CN116903696A - 一种肽类化合物、其制备方法、包含其药物组合物及其应用 - Google Patents
一种肽类化合物、其制备方法、包含其药物组合物及其应用 Download PDFInfo
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- CN116903696A CN116903696A CN202210167736.2A CN202210167736A CN116903696A CN 116903696 A CN116903696 A CN 116903696A CN 202210167736 A CN202210167736 A CN 202210167736A CN 116903696 A CN116903696 A CN 116903696A
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- Prior art keywords
- alkyl
- compound
- pro
- protease
- carbocyclyl
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- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 101800000504 3C-like protease Proteins 0.000 claims description 12
- 101800001016 Picornain 3C-like protease Proteins 0.000 claims description 12
- 101800000596 Probable picornain 3C-like protease Proteins 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
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- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- HTNPEHXGEKVIHG-QCNRFFRDSA-N molnupiravir Chemical compound C(OC(=O)C(C)C)[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C(=O)N=C(NO)C=C1 HTNPEHXGEKVIHG-QCNRFFRDSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- HXRAMSFGUAOAJR-UHFFFAOYSA-N n,n,n',n'-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine Chemical compound CN(C)C(N(C)C)OC(C)(C)C HXRAMSFGUAOAJR-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 229940091170 naphthoquine Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
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- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
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- 125000005545 phthalimidyl group Chemical group 0.000 description 1
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- 239000002952 polymeric resin Substances 0.000 description 1
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- 238000002953 preparative HPLC Methods 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 229940043131 pyroglutamate Drugs 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 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
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 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
- 238000007086 side reaction Methods 0.000 description 1
- 229960002091 simeprevir Drugs 0.000 description 1
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- BSPJDKCMFIPBAW-JPBGFCRCSA-M sodium;(2s)-1-hydroxy-2-[[(2s)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonate Chemical compound [Na+].N([C@@H](CC(C)C)C(=O)N[C@@H](CC1C(NCC1)=O)C(O)S([O-])(=O)=O)C(=O)OCC1=CC=CC=C1 BSPJDKCMFIPBAW-JPBGFCRCSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
