商业途径获得；合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
Int A的合成路线
1)Cpd.2的合成操作步骤
1.将Cpd.1(10g,34.9mmol,1eq)溶解到MeOH(200mL)。
2.将NH3.H2O(200mL,30％纯度)添加到上述混合溶液中。
3.然后在25℃条件下搅拌12小时。
4.LC-MS测试显示Cpd.1已经消耗完，同时目标产物MS出现。
5.直接旋干混合溶剂。
6.硅胶柱纯化(SiO2,DCM:MeOH＝10/1至5/1)。
7.纯化旋干后得到黄色固体Cpd.2(8.2g,30.2mmol,86.5％收率)。
2、Cpd.3的合成操作步骤
1.在0℃条件下，将TFAA(19.0g,90.7mmol,12.6mL,3eq)加入到Cpd.2(8.2g,30.2mmol,1eq)和TEA(18.3g,181mmol,25.2mL,6eq)的DCM(164mL)溶液中。
2.继续在0℃条件下搅拌2小时。
3.LC-MS显示目标产物MS出现。
4.将冰水(500mL)逐滴加入到反应中。
5.0℃下，用2M柠檬酸将pH调到5～6。
6.用EtOAc(100mL*3)萃取。
7.MgSO4干燥后旋干的到粗品固体。
8.prep-HPLC纯化。
9.得到白色固体Cpd.3(4.5g,17.8mmol,58.8％收率)。
3、Int A的合成操作步骤
1.将Cpd.3(4.3g,17.0mmol,1eq)加入HCOOH(90mL)中。
2.40℃下搅拌1小时。
3.TLC显示Cpd.3消耗完，出现一个极性较大的点。
4.旋干反应液。
5.在0～5℃条件下，用饱和的NaHCO3调节pH＝8，并继续搅拌30分钟。
6.旋干反应也得到粗品。
7.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
8.得到黄色固体Int A(1.85g,11.3mmol,66.9％收率)。
实施例1：化合物GDI-002624-001的制备((S,E)-4-((S)-2-(3-((叔丁氧羰基)氨基)-2-氧吡啶-1(2H)-基)-4-甲基五酰胺)-5-((S)-2-氧吡咯烷-3-基)戊-2-烯酸乙酯)
1)Cpd.5的合成操作步骤
1.将Cpd.4(2g,7.2mmol,1eq)和Cpd.4B(1.5g,7.2mmol,1eq)溶解到THF(20mL)。
2.在0℃将NaH(65％,1eq)添加到上述混合溶液中。
3.然后在25℃条件下搅拌4小时。
4.LC-MS测试显示Cpd.4已经消耗完，同时目标产物MS出现。
5.饱和氯化铵溶液(10mL)淬灭上述反应液，乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相。
6.硅胶柱纯化(SiO2,EA:PE＝5/1至1/1)。
7.纯化旋干后得到无色液体Cpd.5(2.1g,6.2mmol,86.3％收率)。
2)Cpd.6的合成操作步骤
1.将Cpd.5(2.1g,6.2mmol,1eq)溶解到MeOH(20mL)/H2O(6mL)。
2.在0℃将LiOH·H2O(0.26g,6.2mmol,1eq)添加到上述混合溶液中。
3.然后在0℃条件下搅拌3小时。
4.LC-MS测试显示Cpd.4已经消耗完，同时目标产物MS出现。
5.1N HCl调节上述反应液至pH＝2-3,乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相，得到白色固体Cpd.6(1.98g,6.1mmol,99％收率)。
3)Cpd.7的合成操作步骤
1.将Cpd.1(2g,7.0mmol,1eq)加入HCl的二恶烷溶液(4M,10mL)中。
2.0℃下搅拌2小时。
3.TLC显示Cpd.1消耗完，出现一个极性较大的点。
4.旋干反应液。
5.在0～5℃条件下，用饱和的NaHCO3调节pH＝8，并继续搅拌30分钟。
6.旋干反应也得到粗品。
7.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
8.得到黄色固体Cpd.7(1.3g,6.9mmol,100％收率)。
4)Cpd.8的合成操作步骤
1.0℃下，先后将DIEA(774mg,6mmol,4eq),HOBt(303.75mg,2.25mmol,
1.5eq)和BOP(994.5mg,2.25mmol,1.5eq)加入到溶有Cpd.6(500.00mg,1.5mmol,1eq)和Cpd.7(287mg,1.5mmol,1eq)的DMF(15mL)溶液中。
2.0℃下继续搅拌3小时。
3.LC-MS显示目标产物出现。
4.H2O(20mL)淬灭反应液，乙酸乙酯(20mL x 3)萃取反应液，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相。
5.硅胶柱分离(SiO2,DCM:MeOH＝10/1在5/1)。
6.得到白色固体Cpd.8(553.5mg,1.12mmol,75％收率)。
5)Cpd.9的合成操作步骤
1.0℃条件下，先后将Cpd.8(500mg,1mmol,1eq)溶解到的MeOH(15mL)溶液中。
2.0℃下加入NaBH4(378mg，10mmol,10eq),继续搅拌5小时。
3.LC-MS显示目标产物出现。
4.H2O(20mL)淬灭反应液，乙酸乙酯(20mL x 3)萃取反应液，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相。
5.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
6.得到白色固体Cpd.9(301.6mg,0.65mmol,65％收率)。
6)Int B的合成操作步骤
1.0℃条件下，先后将Cpd.9(100mg,0.215mmol,1eq)溶解到的DCM(5mL)溶液中。
2.10℃下加入DMP(373mg，0.645mmol,3eq),继续搅拌5小时。
3.LC-MS显示目标产物出现。
4.饱和五水硫代硫酸钠溶液(10mL)淬灭反应液，DCM(10mL x 3)萃取反应液，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相。
5.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
6.得到棕色液体Int B(60mg,0.129mmol,60％收率)。
7)GDI-002624-001的合成操作步骤
1.0℃条件下，先后将Int B(60mg,0.129mmol,1eq)和Cpd.10溶解到的THF(5mL)溶液中。
2.65℃下继续搅拌2小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，旋干滤液。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到45mg的消旋体。
7.进一步利用SFC白色固体GDI-002624-001(20mg,37.6umol,29％收率)。
1H NMR(400MHz,氯仿-d)δ7.88(dd,J＝12.0,7.1Hz,2H),7.55(s,1H),7.10(dd,J＝7.1,1.7Hz,1H),6.75(dd,J＝15.7,5.8Hz,1H),6.19(t,J＝7.2Hz,1H),5.89(d,J＝1.5Hz,1H),5.87–5.81(m,1H),5.62(dd,J＝9.4,6.3Hz,1H),4.42(dd,J＝11.7,5.8Hz,1H),4.12(q,J＝7.1Hz,2H),3.28–3.10(m,2H),2.13(q,J＝7.1Hz,2H),2.00–1.91(m,1H),1.91–1.75(m,2H),1.69–1.58(m,1H),1.43(s,9H),1.37–1.31(m,1H),1.21(q,J＝6.7Hz,4H),0.87(d,J＝6.6Hz,6H).
实施例2：化合物GDI-002645-002的制备(叔丁基(1-((S)-4-甲基-1-氧代-1-((S)-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)氨基)戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
1)Cpd.10的合成操作步骤
1.将Cpd.8(200mg,0.406mmol,1eq)溶解到MeOH(6mL)/H2O(2mL)。
2.在0℃将LiOH·H2O(16mg,0.406mmol,1eq)添加到上述混合溶液中。
3.然后在0℃条件下搅拌2小时。
4.LC-MS测试显示Cpd.8已经消耗完，同时目标产物MS出现。
5.1N HCl调节上述反应液至pH＝2-3,乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相，得到白色固体Cpd.10(190mg,0.397mmol,98％收率)。
2)Cpd.11的合成操作步骤
1.0℃下，先后将Cpd.9(198mg,0.397mmol,1eq)和CDI(83mg,0.516mmol,
1.3eq)溶解到的DMF(5mL)溶液中。
2.0℃下加入NH3(aq,25％,1.5eq),继续搅拌4.5小时。
3.LC-MS显示目标产物出现。
4.然后旋干有机相。
5.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
6.得到黄色固体Cpd.11(152mg,0.318mmol,80％收率)。
3)GDI-002645-002的合成操作步骤
1.0℃条件下，先后将Cpd.11(100mg,0.209mmol,1eq),TEA(6eq)和TFAA(3eq)溶解到的DCM(6mL)溶液中。
2.25℃下继续搅拌4.5小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，旋干滤液。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到60mg的消旋体。
7.进一步利用SFC白色固体GDI-002645-002(30mg,65.3umol,31.2％收率)。
1H NMR(400MHz,CDCl3)δ8.68(d,J＝5.6Hz,1H),7.98(d,J＝6.4Hz,1H),7.57(s,1H),7.23(d,J＝6.8Hz,1H),6.39(s,1H),6.31(t,J＝7.6Hz,1H),5.68(t,J＝5.2Hz,1H),4.73–4.68(m,1H),3.39–3.30(m,2H),2.45–2.39(m,1H),2.32–2.29(m,2H),1.99–1.91(m,2H),1.80–1.75(m,1H),1.51(s,9H),1.26(s,1H),0.94(d,J＝6.8Hz,6H).