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- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000331 teriflunomide Drugs 0.000 description 1
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229940098465 tincture Drugs 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
- 238000011200 topical administration Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
本发明提供了一种肽类化合物、其制备方法、包含其药物组合物及其应用,具体地,所述化合物具有式I所示结构,其具有显著地抑制主蛋白酶(Mpro或3CLpro)的活性,有望用于制备治疗包括SARS‑CoV‑2、SARS‑CoV‑1、MERS‑CoV、HCoV、TGEV、MHV、BCoV、IBV等冠状病毒感染引起的疾病的药物。
Description
技术领域
本发明属于药物化学领域,具体涉及一种肽类化合物、其制备方法、包含其药物组合物及其应用。
背景技术
新冠肺炎是由于被SARS-CoV-2病毒感染而引起的疾病。SARS-CoV-2病毒是一种单链RNA病毒,不断发生变异,使得疫苗及中和抗体的有效性降低。SARS-CoV-2病毒入侵宿主细胞后,翻译出两个折叠的多聚蛋白。这两种多聚蛋白主要由一种33.8-k道尔顿病毒特异性的主蛋白酶(Mpro,又称3C样蛋白酶,3CLpro)水解处理,提供结构和功能不同的蛋白,达到病毒复制的目的。Mpro在SARS-CoV-1,MERS-CoV和SARS-CoV-2等冠状病毒中高度保守(Ullrich S,Nitsche C.The SARS-CoV-2main protease as drug target.Bioorg.Med.Chem.Lett.2020;30(17):127377.),有望开发出广谱的抗冠状病毒药物。在SARS-CoV-2出现之前,Mpro就被认为是潜在的抗SARS-CoV-1和MERS-CoV病毒的靶标。然而,由于之前的Mpro抑制剂的PK非常差,临床上只能通过静脉注射给药,限制了这些化合物的临床应用价值。在2021年4月,由辉瑞开发的首个口服吸收的Mpro抑制剂PF-07321332进入临床试验。然而PF-07321332生物利用度较低,需要和CYP3A4抑制剂利托那韦联用(NCT04960202)。
因此,目前本领域尚迫切需要研发出更多更加高效、成药性更好的Mpro抑制剂。
发明内容
本发明目的是提供一种更加高效、成药性更好的Mpro抑制剂。
本发明第一方面,提供一种式I所示的化合物、或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,
其中,
R1选自:C1-C3烷基、-COORa、-CONRaRb;优选地,R1为-COORa;
Ra和Rb各自独立地选自:H、任选取代的C1-C4烷基、任选取代的3-8元碳环基或任选取代的4-8元杂环基,或Ra和Rb与它们相连的N原子形成任选取代的4-8元杂环,其中,所述杂环包含1-3个选自N、O、S、P的杂原子,所述取代是指被选自下组的1-3个取代基取代:卤素、C3-C8碳环基、3-8元杂环基、C1-C4烷基和C1-C4卤代烷基;
A为C3-C6碳环基,其中,所述碳环基可任选地被1-3个选自下组的取代基取代:卤素、C1-C3烷基和C1-C3烷氧基;
R2选自:C1-C6烷基、C2-C6烯基、C2-C6炔基或C3-C8碳环基,其中,所述烷基、烯基、炔基、碳环基可任选地被1-3个R’取代;
每个R’独立地选自:卤素、氧代(=O)、C1-C6烷基、C1-C4烷氧基、或C3-C8碳环基;
R3选自:H、C1-C6烷基、C1-C6卤代烷基、-(CH2)m-R、-C(=O)-C1-C6烷基、-C(=O)-C1-C6卤代烷基、-C(=O)O-C1-C6烷基、-C(=O)NRcRd、-SO2-C1-C6烷基、-SO2-C1-C6卤代烷基;
R选自:任选取代的3-8元碳环基或任选取代的4-8元杂环基,其中,所述取代是指被选自下组的1-3个取代基取代:卤素、氧代(=O)、C3-C8碳环基、4-8元杂环基、C1-C4烷基、C1-C4卤代烷基和C1-C3烷氧基;
Rc、Rd各自独立地选自:H、任选取代的C1-C6烷基,或Rc和Rd与它们相连的N原子形成任选取代的4-8元杂环,其中,所述杂环包含1-3个选自N、O、S、P的杂原子,所述取代是指被选自下组的1-3个取代基取代:卤素、C1-C4烷基和C1-C4卤代烷基;
m为0、1、2、3或4。
在另一优选例中,选自:/>
在另一优选例中,R1为COORa;其中,Ra选自:H、C1-C6烷基或C1-C6卤代烷基;优选地,Ra为甲基、乙基或异丙基。
在另一优选例中,R2为C1-C6烷基或C3-C8碳环基;优选地,R2为叔丁基、异丙基或环丙基。
在另一优选例中,R3选自:三氟乙酰基、三氟甲磺酰基、甲磺酰基、特戊酰基、新戊酰基、叔丁氧羰基、甲氧基羰基和乙氧基羰基。
在另一优选例中,所述化合物具有式I’所示的结构:
其中,*各自独立地表示R或S构型。
在另一优选例中,R1、R2、A和R3分别为实施例中各具体化合物所对应基团。
在另一优选例中,所述化合物选自下组:
在另一优选例中,所述化合物为实施例中所示化合物。
本发明第二方面,提供一种药物组合物,其中,所述药物组合物包括根据第一方面所述的化合物和药学上可接受的载体。
在另一优选例中,所述含药物组合物还可以含有其他抗病毒药。
在另一优选例中,所述的其他抗病毒药物还包括选自下组的额外组分:
Remdesivir(瑞德西韦)、法匹拉韦(favipiravir)、Galidesivir、GS-441524、NHC(EIDD-1931)、EIDD-2801、GC-376、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir)、氯喹(Chloroquine)、羟氯喹(hydroxychloroquine)、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、连翘脂苷(forsythoside)、绿原酸(chlorogenic acid)、大黄素(emodin)、霉酚酸(mycophenolicacid)、霉酚酸酯(Mycophenolate mofetil)、萘酚喹(Naphthoquine)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、帕利珠单抗、莫维珠单抗(Motavizumab)、RSV-IGIVMEDI-557、A-60444(RSV-604)、MDT-637、BMS-433771、或其药学上可接受的盐、或其组合。
在另一优选例中,所述的化合物或药物组合物可以是口服制剂和非口服制剂的形式存在。
在另一优选例中,所述的制剂包括:粉剂、颗粒剂、胶囊剂、注射剂、吸入剂、酊剂、口服液、片剂、含片、或滴丸。
本发明第二方面,提供一种第一方面所述的化合物或第二方面所述的药物组合物的用途,其中,所述用途选自下述(a)-(c)中的任意一种:
(a)制备用于预防和/或治疗与主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)有关的病毒感染相关疾病的药物;
(b)制备用于体外非治疗性与主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)的活性有关的抑制剂;或
(c)制备用于体外非治疗性冠状病毒的增殖抑制剂。
在另一优选例中,所述病毒选自:新型冠状病毒(SARS-CoV-2)、冠状病毒(SARS-CoV-1)、中东呼吸综合征冠状病毒(MERS-CoV)、人冠状病毒(HCoV)、猪传染性胃肠炎病毒(TGEV)、小鼠肝炎病毒(MHV)、牛冠状病毒(BCoV)、鸡传染性支气管炎病毒(IBV)。
在另一优选例中,所述冠状病毒感染引起的相关疾病选自下组:感冒、呼吸道感染、肺炎及其并发症、或其组合。
本发明第四方面,提供一种抑制主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)活性的方法,包括步骤:将第一方面所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合或第二方面所述的药物组合物与主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)接触,从而抑制主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)的活性,优选地,所述方法是非治疗性和非诊断性,更优选地,所述方法是体外的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过广泛而深入地研究,首次意外地开发了一种可有效抑制主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)活性的肽类化合物,可用于制备治疗和/或预防包括新型冠状病毒(SARS-CoV-2)、冠状病毒(SARS-CoV-1)、中东呼吸综合征冠状病毒(MERS-CoV)、人冠状病毒(HCoV)、猪传染性胃肠炎病毒(TGEV)、小鼠肝炎病毒(MHV)、牛冠状病毒(BCoV)、鸡传染性支气管炎病毒(IBV)等冠状病毒感染引起的疾病的药物。在此基础上,完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(=O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳基烷基、杂芳基烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳基烷基氨基、杂芳基烷基氨基。
“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子,且通过1个或多个单键与分子的其余部分连接,例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言,术语“烷基”优选指含有1至6个碳原子的烷基,烷基可任选地为被取代烷基。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
本文中作为基团或是其它基团的一部分,术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个碳-碳三键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“碳环(基)”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,更优选3至6个碳原子(即C3-C6),且其为饱和或不饱和环(即环烷基、环烯基等)并可经由任何适宜的碳原子通过1个或多个单键与分子的其余部分连接。除非本说明书中另外特别指明,碳环基中的碳原子可以任选地被氧化。