实施例3：化合物GDI-002650-001的制备(叔丁基(1-((S)-1-((S)-1-氰基-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)氨基)-4-甲基-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
1)Cpd.12的合成操作步骤
1.20℃下，先后将Int B(200mg,0.433mmol,1eq)和KCN(56mg,0.866mmol,2.0eq)溶解到的DCM(10mL)溶液中。
2.0℃下加入NaHSO3(1.4eq),继续搅拌15.5小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，然后旋干有机相。
5.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
6.得到黄色固体Cpd.12(150mg,0.307mmol,70.8％收率)。
2)Cpd.13的合成操作步骤
1.0℃条件下，先后将Cpd.12(150mg,0.307mmol,1eq)和DMAP(300mg,2.456mmol,8.0eq)溶解到的DCM(10mL)溶液中。
2.0℃下加入硫代氯甲酸苯酯(212mg,1.228mmol,4eq),继续在20℃搅拌2小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，然后旋干有机相。
5.硅胶柱分离(SiO2,DCM:MeOH＝10/1至5/1)。
6.得到黄色固体Cpd.13(175mg,0.279mmol,91％收率)。
3)GDI-002650-001的合成操作步骤
1.室温条件下，先后将Cpd.13(100mg,0.16mmol,1eq),Bu3SnH(3eq)和AIBN(0.1eq)溶解到的Tol(6mL)溶液中。
2.100℃下继续搅拌4.5小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，旋干滤液。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到50mg的消旋体。
7.进一步利用SFC白色固体GDI-002650-001(28mg,59.1umol,36.9％收率)。
1H NMR(400MHz,氯仿-d)δ8.59(s,1H),7.90(s,1H),7.61(s,1H),7.13(s,1H),6.24(s,1H),5.87(s,1H),5.61(s,1H),3.98(s,1H),3.29(s,2H),2.72(d,J＝
5.6Hz,2H),2.29(s,2H),2.10(s,1H),1.97(s,1H),1.87(s,1H),1.74(s,2H),1.48(s,10H),0.93(d,J＝6.4Hz,6H).
实施例4：化合物GDI-002706-001的制备(叔丁基(1-((2S)-4-甲基-1-((1S)-1-(环氧乙烷-2-基)-2-((S)-2-氧吡咯烷-3-基)乙基)氨基)-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
1.20℃条件下，先后将Int B(100mg,0.216mmol,1eq)和t-BuOK(31.5mg,0.281mmol,1.3eq)溶解到的DMSO(6mL)溶液中。
2.20℃下加入(CH3)3SOI(1.3eq),继续搅拌2小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，旋干滤液。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到65mg的消旋体。
7.进一步利用SFC白色固体GDI-002706-001(30mg,63umol,29.1％收率)。
1H NMR(400MHz,氯仿-d)δ7.97(t,J＝9.8Hz,1H),7.67(d,J＝2.5Hz,1H),6.98(dt,J＝7.1,1.9Hz,1H),6.26(dt,J＝12.8,7.2Hz,1H),5.88(dd,J＝10.1,5.5Hz,1H),5.64(d,J＝14.6Hz,1H),4.67–4.55(m,1H),4.34–4.05(m,2H),3.78(dd,J＝5.5,3.6Hz,1H),3.74–3.64(m,1H),3.35(dd,J＝8.1,5.6Hz,2H),2.80–2.71(m,1H),2.42(ddd,J＝12.4,6.4,3.2Hz,2H),2.13–1.80(m,3H),1.58–1.52(m,1H),1.49(d,J＝1.2Hz,9H),1.45–1.35(m,1H),1.00–0.86(m,6H).
实施例5：化合物GDI-002738-001的制备((S)-4-甲基-N-((S)-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-2-(2-氧吡啶-1(2H)-基)戊二胺)
以与实施例1类似的方式得到化合物GDI-002738-001。
1H NMR(400MHz,氯仿-d)δ9.44(s,1H),8.73(d,J＝6.0Hz,1H),7.70(dd,J＝7.0,2.0Hz,1H),7.28(ddd,J＝8.9,6.6,2.1Hz,1H),7.19(d,J＝4.5Hz,1H),6.48(d,J＝9.1Hz,1H),6.21(td,J＝6.8,1.4Hz,1H),5.91(dd,J＝9.4,6.3Hz,1H),4.16(ddd,J＝10.5,6.1,3.7Hz,1H),3.35–3.17(m,2H),2.32–2.07(m,3H),1.99–1.89(m,1H),1.81(td,J＝8.9,4.7Hz,1H),1.74–1.60(m,2H),1.43(dt,J＝14.1,6.6Hz,1H),0.89(d,J＝6.6Hz,6H).
实施例6：化合物GDI-002741-001的制备((2S)-2-((S)-2-(3-((叔丁氧羰基)氨基)-2-氧吡啶-1(2H)-基)-4-甲基五酰胺)-1-羟基-3-((S)-2-氧吡咯烷-3-基)丙烷-1-磺酸钠)
1.20℃条件下，先后将Int B(100mg,0.216mmol,1eq)和NaHSO3(1eq)溶解到的EtOAc(4mL),EtOH(2ml)和H2O(1mL)溶液中。
2.60℃下继续搅拌16小时。
3.LC-MS显示目标产物出现。
4.过滤反应液，旋干滤液。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到50mg的消旋体。
7.进一步利用SFC白色固体GDI-002741-001(20mg,35.3umol,16.3％收率)。
1H NMR(400MHz,DMSO)δ9.89(s,1H),8.18–7.70(m,1H),7.82–7.76(m,2H),7.72(d,J＝9.0Hz,1H),7.46(d,J＝3.3Hz,1H),7.42–7.31(m,1H),6.30(td,J＝7.2,2.4Hz,1H),5.59(ddd,J＝28.7,10.5,5.4Hz,1H),5.41(dd,J＝9.2,5.9Hz,1H),4.25–4.05(m,1H),4.01–3.82(m,1H),3.16–2.98(m,2H),2.05–1.78(m,5H),1.55(d,J＝11.8Hz,1H),1.47(s,9H),1.32–1.18(m,2H),0.85(td,J＝6.7,2.0Hz,6H).
实施例7：化合物GDI-002821-001的制备(叔丁基(1-((S)-4-甲基-1-氧代-1-((S)-1-氧代-3-(吡啶-2-基)丙烷-2-基)氨基)戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
以与实施例1类似的方式得到化合物GDI-002821-001。
1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.28(d,J＝4.7Hz,1H),7.84(d,J＝7.4Hz,1H),7.51(d,J＝7.7Hz,1H),7.47–7.30(m,2H),6.99(dd,J＝7.4,5.0Hz,1H),6.91(dd,J＝7.1,1.7Hz,1H),6.83(d,J＝7.8Hz,1H),6.14(t,J＝7.2Hz,1H),5.54(dd,J＝9.2,6.5Hz,1H),4.66(dt,J＝7.4,5.1Hz,1H),3.30(dd,J＝15.4,5.1Hz,1H),3.16(dd,J＝15.5,5.1Hz,1H),1.97–1.88(m,1H),1.83–1.73(m,1H),1.46(s,9H),1.43–1.28(m,1H),0.85(dd,J＝7.9,6.6Hz,6H).
实施例8：化合物GDI-002823-001的制备(叔丁基(1-((S)-1-((S)-1-氰基-2-(吡啶-2-基)乙基)氨基)-4-甲基-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
以与实施例2类似的方式得到化合物GDI-002823-001。
1H NMR(400MHz,CDCl3)δ8.38–8.32(m,1H),8.19(d,J＝7.8Hz,1H),7.89(d,J＝7.4Hz,1H),7.55–7.44(m,2H),7.10–7.02(m,2H),6.90(dd,J＝7.1,1.7Hz,1H),6.18(t,J＝7.2Hz,1H),5.47(dd,J＝9.3,6.4Hz,1H),5.21–5.15(m,1H),3.18–3.05(m,2H),1.99–1.89(m,1H),1.85–1.76(m,1H),1.45(s,9H),1.40–1.28(m,1H),0.86(dd,J＝6.6,4.5Hz,6H).
实施例9：化合物GDI-002890-001的制备(叔丁基(1-((S)-4-甲基-1-氧代-1-((S)-1-氧代-3-(1H-吡唑-1-基)丙烷-2-基)氨基)戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
以与实施例1类似的方式得到化合物GDI-002890-001。
1H NMR(400MHz,CDCl3)δ9.60–9.48(m,1H),7.99–7.88(m,1H),7.55–7.45(m,1H),7.40–7.27(m,1H),7.14–6.88(m,2H),6.24(t,J＝7.3Hz,1H),6.10–5.94(m,1H),5.59–5.40(m,1H),4.65–4.09(m,4H),1.96–1.87(m,1H),1.85–1.77(m,1H),1.51–1.31(m,10H),0.85(td,J＝7.1,2.6Hz,6H).
实施例10：化合物GDI-003020-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(2-氧吡咯烷-1(2H)-基)五酰胺)
1.0℃条件下，先后将DIEA(123mg,0.956mmol,4eq),HOBt(48mg,0.359mmol,1.5eq)和BOP(159mg,0.359mmol,1.5eq)加入到溶有Cpd.14(50.00mg,0.239mmol,1eq)和Int A(47.6mg,0.239mmol,1eq)的DMF(5mL)溶液中。
2.0℃下继续搅拌2小时。
3.LC-MS显示目标产物出现。
4.H2O(20mL)淬灭反应液，乙酸乙酯(20mL x 3)萃取反应液，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到55mg的消旋体。
7.进一步利用SFC白色固体GDI-003020-001(25mg,72.7umol,30.5％收率)。
1H NMR(400MHz,CDCl3)δ8.70(d,J＝6.6Hz,1H),7.59(dd,J＝6.9,2.0Hz,1H),7.29(ddd,J＝8.8,6.5,2.0Hz,1H),6.64(d,J＝10.5Hz,1H),6.48(d,J＝9.1Hz,1H),6.24–6.19(m,1H),5.74–5.63(m,1H),4.68–4.62(m,1H),3.37–3.19(m,2H),2.43–2.33(m,1H),2.31–2.19(m,1H),1.92–1.82(m,2H),1.81–1.67(m,2H),1.46–1.33(m,2H),0.91–0.84(m,6H).
实施例11：化合物GDI-003457-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(3-甲酰胺-2-氧吡咯烷-1(2H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003457-002。
1H NMR(400MHz,DMSO)δ9.84(d,J＝1.9Hz,1H),9.19(d,J＝7.7Hz,1H),8.35(d,J＝1.8Hz,1H),8.24(dd,J＝7.3,1.7Hz,1H),7.72(s,1H),7.45(dd,J＝7.1,1.8Hz,1H),6.32(t,J＝7.2Hz,1H),5.57(dd,J＝11.1,5.1Hz,1H),4.94(dt,J＝9.0,7.2Hz,1H),3.18–3.06(m,2H),2.30–2.20(m,1H),2.17–1.94(m,3H),1.85–1.73(m,2H),1.72–1.61(m,1H),1.29(d,J＝16.1Hz,1H),0.88(t,J＝6.6Hz,6H).
实施例12：化合物GDI-003489-002的制备((S)-2-(3-氨基-2-氧吡啶-1(2H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003489-002。
1H NMR(400MHz,DMSO)δ9.15(d,J＝7.8Hz,1H),7.76(s,1H),6.96(dd,J＝7.1,1.7Hz,1H),6.49(dd,J＝7.1,1.6Hz,1H),6.14(t,J＝7.0Hz,1H),5.61(dd,J＝10.6,5.4Hz,1H),5.14(s,2H),4.97(dt,J＝9.0,7.2Hz,1H),3.24–3.11(m,2H),2.35–2.25(m,1H),2.23–2.09(m,2H),2.00–1.91(m,1H),1.88–1.78(m,2H),1.77–1.66(m,1H),1.39–1.27(m,1H),0.93(t,J＝6.0Hz,6H).
实施例13：化合物GDI-003517-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(3-(甲氨基)-2-氧吡咯烷-1(2H)-基)戊二胺)
以与实施例10类似的方式得到化合物GDI-003517-001。
1H NMR(400MHz,DMSO)δ9.08(d,J＝7.8Hz,1H),7.70(s,1H),6.88(d,J＝7.0Hz,1H),6.17(t,J＝7.0Hz,1H),6.09(d,J＝7.1Hz,1H),5.54(dq,J＝10.9,5.2Hz,2H),4.91(q,J＝7.9Hz,1H),3.19–3.02(m,2H),2.67(d,J＝5.1Hz,3H),2.28–2.18(m,1H),2.15–2.02(m,2H),1.96–1.87(m,1H),1.84–1.71(m,2H),1.70–1.60(m,1H),1.32–1.20(m,1H),0.86(t,J＝6.2Hz,6H).
实施例14：化合物GDI-003551-002的制备((S)-2-(3-乙酰氨基-2-氧吡啶-1(2H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡啶-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003551-002。
1H NMR(400MHz,DMSO)δ9.25(s,1H),9.16(d,J＝7.7Hz,1H),8.20(dd,J＝7.4,1.8Hz,1H),7.72(s,1H),7.41(dd,J＝7.1,1.8Hz,1H),6.30(t,J＝7.2Hz,1H),5.57(dd,J＝11.2,4.9Hz,1H),4.94(dt,J＝9.1,7.3Hz,1H),3.20–3.04(m,2H),2.30–2.19(m,1H),2.18–2.13(m,1H),2.12(s,3H),2.10–2.04(m,1H),2.04–1.98(m,1H),1.85–1.74(m,2H),1.73–1.63(m,1H),1.32–1.20(m,1H),0.88(t,6.0Hz,6H).
实施例15：化合物GDI-003552-002的制备(叔丁基(1-((S)-1-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)氨基)-4-氟-4-甲基-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
以与实施例10类似的方式得到化合物GDI-003552-002。
1H NMR(400MHz,DMSO)δ9.08(d,J＝7.7Hz,1H),7.79(d,J＝7.3Hz,1H),7.73(d,J＝19.4Hz,2H),7.42(d,J＝7.0Hz,1H),6.30(t,J＝7.2Hz,1H),5.67(dd,J＝8.9,4.9Hz,1H),4.92(q,J＝7.9Hz,1H),3.10(dq,J＝17.2,9.3Hz,2H),2.47–2.30(m,2H),2.21(dt,J＝15.2,8.8Hz,1H),2.12–2.01(m,2H),1.76(dt,J＝13.2,8.0Hz,1H),1.70–1.58(m,1H),1.46(s,9H),1.29(dd,J＝21.5,13.8Hz,6H).
实施例16：化合物GDI-003555-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(1-氧异喹啉-2(1H)-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-003555-002。
1H NMR(400MHz,DMSO)δ9.13(d,J＝7.7Hz,1H),8.22(d,J＝8.0Hz,1H),7.69(dt,J＝13.7,7.6Hz,3H),7.55–7.43(m,2H),6.67(d,J＝7.5Hz,1H),5.61(dd,J＝11.0,5.1Hz,1H),4.95(q,J＝8.0Hz,1H),3.09(dt,J＝21.3,8.7Hz,2H),2.24(td,J＝9.3,6.0Hz,1H),2.07(dddd,J＝34.3,14.9,10.4,5.6Hz,3H),1.93–1.75(m,2H),1.67(dt,J＝11.8,9.0Hz,1H),1.30(q,J＝7.0Hz,1H),0.88(dt,J＝6.7,1.8Hz,6H).
实施例17：化合物GDI-003616-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(2-氧哌啶-1-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-003616-002。
1H NMR(400MHz,DMSO)δ8.29(d,J＝6.8Hz,1H),7.05(s,1H),5.25(dd,J＝9.6,6.0Hz,1H),4.91(q,8.0Hz,1H),3.35–3.32(m,2H),3.26–3.22(m,1H),2.51–2.31(m,4H),2.20–2.0(m,2H),1.83–1.74(m,7H),1.69–1.46(m,1H),0.88(dt,J＝6.7,1.8Hz,6H).
实施例18：化合物GDI-003618-001的制备(叔丁基(1-((S)-1-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)氨基)-3-环己基-1-氧丙烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
以与实施例10类似的方式得到化合物GDI-003618-001。
1H NMR(400MHz,DMSO)δ9.16(d,J＝7.6Hz,1H),7.80(d,J＝7.3Hz,1H),7.77(s,1H),7.72(s,1H),7.39(d,J＝7.1Hz,1H),6.32(t,J＝7.2Hz,1H),5.55(dd,J＝10.9,5.2Hz,1H),4.92(q,J＝7.9Hz,1H),3.11(dq,J＝17.1,9.1Hz,2H),2.30–2.20(m,1H),2.15–2.05(m,2H),2.02–1.91(m,1H),1.88–1.75(m,2H),1.74–1.66(m,2H),1.65–1.58(m,3H),1.57–1.52(m,1H),1.46(s,9H),1.19–1.03(m,3H),0.99–0.91(m,3H).
实施例19：化合物GDI-003643-002的制备(叔丁基(1-((2S)-1-((5-溴吡啶-3-基)(氰基)甲基)氨基)-4-甲基-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
1.0℃条件下，先后将DIEA(79.5mg,0.616mmol,4eq),HOBt(31.2mg,0.231mmol,1.5eq)和BOP(97.5mg,0.231mmol,1.5eq)加入到溶有Cpd.6(50.00mg,0.154mmol,1eq)和Cpd.15(32mg,0.154mmol,1eq)的DMF(3mL)溶液中。
2.0℃下继续搅拌2小时。
3.LC-MS显示目标产物出现。
4.H2O(20mL)淬灭反应液，乙酸乙酯(20mL x 3)萃取反应液，合并有机相，饱和食盐水洗涤，分离有机相，无水硫酸钠干燥有机相，然后旋干有机相。
5.利用prep-HPLC(中性条件)直接纯化。
6.得到58mg的消旋体。
7.进一步利用SFC白色固体GDI-003643-002(20mg,38.7umol,25.1％收率)。
1H NMR(400MHz,DMSO)δ9.69(dd,J＝34.8,7.3Hz,1H),8.78(s,1H),8.64(d,J＝3.5Hz,1H),8.10(s,1H),7.83(d,J＝6.0Hz,1H),7.76(d,J＝13.8Hz,1H),7.40(t,J＝8.4Hz,1H),6.40–6.24(m,2H),5.65–5.47(m,1H),2.02(q,J＝13.3Hz,1H),1.80(dd,J＝27.0,13.5Hz,1H),1.46(s,9H),1.25(s,1H),0.85(dt,J＝12.5,7.1Hz,6H).
实施例20：化合物GDI-003665-002的制备((S)-2-(7-溴-1-氧异喹啉-2(1H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003665-002。
1H NMR(400MHz,DMSO)δ9.15(d,J＝7.7Hz,1H),8.31(s,1H),7.89(dd,J＝8.4,2.5Hz,1H),7.75–7.62(m,2H),7.55(d,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,1H),5.59(dd,J＝11.1,5.0Hz,1H),4.95(q,J＝7.9Hz,1H),3.10(dt,J＝18.0,8.9Hz,2H),2.34–2.22(m,1H),2.18–1.96(m,3H),1.81(ddt,J＝22.3,14.9,6.8Hz,2H),1.67(t,J＝10.4Hz,1H),1.28(d,J＝9.5Hz,1H),0.96–0.79(m,6H).
实施例21：化合物GDI-003666-002的制备((S)-2-(6-溴-1-氧异喹啉-2(1H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003666-002。
1H NMR(400MHz,DMSO)δ9.14(d,J＝7.7Hz,1H),8.12(d,J＝8.6Hz,1H),7.97(s,1H),7.74–7.64(m,2H),7.56(d,J＝7.6Hz,1H),6.66(d,J＝7.6Hz,1H),5.58(dd,J＝11.2,4.9Hz,1H),4.95(q,J＝7.9Hz,1H),3.09(dq,J＝17.4,9.2Hz,2H),2.25(q,J＝8.4Hz,1H),2.16–1.97(m,3H),1.89–1.75(m,2H),1.73–1.60(m,1H),1.36–1.20(m,1H),0.88(t,J＝5.5Hz,6H).
实施例22：化合物GDI-003683-002的制备((S)-2-(5-溴-1-氧异喹啉-2(1H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003683-002。
1H NMR(400MHz,DMSO)δ9.15(d,J＝7.7Hz,1H),8.26(d,J＝8.0Hz,1H),8.06(d,J＝7.7Hz,1H),7.74–7.62(m,2H),7.44(t,J＝7.9Hz,1H),6.78(d,J＝7.7Hz,1H),5.57(dd,J＝11.3,5.0Hz,1H),3.10(dt,J＝18.1,9.0Hz,2H),2.25(q,J＝8.4Hz,1H),2.17–2.00(m,3H),1.83(ddt,J＝29.5,13.7,6.0Hz,2H),1.68(q,J＝10.0Hz,1H),1.30(q,J＝7.7Hz,1H),0.88(t,J＝5.3Hz,6H).
实施例23：化合物GDI-003685-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(6-甲氧基-1-氧异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-003685-002。
1H NMR(400MHz,DMSO)δ9.12(d,J＝7.7Hz,1H),8.12(d,J＝8.9Hz,1H),7.69(s,1H),7.44(d,J＝7.5Hz,1H),7.13(d,J＝2.4Hz,1H),7.07(dd,J＝9.0,2.3Hz,1H),6.59(d,J＝7.5Hz,1H),5.59(dd,J＝11.0,5.1Hz,1H),4.94(q,J＝8.0Hz,1H),3.87(s,3H),3.09(dt,J＝22.2,8.7Hz,2H),2.35–2.19(m,1H),2.17–2.07(m,2H),2.03–1.93(m,1H),1.80(td,J＝13.6,5.8Hz,2H),1.67(q,J＝10.0Hz,1H),1.32(d,J＝14.5Hz,1H),0.88(dd,J＝6.8,3.7Hz,6H).
实施例24：化合物GDI-003702-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(3-(3-甲基脲基)-2-氧吡咯烷-1(2H)-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-003702-002。
1H NMR(400MHz,DMSO)δ9.12(d,J＝7.0Hz,1H),8.26(s,1H),8.00(d,J＝7.3Hz,1H),7.71(s,1H),7.22(d,J＝7.0Hz,1H),6.95(d,J＝5.0Hz,1H),6.25(t,J＝7.2Hz,1H),5.54(dd,J＝11.3,4.9Hz,1H),4.93(q,J＝7.3Hz,1H),3.12(dt,J＝14.8,8.9Hz,2H),2.62(d,J＝4.3Hz,3H),2.23(q,J＝8.5Hz,1H),2.10(dq,J＝15.1,8.8Hz,2H),2.04–1.93(m,1H),1.78(dt,J＝14.7,7.3Hz,2H),1.72–1.58(m,1H),1.24(s,1H),0.87(t,J＝5.8Hz,6H).
实施例25：化合物GDI-003703-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(2-氧-3-(2,2,2-三氟乙酰氨基)吡啶-1(2H)-基)五酰胺)以与实施例10类似的方式得到化合物GDI-003703-002。
1H NMR(400MHz,DMSO)δ10.30(s,1H),9.23(t,J＝5.9Hz,1H),7.93(dd,J＝7.2,2.5Hz,1H),7.72(s,1H),7.62(t,J＝8.1Hz,1H),6.37(t,J＝6.8Hz,1H),5.58(dd,J＝11.4,4.6Hz,1H),4.92(t,J＝7.7Hz,1H),3.12(t,J＝9.7Hz,2H),2.38–2.20(m,1H),2.18–1.97(m,3H),1.81(dd,J＝13.6,7.1Hz,2H),1.68(t,J＝10.2Hz,1H),1.35–1.22(m,1H),0.88(t,J＝8.0Hz,6H).
实施例26：化合物GDI-003704-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(7-氧-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-003704-001。
1H NMR(400MHz,DMSO)δ11.97(s,1H),9.05(d,J＝7.9Hz,1H),7.68(s,1H),7.29(d,J＝2.7Hz,1H),7.16(d,J＝7.2Hz,1H),6.54(d,J＝7.3Hz,1H),6.30(d,J＝2.8Hz,1H),5.65(dd,J＝11.0,5.1Hz,1H),4.93(q,J＝8.1Hz,1H),3.15–3.01(m,2H),2.23(q,J＝8.4Hz,1H),2.16–2.01(m,2H),2.00–1.91(m,1H),1.85–1.72(m,2H),1.67(q,J＝10.0Hz,1H),1.34–1.19(m,1H),0.87(dt,J＝5.9,2.5Hz,6H).
实施例27：化合物GDI-003705-001的制备(N-(1-((S)-1-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)氨基)-4-甲基-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)-1-羟基氯丁烷-1-甲酰胺)
以与实施例10类似的方式得到化合物GDI-003705-001。
1H NMR(400MHz,DMSO)δ9.47(s,1H),9.15(d,J＝7.6Hz,1H),8.30(d,J＝7.3Hz,1H),7.71(s,1H),7.43(d,J＝7.1Hz,1H),6.58(s,1H),6.35(t,J＝7.3Hz,1H),5.55(dd,J＝11.3,4.9Hz,1H),4.93(q,J＝7.9Hz,1H),3.13(q,J＝9.8Hz,2H),2.33–2.20(m,1H),2.11(q,J＝10.0Hz,4H),2.05–1.94(m,1H),1.88–1.73(m,4H),1.69(q,J＝9.9Hz,1H),1.36–1.17(m,1H),0.87(t,J＝6.7Hz,6H).
实施例28：化合物GDI-003718-002的制备(叔丁基(1-((2S)-1-((5-溴吡啶-3-基)(氰基)甲基)氨基)-4-甲基-1-氧代戊烷-2-基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酸酯)
以与实施例19类似的方式得到化合物GDI-003718-002。
1H NMR(400MHz,dmso)δ9.60(dd,J＝30.4,7.6Hz,1H),8.73(d,J＝2.2Hz,1H),8.68–8.52(m,1H),8.13–7.92(m,1H),6.87(t,J＝6.6Hz,1H),6.47–6.34(m,1H),6.24(dd,J＝14.3,7.3Hz,1H),6.05(td,J＝7.0,3.9Hz,1H),5.52(ddd,J＝15.5,10.8,5.3Hz,1H),5.07(d,J＝9.7Hz,3H),1.90(q,J＝15.3Hz,1H),1.80–1.63(m,1H),1.27–1.20(m,1H),0.93–0.72(m,6H).
实施例29：化合物GDI-003722-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(1-氧异喹啉-2-基)五酰胺)
以与实施例10类似的方式得到化合物物GDI-003722-002。
1H NMR(400MHz,DMSO)δ9.10(d,J＝7.7Hz,1H),7.71(d,J＝8.6Hz,2H),7.62(d,J＝4.2Hz,2H),7.50(q,J＝5.4Hz,1H),5.04–4.83(m,2H),4.64(d,J＝17.7Hz,1H),4.48(d,J＝17.6Hz,1H),3.09(dt,J＝21.6,8.9Hz,2H),2.26(q,J＝8.0Hz,1H),2.10(dt,J＝10.6,7.2Hz,2H),1.89–1.76(m,2H),1.69(p,J＝9.4Hz,2H),1.34(d,J＝8.8Hz,1H),0.91(t,J＝6.3Hz,6H).
实施例30：化合物GDI-003723-002的制备((2S)-2-(3-乙酰氨基-2-氧吡啶-1(2H)-基)-N-((5-溴吡啶-3-基)(氰基)甲基)-4-甲基五酰胺)
以与实施例19类似的方式得到化合物GDI-003723-002。
1H NMR(400MHz,DMSO)δ9.68(dd,J＝30.6,7.4Hz,1H),9.23(d,J＝15.0Hz,1H),8.78(s,1H),8.64(d,J＝5.6Hz,1H),8.21(t,J＝6.6Hz,1H),8.09(dd,J＝6.5,2.2Hz,1H),7.41(t,J＝8.2Hz,1H),6.30(p,J＝6.5Hz,2H),5.59(td,J＝12.3,4.7Hz,1H),2.18–2.09(m,3H),2.03(t,J＝12.3Hz,1H),1.86–1.71(m,1H),1.30–1.15(m,1H),0.86(dt,J＝9.6,5.8Hz,6H).
实施例31：化合物GDI-003758-002的制备(S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(1-氧-6-(三氟甲基)异喹啉-2(1H)-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-003758-002。
1H NMR(400MHz,DMSO)δ9.16(d,J＝7.4Hz,1H),8.41(d,J＝8.5Hz,1H),8.17(s,1H),7.79(d,J＝8.5Hz,1H),7.70(s,1H),7.65(d,J＝7.6Hz,1H),6.85(d,J＝7.5Hz,1H),5.61(dd,J＝11.2,4.9Hz,1H),4.96(q,J＝7.8Hz,1H),3.10(dt,J＝17.7,8.9Hz,2H),2.26(q,J＝8.4Hz,1H),2.15–2.01(m,3H),1.91–1.75(m,2H),1.68(q,J＝10.0Hz,1H),1.36–1.24(s,1H),0.98–0.80(m,6H).
实施例32：化合物GDI-004067-002的制备((S)-2-(7-氯-1-氧异喹啉-2(1H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004067-002。
1H NMR(400MHz,DMSO)δ9.15(d,J＝7.7Hz,1H),8.16(s,1H),7.82–7.67(m,3H),7.54(d,J＝7.6Hz,1H),6.72(d,J＝7.5Hz,1H),5.59(dd,J＝11.4,5.0Hz,1H),4.95(q,J＝7.9Hz,1H),3.09(dd,J＝19.2,9.2Hz,2H),2.36–2.22(m,1H),2.15–2.02(m,3H),1.82(ddt,J＝29.8,14.6,6.6Hz,2H),1.67(p,J＝9.5Hz,1H),1.31(d,J＝10.5Hz,1H),0.88(t,J＝5.5Hz,6H).
实施例33：化合物GDI-004069-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(5-(甲基磺酰胺基)-6-氧吡咯嘧啶-1(6H)-基)五酰胺)以与实施例10类似的方式得到化合物GDI-004069-001。
1H NMR(400MHz,DMSO)δ9.25(d,J＝8.3Hz,2H),8.43(s,1H),7.91(s,1H),7.72(s,1H),5.36(dd,J＝11.5,4.9Hz,1H),4.97(q,J＝7.9Hz,1H),3.12(t,J＝8.8Hz,2H),3.06(s,3H),2.29(p,J＝9.0Hz,1H),2.20–2.04(m,3H),1.82–1.74(m,2H),1.73–1.63(m,1H),1.31(s,1H),0.88(t,J＝6.7Hz,6H).
实施例34：化合物GDI-004092-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(7-硝基-1-氧异喹啉-2(1H)-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004092-001。
1H NMR(400MHz,DMSO)δ9.23(d,J＝7.7Hz,1H),8.94(d,J＝2.6Hz,1H),8.48(dd,J＝8.9,2.5Hz,1H),7.94(d,J＝9.1Hz,1H),7.80(d,J＝7.6Hz,1H),7.70(s,1H),6.88(d,J＝7.5Hz,1H),5.62(dd,J＝11.1,4.9Hz,1H),4.96(q,J＝7.9Hz,1H),3.11(dt,J＝16.6,8.8Hz,2H),2.27(t,J＝8.3Hz,1H),2.11(dt,J＝14.5,7.1Hz,3H),1.92–1.78(m,2H),1.69(q,J＝9.9Hz,1H),1.32(s,1H),0.93–0.83(m,6H).
实施例35：化合物GDI-004093-002的制备((S)-2-(6-溴-1-氧异喹啉-2-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004093-002。
1H NMR(400MHz,DMSO)δ9.11(d,J＝7.7Hz,1H),7.90–7.79(m,2H),7.71(s,1H),7.61(d,J＝8.0Hz,1H),5.05–4.82(m,2H),4.62(d,J＝18.0Hz,1H),4.47(d,J＝18.0Hz,1H),3.10(dt,J＝17.6,8.8Hz,2H),2.26(q,J＝8.4Hz,1H),2.09(dt,J＝14.9,7.7Hz,2H),1.88–1.77(m,2H),1.75–1.62(m,2H),1.35(t,J＝10.7Hz,1H),0.91(t,J＝6.8Hz,6H).
实施例36：化合物GDI-004094-002的制备((S)-2-(5-溴-1-氧异喹啉-2-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004094-002。
1H NMR(400MHz,DMSO)δ9.11(d,J＝7.7Hz,1H),7.89(s,1H),7.67(dd,J＝20.2,7.7Hz,3H),4.95(q,J＝7.9Hz,1H),4.88(dd,J＝10.6,5.2Hz,1H),4.65(d,J＝18.0Hz,1H),4.49(d,J＝18.0Hz,1H),3.10(dt,J＝20.4,8.7Hz,2H),2.27(p,J＝8.8Hz,1H),2.15–2.02(m,2H),1.87–1.75(m,2H),1.73–1.61(m,2H),1.42–1.27(m,1H),0.91(t,J＝6.7Hz,6H).
实施例37：化合物GDI-004119-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(5-甲氧基-1-氧异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004119-002。
1H NMR(400MHz,DMSO)δ9.13(s,1H),7.79(d,J＝8.1Hz,1H),7.69(s,1H),7.45(t,J＝8.6Hz,2H),7.27(d,J＝8.0Hz,1H),6.78(d,J＝7.6Hz,1H),5.60(dd,J＝11.2,5.1Hz,1H),4.94(s,1H),3.93(s,3H),3.09(dt,J＝21.4,9.0Hz,2H),2.25(p,J＝8.8Hz,1H),2.15–2.05(m,2H),2.04–1.94(m,1H),1.89–1.73(m,2H),1.66(p,J＝9.7Hz,1H),1.37–1.23(m,1H),0.87(d,J＝6.3Hz,6H).
实施例38：化合物GDI-004120-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(5-氟-1-氧异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004120-002。
1H NMR(400MHz,DMSO)δ9.16(d,J＝7.7Hz,1H),8.06(d,J＝8.0Hz,1H),7.69(s,1H),7.60(d,J＝8.4Hz,2H),7.52(q,J＝7.0Hz,1H),6.72(d,J＝7.6Hz,1H),5.60(dd,J＝10.9,5.0Hz,1H),4.95(q,J＝7.9Hz,1H),3.09(dq,J＝17.3,9.3Hz,2H),2.26(t,J＝8.1Hz,1H),2.17–1.96(m,3H),1.90–1.62(m,2H),1.68(q,J＝9.9Hz,1H),1.32(d,J＝10.1Hz,1H),0.88(dt,J＝5.9,2.5Hz,6H).
实施例39：化合物GDI-004121-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(7-氟-1-氧异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004121-002。
1H NMR(400MHz,DMSO)δ9.16(d,J＝7.7Hz,1H),7.89(dd,J＝9.5,2.8Hz,1H),7.80(dd,J＝8.8,5.3Hz,1H),7.72(s,1H),7.66(td,J＝8.7,2.8Hz,1H),7.50(d,J＝7.5Hz,1H),6.74(d,J＝7.5Hz,1H),5.61(dd,J＝11.1,5.0Hz,1H),4.96(q,J＝7.8Hz,1H),3.22–2.99(m,2H),2.25(td,J＝9.2,6.0Hz,1H),2.17–1.99(m,3H),1.91–1.77(m,2H),1.68(dq,J＝12.1,9.0Hz,1H),1.38–1.24(m,1H),0.89(dd,J＝6.6,3.7Hz,6H).
实施例40:化合物GDI-004133-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(7-甲氧基-1-氧异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004133-002。
1H NMR(400MHz,DMSO)δ9.11(d,J＝7.8Hz,1H),7.72–7.59(m,3H),7.38–7.33(m,2H),6.64(d,J＝7.5Hz,1H),5.63(dd,J＝11.0,5.0Hz,1H),4.95(q,J＝7.9Hz,1H),3.87(s,3H),3.23–3.01(m,2H),2.25(dt,J＝15.0,9.0Hz,1H),2.15–1.95(m,3H),1.93–1.77(m,2H),1.75–1.59(m,1H),1.37–1.22(m,1H),0.88(d,J＝6.6Hz,6H).
实施例41:化合物GDI-004337-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(1-氧-7-(三氟甲基)异喹啉-2(1H)-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004337-001。
1H NMR(400MHz,DMSO)δ9.17(d,J＝7.7Hz,1H),8.47(s,1H),8.04(dd,J＝8.3,2.1Hz,1H),7.93(d,J＝8.4Hz,1H),7.76–7.63(m,2H),6.82(d,J＝7.6Hz,1H),5.62(dd,J＝11.1,4.9Hz,1H),4.96(q,J＝7.8Hz,1H),3.11(ddd,J＝17.5,9.7,7.5Hz,2H),2.26(q,J＝8.0Hz,1H),2.16–2.03(m,3H),1.92–1.75(m,2H),1.73–1.57(m,1H),1.38–1.24(m,1H),0.89(dd,J＝6.5,3.3Hz,6H).
实施例42:化合物GDI-004451-001的制备((S)-2-(3-溴-7-氧代-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004451-001。
1H NMR(400MHz,DMSO)δ12.44(s,1H),9.06(d,J＝7.8Hz,1H),7.68(s,1H),7.52(s,1H),7.30(d,J＝7.4Hz,1H),6.41(d,J＝7.3Hz,1H),5.63(dd,J＝11.0,5.2Hz,1H),4.94(q,J＝7.9Hz,1H),3.14–2.98(m,2H),2.30–2.17(m,1H),2.15–2.17(m,2H),2.01–1.92(m,1H),1.88–1.73(m,2H),1.72–1.61(m,1H),1.25(s,1H),0.88(d,J＝6.6Hz,6H).
实施例43:化合物GDI-004452-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(1-氧-4-(三氟甲基)异吲哚-2-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004452-002。
1H NMR(400MHz,DMSO)δ9.16(d,J＝7.7Hz,1H),8.02(dd,J＝13.7,7.7Hz,2H),7.77(t,J＝7.7Hz,1H),7.71(s,1H),5.00–4.90(m,2H),4.82(d,J＝18.2Hz,1H),4.68(d,J＝18.3Hz,1H),3.21–2.99(m,2H),2.34–2.23(m,1H),2.15–2.06(m,2H),1.95–1.87(m,1H),1.86–1.76(m,1H),1.76–1.63(m,2H),1.48–1.33(m,1H),0.93(dd,J＝6.6,5.3Hz,6H).
实施例44:化合物GDI-004469-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(5-甲氧基-1-氧异异喹啉-2-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004469-002。
1H NMR(400MHz,DMSO)δ9.09(d,J＝7.7Hz,1H),7.72(s,1H),7.62(d,J＝8.4Hz,1H),7.19(d,J＝2.2Hz,1H),7.04(dd,J＝8.4,2.3Hz,1H),5.01–4.91(m,1H),4.86(dd,J＝10.7,5.1Hz,1H),4.59(d,J＝17.6Hz,1H),4.41(d,J＝17.6Hz,1H),3.85(s,3H),3.18–3.02(m,2H),2.33–2.23(m,1H),2.15–2.03(m,2H),1.88–1.75(m,2H),1.72–1.62(m,2H),1.39–1.29(m,1H),0.91(t,J＝6.6Hz,6H).
实施例45:化合物GDI-004470-002的制备((S)-2-(7-溴-1-氧异喹啉-2-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
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以与实施例10类似的方式得到化合物GDI-004470-002。
1H NMR(400MHz,DMSO)δ9.10(d,J＝7.8Hz,1H),7.78–7.64(m,3H),7.54(t,J＝7.7Hz,1H),4.97(q,J＝7.9Hz,1H),4.89(dd,J＝10.7,5.0Hz,1H),4.60(d,J＝17.9Hz,1H),4.47(d,J＝18.0Hz,1H),3.20–3.04(m,2H),2.31(ddd,J＝17.8,12.8,5.6Hz,1H),2.18–2.03(m,2H),1.93–1.79(m,2H),1.78–1.65(m,2H),1.39(q,J＝7.4Hz,1H),0.93(dd,J＝6.6,4.9Hz,7H).
实施例46:化合物GDI-004473-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(4-甲氧基-1-氧异异喹啉-2-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004473-001。
1H NMR(400MHz,DMSO)δ9.07(d,J＝7.8Hz,1H),7.71(s,1H),7.49(t,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.24(d,J＝8.1Hz,1H),4.95(q,J＝7.8Hz,1H),4.87(dd,J＝10.9,5.0Hz,1H),4.54(d,J＝17.7Hz,1H),4.38(d,J＝17.8Hz,1H),3.90(s,3H),3.10(ddd,J＝20.1,9.6,7.3Hz,2H),2.26(td,J＝9.1,5.8Hz,1H),2.10(ddd,J＝14.0,8.8,5.9Hz,2H),1.89(ddd,J＝15.0,10.8,4.6Hz,1H),1.83–1.76(m,1H),1.72–1.64(m,2H),1.34(d,J＝10.2Hz,1H),0.91(t,J＝6.9Hz,6H).
实施例47:化合物GDI-004474-002的制备((S)-2-(4-溴-1-氧异喹啉-2-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004474-002。
1H NMR(400MHz,DMSO)δ9.14(d,J＝7.4Hz,1H),7.86(d,J＝7.9Hz,1H),7.80–7.64(m,2H),7.50(t,J＝7.7Hz,1H),5.04–4.83(m,2H),4.57(d,J＝17.9Hz,1H),4.44(d,J＝17.8Hz,1H),3.09(dd,J＝19.3,9.2Hz,2H),2.27(t,J＝8.0Hz,1H),2.10(s,2H),1.97–1.64(m,4H),1.39(s,1H),0.92(t,J＝7.1Hz,6H).
实施例48:化合物GDI-004515-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(3,4-二溴-7-氧-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004515-001。
1H NMR(400MHz,DMSO)δ12.82(s,1H),9.09(d,J＝7.8Hz,1H),7.70(s,1H),7.60(s,1H),7.46(s,1H),5.53(dd,J＝10.8,5.0Hz,1H),4.95(q,J＝7.8Hz,1H),3.17–3.05(dt,J＝15.5,9.0Hz,3H),2.31–2.00(m,3H),1.90–1.57(m,4H),1.32–1.21(m,2H),0.88(d,J＝6.6Hz,6H).
实施例49:化合物GDI-004586-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(7-氧-4,5,6,7-四氢-1H-吡咯[2,3-c]吡啶-1-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004586-001。
1H NMR(400MHz,DMSO)δ9.04(d,J＝7.8Hz,1H),7.73(s,1H),7.24(t,J＝2.7Hz,1H),7.12(d,J＝2.7Hz,1H),6.12–5.96(m,2H),4.94(q,J＝7.9Hz,1H),3.31(s,2H),3.22–3.07(m,2H),2.65(t,J＝6.8Hz,2H),2.30–2.22(m,1H),2.20–2.06(m,2H),1.9–1.87(m,1H),1.84–1.65(m,3H),1.30–1.19(m,1H),0.85(dd,J＝10.7,6.6Hz,6H).
实施例50:化合物GDI-004586-002的制备(R)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(7-氧-4,5,6,7-四氢-1H-吡咯[2,3-c]吡啶-1-基)五酰胺
以与实施例10类似的方式得到化合物GDI-004586-002。
1H NMR(400MHz,DMSO)δ8.97(d,J＝7.9Hz,1H),7.68(s,1H),7.25(d,J＝2.9Hz,1H),7.12(d,J＝2.8Hz,1H),6.07–5.90(m,2H),4.88(q,J＝7.7Hz,1H),3.31–3.27(m,2H),3.11(ddd,J＝16.2,9.6,7.3Hz,2H),2.68–2.61(m,2H),2.23(dt,J＝14.9,9.4Hz,1H),2.16–2.07(m,1H),2.05–1.92(m,2H),1.81–1.61(m,3H),1.36–1.24(m,1H),0.87(dd,J＝6.6,5.2Hz,6H).
实施例51:化合物GDI-004589-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(2-甲基-4-氧代-3,4-二氢-5H-咪唑[4,5-c]吡啶-5-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004589-002。
1H NMR(400MHz,DMSO)δ9.10(d,J＝7.8Hz,1H),7.69(s,1H),7.38(d,J＝7.4Hz,1H),6.55(d,J＝7.4Hz,1H),5.64(dd,J＝10.9,5.2Hz,1H),4.93(q,J＝7.8Hz,1H),3.16–3.02(m,2H),2.41(s,3H),2.23(td,J＝9.1,5.7Hz,1H),2.15–2.06(m,2H),1.97(td,J＝12.7,4.6Hz,1H),1.85–1.73(m,2H),1.72–1.60(m,1H),1.25(s,1H),0.87(d,J＝6.6Hz,6H).
实施例52:化合物GDI-004628-001的制备(R)-2-(2-溴-7-氧代-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺
以与实施例10类似的方式得到化合物GDI-004628-001。
1H NMR(400MHz,DMSO)δ12.80(s,1H),9.11(d,J＝7.9Hz,1H),7.74(s,1H),7.19(d,J＝7.4Hz,1H),6.58–6.29(m,2H),5.66(dd,J＝11.2,5.0Hz,1H),4.97(q,J＝7.9Hz,1H),3.26–3.09(m,2H),2.39–2.24(m,1H),2.20–2.06(m,2H),1.97(td,J＝12.8,4.4Hz,1H),1.84–1.67(m,3H),1.21(d,J＝15.4Hz,1H),0.86(dd,J＝6.6,4.6Hz,6H).
实施例53:化合物GDI-004628-002的制备((S)-2-(2-溴-7-氧代-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004628-002。
1H NMR(400MHz,DMSO)δ12.79(s,1H),9.06(d,J＝7.9Hz,1H),7.69(s,1H),7.20(d,J＝7.3Hz,1H),6.48(d,J＝7.3Hz,1H),6.41(s,1H),5.62(dd,J＝11.0,5.1Hz,1H),4.94(dt,J＝9.0,7.1Hz,1H),3.20–3.02(m,2H),2.30–2.19(m,1H),2.16–2.02(m,2H),2.00–1.90(m,1H),1.86–1.73(m,2H),1.69–1.59(m,1H),1.31–1.20(m,1H),0.87(dd,J＝6.6,2.0Hz,6H).
实施例54:化合物GDI-004651-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(6-甲氧基-1-氧基-7-(三氟甲基)异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004651-002。
1H NMR(400MHz,dmso)δ9.13(d,J＝7.6Hz,1H),8.33(s,1H),7.67(s,1H),7.60(d,J＝7.6Hz,1H),7.41(s,1H),6.67(d,J＝7.6Hz,1H),5.54(dd,J＝11.1,5.0Hz,1H),3.96(s,3H),3.07(dt,J＝18.1,8.7Hz,2H),2.25–2.17(m,1H),2.11–1.96(m,3H),1.84–1.70(m,2H),1.70–1.60(m,1H),1.30–1.20(m,1H),0.84(t,J＝6.0Hz,6H).
实施例55:化合物GDI-004667-001的制备(2R)-N-(氰基(5-氰基吡啶-3-基)甲基)-4-甲基-2-(1-氧代-7-(三氟甲基)异喹啉-2(1H)-基)戊酰胺
以与实施例10类似的方式得到化合物GDI-004667-001。
1H NMR(400MHz,DMSO)δ9.68(dd,J＝31.9,7.5Hz,1H),9.08(dd,J＝3.1,1.9Hz,1H),8.92(dd,J＝3.8,2.3Hz,1H),8.54–8.43(m,1H),8.37(q,J＝2.5Hz,1H),8.05(ddd,J＝8.5,4.3,2.0Hz,1H),7.94(dd,J＝8.4,4.6Hz,1H),7.70(dd,J＝10.6,7.6Hz,1H),6.84(dd,J＝7.6,6.0Hz,1H),6.36(dd,J＝24.1,7.4Hz,1H),5.62(ddd,J＝18.4,11.0,4.8Hz,1H),2.16–2.06(m,1H),1.95–1.80(m,1H),1.36–1.26(m,1H),0.97–0.78(m,6H).
实施例56:化合物GDI-004667-002的制备((2S)-N-(氰基(5-氰基吡啶-3-基)甲基)-4-甲基-2-(1-氧代-7-(三氟甲基)异喹啉-2(1H)-基)戊二胺)
以与实施例10类似的方式得到化合物GDI-004667-002。
1H NMR(400MHz,DMSO)δ9.68(dd,J＝31.9,7.5Hz,1H),9.08(dd,J＝3.1,1.9Hz,1H),8.92(dd,J＝3.8,2.3Hz,1H),8.54–8.43(m,1H),8.37(q,J＝2.5Hz,1H),8.05(ddd,J＝8.5,4.3,2.0Hz,1H),7.94(dd,J＝8.4,4.6Hz,1H),7.70(dd,J＝10.6,7.6Hz,1H),6.84(dd,J＝7.6,6.0Hz,1H),6.36(dd,J＝24.1,7.4Hz,1H),5.62(ddd,J＝18.4,11.0,4.8Hz,1H),2.16–2.06(m,1H),1.95–1.80(m,1H),1.36–1.26(m,1H),0.97–0.78(m,6H).
实施例57:化合物GDI-004672-002的制备(S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(5-氟-1-氧-7-(三氟甲基)异喹啉-2(1H)-基)-4-甲基五酰胺
以与实施例10类似的方式得到化合物GDI-004672-002。
1H NMR(400MHz,DMSO)δ9.21(d,J＝7.6Hz,1H),8.31(s,1H),8.08(dd,J＝9.9,1.8Hz,1H),7.82(d,J＝7.7Hz,1H),7.71(s,1H),6.82(d,J＝7.6Hz,1H),5.61(dd,J＝11.1,5.0Hz,1H),4.96(dt,J＝8.9,7.3Hz,1H),3.11(dtd,J＝18.4,9.8,7.3Hz,2H),2.26(td,J＝9.0,5.8Hz,1H),2.18–2.04(m,3H),1.94–1.75(m,2H),1.73–1.64(m,1H),1.37–1.27(m,1H),0.89(dd,J＝6.6,3.9Hz,6H).
实施例58:化合物GDI-004674-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(5-甲氧基-1-氧基-7-(三氟甲基)异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004674-002。
1H NMR(400MHz,DMSO)δ9.24(d,J＝7.7Hz,1H),8.11(s,1H),7.83–7.67(m,2H),7.54(d,J＝1.7Hz,1H),6.91(d,J＝7.7Hz,1H),5.66(dd,J＝11.1,5.0Hz,1H),5.01(dt,J＝9.0,7.4Hz,1H),4.09(s,3H),3.27–3.04(m,2H),2.39–2.27(m,1H),2.14(dddd,J＝20.2,14.8,9.6,5.9Hz,3H),1.99–1.82(m,2H),1.80–1.66(m,1H),1.38(d,J＝14.9Hz,1H),0.94(dd,J＝6.6,3.0Hz,6H).
实施例59:化合物GDI-004731-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(6-氟-1-氧-7-(三氟甲基)异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004731-002。
1H NMR(400MHz,DMSO)δ9.20(d,J＝7.5Hz,1H),8.49(d,J＝7.3Hz,1H),7.85(d,J＝11.5Hz,1H),7.77(d,J＝7.6Hz,1H),7.71(s,1H),6.78(d,J＝7.6Hz,1H),5.59(dd,J＝11.1,4.9Hz,1H),5.03–4.87(m,1H),3.12(ddd,J＝16.5,9.7,7.5Hz,2H),2.32–2.22(m,1H),2.16–2.01(m,3H),1.89–1.76(m,2H),1.69(dt,J＝12.3,9.1Hz,1H),1.36–1.26(m,1H),0.99–0.78(m,6H).
实施例60:化合物GDI-004735-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(1-氧-7-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004735-002。
1H NMR(400MHz,DMSO)δ8.93(d,J＝8.0Hz,1H),8.14(d,J＝2.1Hz,1H),7.88(dd,J＝7.9,2.1Hz,1H),7.71(s,1H),7.59(d,J＝8.0Hz,1H),5.25(dd,J＝9.8,5.8Hz,1H),5.01(q,J＝8.0Hz,1H),3.54(h,J＝7.1Hz,2H),3.20–2.97(m,4H),2.36–2.22(m,1H),2.22–2.04(m,2H),1.87–1.79(m,1H),1.79–1.65(m,3H),1.53–1.42(m,1H),0.92(t,J＝8.0Hz,6H).
实施例61:化合物GDI-004755-001的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基-2-(7-氧-1,4,5,7-四氢-6H-吡咯[2,3-c]吡啶-6-基)五酰胺)
以与实施例10类似的方式得到化合物GDI-004755-001。
1H NMR(400MHz,DMSO)δ11.59(s,1H),8.84(d,J＝8.2Hz,1H),7.69(s,1H),6.87(d,J＝3.4Hz,1H),5.97(d,J＝3.0Hz,1H),5.12(dd,J＝10.7,5.3Hz,1H),4.97(q,J＝8.2Hz,1H),3.45(ddd,J＝30.7,13.6,7.1Hz,2H),3.13(dt,J＝15.4,9.0Hz,2H),2.81–2.59(m,2H),2.25(q,J＝8.3Hz,1H),2.11(td,J＝12.9,6.8Hz,2H),1.80(dd,J＝14.5,7.3Hz,1H),1.75–1.59(m,3H),1.45(p,J＝6.7Hz,1H),0.91(t,8.0Hz,6H).
实施例62:化合物GDI-004756-002的制备((2S)-2-(3-乙酰氨基-2-氧吡啶-1(2H)-基)-N-(氰基(5-氰基吡啶-3-基)甲基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004756-002。
1H NMR(400MHz,DMSO)δ9.66(dd,J＝28.0,7.5Hz,1H),9.21(d,J＝15.6Hz,1H),9.09(s,1H),8.96–8.88(m,1H),8.36(dd,J＝5.2,2.6Hz,1H),8.21(d,J＝6.7Hz,1H),7.42(q,J＝11.9Hz,1H),6.33(q,J＝8.4Hz,2H),5.58(t,J＝10.1Hz,1H),2.11(s,3H),2.08–1.99(m,1H),1.88–1.70(m,1H),1.30–1.19(s,1H),1.00–0.71(m,6H).
实施例63:化合物GDI-004796-002的制备((S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-2-(7-(二氟甲基)-1-氧异喹啉-2(1H)-基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004796-002。
1H NMR(400MHz,DMSO)δ9.16(d,J＝7.7Hz,1H),8.41(s,1H),7.89(d,J＝8.4Hz,1H),7.83(d,J＝8.3Hz,1H),7.69(s,1H),7.61(d,J＝7.6Hz,1H),7.20(t,J＝55.7Hz,1H),6.76(d,J＝7.5Hz,1H),5.62(dd,J＝11.1,5.0Hz,1H),4.96(q,J＝7.9Hz,1H),3.10(dt,J＝17.4,8.8Hz,2H),2.26(q,J＝8.3Hz,1H),2.18–2.00(m,3H),1.90–1.75(m,2H),1.73–1.62(m,1H),1.36–1.26(m,1H),0.88(t,J＝8.0Hz,6H).
实施例64:化合物GDI-004797-002的制备((S)-2-(4-氯-1-氧代-7-(三氟甲基)异喹啉-2(1H)-基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-4-甲基五酰胺)
以与实施例10类似的方式得到化合物GDI-004797-002。
1H NMR(400MHz,DMSO)δ9.18(d,J＝7.6Hz,1H),8.52(s,1H),8.23(d,J＝8.6Hz,1H),8.14–7.99(m,2H),7.70(s,1H),5.56(dd,J＝11.4,4.7Hz,1H),4.96(q,J＝7.9Hz,1H),3.12(dt,J＝17.1,8.9Hz,2H),2.38–2.24(m,1H),2.20–2.06(m,3H),1.84(ddd,J＝25.1,14.2,6.1Hz,2H),1.70(q,J＝9.9Hz,1H),1.41–1.27(m,1H),0.89(dd,J＝6.3,3.0Hz,6H).
实施例65:化合物GDI-004855-001的制备(2R)-N-(氰基(异喹啉-4-基)甲基)-4-甲基-2-(1-氧代-7-(三氟甲基)异喹啉-2(1H)-基)戊酰胺
以与实施例19类似的方式得到化合物GDI-004855-001。
1H NMR(400MHz,DMSO)δ9.85(dd,J＝30.8,7.3Hz,1H),9.42(d,J＝6.0Hz,1H),8.71(d,J＝2.7Hz,1H),8.43(d,J＝34.5Hz,1H),8.25(dd,J＝13.8,8.2Hz,1H),8.03(q,J＝7.2Hz,1H),7.92(q,J＝7.6Hz,2H),7.81(d,J＝8.4Hz,1H),7.73(d,J＝7.7Hz,1H),6.83(t,J＝6.6Hz,2H),5.67(ddd,J＝17.4,11.1,4.5Hz,1H),2.20–2.01(m,1H),1.95–1.65(m,1H),1.38–1.26(m,1H),0.97–0.70(m,6H).
实施例66:化合物GDI-004855-002的制备((2S)-N-(氰基(异喹啉-4-基)甲基)-4-甲基-2-(1-氧代-7-(三氟甲基)异喹啉-2(1H)-基)五酰胺)
以与实施例19类似的方式得到化合物GDI-004855-002。
1H NMR(400MHz,DMSO)δ9.85(dd,J＝30.8,7.3Hz,1H),9.42(d,J＝6.0Hz,1H),8.71(d,J＝2.7Hz,1H),8.43(d,J＝34.5Hz,1H),8.25(dd,J＝13.8,8.2Hz,1H),8.03(q,J＝7.2Hz,1H),7.92(q,J＝7.6Hz,2H),7.81(d,J＝8.4Hz,1H),7.73(d,J＝7.7Hz,1H),6.83(t,J＝6.6Hz,2H),5.67(ddd,J＝17.4,11.1,4.5Hz,1H),2.20–2.01(m,1H),1.95–1.65(m,1H),1.38–1.26(m,1H),0.97–0.70(m,6H).
实施例67:化合物GDI-004861-002的制备((2S)-N-((5-(1H-吡唑-1-基)吡啶-3-基)(氰基)甲基)-2-(3-乙酰氨基-2-氧吡啶-1(2H)-基)-4-甲基五酰胺)
以与实施例19类似的方式得到化合物GDI-004861-002。
1H NMR(400MHz,DMSO)δ9.77(dd,J＝21.9,7.6Hz,1H),9.23(d,J＝17.9Hz,1H),9.17(s,1H),8.67(d,J＝3.2Hz,1H),8.60–8.52(m,1H),8.34(d,J＝7.1Hz,1H),8.20(t,J＝8.3Hz,1H),7.87(s,1H),7.43(t,J＝8.9Hz,1H),6.65(s,1H),6.40–6.24(m,2H),5.65(d,J＝11.7Hz,1H),2.16–2.09(m,3H),1.88–1.72(m,1H),1.32–1.20(m,2H),0.96–0.79(m,6H).
实施例68:化合物GDI-004870-002的制备((2S)-2-(3-乙酰氨基-2-氧吡啶-1(2H)-基)-N-(氰基(异喹啉-4-基)甲基)-4-甲基五酰胺)
以与实施例19类似的方式得到化合物GDI-004870-002。
1H NMR(400MHz,DMSO)δ9.82(dd,J＝35.1,7.3Hz,1H),9.43(d,J＝3.0Hz,1H),9.21(d,J＝31.0Hz,1H),8.70(d,J＝2.7Hz,1H),8.22(dt,J＝30.2,7.7Hz,2H),8.05–7.74(m,3H),7.43(d,J＝7.1Hz,1H),6.81(t,J＝7.0Hz,1H),6.31(dd,J＝12.9,6.9Hz,1H),5.63(td,J＝14.2,4.5Hz,1H),2.11(d,J＝12.8Hz,3H),2.05–1.93(m,1H),1.85–1.57(m,1H),1.31–1.17(m,1H),1.01–0.66(m,6H).
实施例69:化合物GDI-004872-002的制备((2S)-N-((5-(1H-吡唑-1-基)吡啶-3-基)(氰基)甲基)-4-甲基-2-(1-氧代-7-(三氟甲基)异喹啉-2(1H)-基)五酰胺)
以与实施例19类似的方式得到化合物GDI-004872-002。
1H NMR(400MHz,DMSO)δ9.79(dd,J＝21.5,7.5Hz,1H),9.16(d,J＝2.8Hz,1H),8.68(d,J＝2.7Hz,1H),8.59(dd,J＝4.1,2.3Hz,1H),8.49(s,1H),8.33(d,J＝8.5Hz,1H),8.04(t,J＝7.8Hz,1H),7.92(q,J＝8.1Hz,1H),7.86(d,J＝2.5Hz,1H),7.72(t,J＝9.1Hz,1H),6.83(t,J＝7.4Hz,1H),6.65(s,1H),6.40(dd,J＝16.1,7.3Hz,1H),5.66(td,J＝13.4,4.4Hz,1H),2.17–2.05(m,1H),1.95–1.80(m,1H),1.45–1.21(d,J＝33.4Hz,2H),1.04–0.72(m,6H).
测试例1：化合物的活性测定
SARS-CoV-2/Hela-ACE2测试
化合物转移到384孔板(Greiner,Part.No.781090-2B)，然后加入Hela-ACE2细胞(细胞密度5000细胞/20微升培养液MEM with 2％FBS)。植入细胞的板子转移到BSL3实验室。SARS-CoV-2(USA-WA1/2020Vero E6细胞增殖)稀释到MOI 0.75到1，达到～30-60％细胞感染。测试板在37℃5％CO2孵育48小时后，加入甲醛达到4％最终浓度固定细胞。人源多克隆血清抗体作为一抗，山羊抗人H+L缀合Alexa 488(Thermo Fisher Scientific A11013)作为二抗。DAPI(Thermo Fisher Scientific D1306)DNA染色。
未感染细胞毒性测试
化合物转移到1536孔板(Corning No.9006BC)，然后加入Hela-ACE2细胞(细胞密度600细胞/5微升培养液MEM，含2％FBS)。测试板在37℃5％CO2孵育48小时后，细胞活性测试。2μL 50％Cell-Titer Glo(Promega No G7573)水中稀释加入细胞测试板，然后用EnVision Plate Reader(Perkin Elmer)读取数值。
酶活性测试
使用200nM重组SARS-CoV-2主蛋白酶和15μM荧光底物(Dabcyl-TSAVL QSGFRK-Glu(EDANS)；Genscript)进行抑制试验。测定缓冲液由50mM Tris-HCl、pH 7.3、1mM EDTA组成。SARS-CoV-2 3CLpro溶解在25μL测定缓冲液中，与不同浓度的化合物混合。将混合物在37℃下孵育30分钟。然后加入溶解在25μL测定缓冲液中的底物以启动反应。使用M5多模式酶标仪在37℃下每1分钟立即测量350nm(激发)/490nm(发射)的荧光信号，持续10分钟。与具有最低浓度的反应相比，在与不同浓度的化合物反应的第6分钟的RFU用于生成IC50曲线。对于每种化合物，在12个浓度下测量了对SARS-CoV-2 3CLpro的IC50值。实验数据通过GraphPad Prism软件进行分析。
示例性化合物的活性结果如下表1所示。
表1：示例性化合物的活性结果
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Claims (10)
1.式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，
其中，
环A选自五元或六元杂脂环或杂芳环；
环B为存在的或不存在的；
其中，1)当环B存在时，环B选自任选地被卤素、C1-C3烷基、C1-C3卤代烷基、C1-C3烷氧基、氨基或硝基取代的五元或六元脂族环、芳族环、杂脂环或杂芳环，并且环A任选地被卤素或C1-C3烷基取代；
2)当环B不存在时，环A任选地被R1NH-取代，其中R1选自H、卤素、C1-C3烷基、R2C(＝O)、R2S(＝O)2或叔丁氧羰基，其中R2选自H、任选地被羟基或卤素取代的C1-C3烷基或C3-C4环烷基、或任选地被卤素或C1-C3烷基取代的氨基；
P1选自任选地被卤素、C1-C3烷基、氨基、氰基或C1-C3卤代烷基取代的其中R3选自H、卤素、C1-C3烷基、氰基或吡唑基；并且
P2选自任选地被卤素取代的C1-C5烷基、C3-C6环烷基或苯基。
2.根据权利要求1所述的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中，
环A选自五元或六元杂脂环或杂芳环且包含1或2个选自O、S或N的杂原子，优选为吡咯、咪唑、吡唑、吡啶、嘧啶、吡嗪、哒嗪、氮杂环戊烷或氮杂环己烷；并且
环B当存在时选自五元或六元脂族环、芳族环、杂脂环或杂芳环且所述杂脂环或杂芳环包含1或2选自O、S或N的杂原子，优选为环戊烷、环己烷、苯、吡咯、咪唑、吡唑、吡啶、嘧啶、吡嗪、哒嗪、氮杂环戊烷或氮杂环己烷。
3.根据权利要求1所述的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中，
1)当环B存在时，环B任选地被氟、氯、溴、甲基、乙基、丙基、二氟甲基、三氟甲基、甲氧基、乙氧基或硝基取代，并且环A任选地被氟、氯、溴、甲基、乙基或丙基取代；并且
2)当环B不存在时，环A任选地被R1NH-取代，其中R1选自H、氟、氯、溴、甲基、乙基、丙基、R2C(＝O)、R2S(＝O)2或叔丁氧羰基，其中R2选自H、任选地被羟基、氟、氯或溴取代的甲基、乙基、丙基、环丙基或环丁基、或任选地被氟、氯、溴、甲基、乙基或丙基取代的氨基。
4.根据权利要求1所述的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中，
P1选自任选地被氟、氯、溴、甲基或乙基取代的 其中R3选自氢、氰基或吡唑基。
5.根据权利要求1所述的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中，
P2选自任选地被氟、氯或溴取代的异丙基、环己基、苯基，优选地，选自
6.一种药物组合物，其包含根据权利要求1-5中任一项所述的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，以及药学上可接受的载体。
7.根据权利要求6所述的药物组合物，其剂型选自片剂、颗粒剂、散剂、糖浆剂、吸入剂和注射剂。
8.根据权利要求1-5中任一项所述的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物在制备药物中的用途，所述药物用于在有此需要的受试者中治疗或预防冠状病毒感染或由冠状病毒引起的疾病或症状。
9.根据权利要求8所述的用途，其中所述冠状病毒选自严重急性呼吸综合征冠状病毒(SARS-CoV)、新型冠状病毒(SARS-CoV-2)、中东呼吸综合征冠状病毒(MERS-CoV)、冠状病毒OC43(HCoV-OC43)、鼠肝炎冠状病毒(MHV)和与以上任一种冠状病毒的同源性大于85％且具备病毒活性的冠状病毒。
10.根据权利要求8或9所述的用途，其中所述由冠状病毒引起的疾病或症状选自以下中的一种或更多种：呼吸系统感染、急性呼吸综合征(SARS)、肺炎(包括重症肺炎)、肠胃炎(包括急性肠胃炎)、咳嗽、发热、寒战、呕吐、头痛、畏寒、呼吸急促和细胞因子风暴。
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