碳环基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、2,3-二氢化茚基、八氢-4,7-亚甲基-1H-茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、环戊烯基、环己烯基、环己二烯基、1H-茚基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[1.1.1]戊烷、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烷基”是指上述完全饱和的碳环(基),典型的环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烯基”是指部分不饱和的碳环(基),典型的环烯基包括但不限于环丁烯基、环戊烯基、环己烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环(基)”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过1个或多个单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2-氮杂双环[2.2.2]辛烷基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的碳环基或杂环基稠合,条件是芳基经由芳香环上的原子通过1个或多个单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的碳环基或杂环基稠合,条件是杂芳基经由杂芳香环上的原子通过1个或多个单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,术语“不存在”是指被上文所定义的基团的两侧直接通过化学键相连。例如,“A-B-C中B是不存在”表示“A-C”。
在本申请中,中的/>表示基团R的连接位置。
在本申请中,除权利要求中特殊说明外,“任选地”、“任选”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选取代的芳基”表示芳基上的氢被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。例如,在没有明确列出取代基的情况下,本文所用的术语“任选取代的”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代,所述取代基独立地选自:氘(D)、卤素、-OH、氧代(=O)、巯基、氰基、-CD3、-C1-C6烷基(优选-C1-3烷基)、C2-C6烯基、C2-C6炔基、环烷基(优选C3-C8环烷基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基-C1-C6烷基-、杂芳基-C1-C6烷基-、C1-C6卤代烷基-、-OC1-C6烷基(优选-OC1-C3烷基)、-OC2-C6烯基、-O环烷基、-O杂环基、-O芳基、-O杂芳基、-OC1-C6烷基苯基、-C1-C6烷基-OH(优选-C1-C4烷基-OH)、-C1-C6烷基-SH、-C1-C6烷基-O-C1-C6烷基、-OC1-C6卤代烷基、-NH2、-C1-C6烷基-NH2(优选-C1-C3烷基-NH2)、-N(C1-C6烷基)2(优选-N(C1-C3烷基)2)、-NH(C1-C6烷基)(优选-NH(C1-C3烷基))、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、硝基、-C(O)-OH、-C(O)OC1-C6烷基(优选-C(O)OC1-C3烷基)、-CONRiRii(其中Ri和Rii是H、D和C1-6烷基,优选C1-3烷基)、-NHC(O)(C1-C6烷基)、-NHC(O)(苯基)、-N(C1-C6烷基)C(O)(C1-C6烷基)、-N(C1-C6烷基)C(O)(苯基)、-C(O)C1-C6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C1-C6烷基苯基、-C(O)C1-C6卤代烷基、-OC(O)C1-C6烷基(优选-OC(O)C1-C3烷基)、-S(O)2-C1-C6烷基、-S(O)-C1-C6烷基、-S(O)2-苯基、-S(O)2-C1-C6卤代烷基、-S(O)2NH2、-S(O)2NH(C1-C6烷基)、-S(O)2NH(苯基)、-NHS(O)2(C1-C6烷基)、-NHS(O)2(苯基)和-NHS(O)2(C1-C6卤代烷基),其中所述的烷基、烯基、炔基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代:卤素、-OH、氧代(=O)、-NH2、环烷基、3-8元杂环基、C1-C4烷基、C1-C4卤代烷基-、-OC1-C4烷基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)2、-CONH(C1-C6烷基)、-CONH2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2(苯基)、-SO2(C1-C6卤代烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(苯基)、-NHSO2(C1-C6烷基)、-NHSO2(苯基)和-NHSO2(C1-C6卤代烷基)。当一个原子或基团被多个取代基取代时,所述取代基可以相同或不同。本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
在本发明中,“C1-C3烷氨基”是指包含(C1-C3烷基)NH和(C1-C3烷基)2N的基团,例如可以是甲氨基、等。
本发明中,“甲酰基氨基”指HC(O)NH2。
本发明中,“多个”是指2、3或4个。
活性成分
如本文所用,“本发明化合物”或“活性成分”指式I所示的化合物,并且还包含其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIAOFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
药物组合物和施用方法
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“冠状病毒相关疾病”包括但不限于新冠肺炎(COVID-19)、严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)、急性上呼吸道感染、猪传染性胃肠炎、禽传染性支气管炎、鼠肝炎、新生犊牛腹泻、牛呼吸道感染等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
化合物的制备方法
以下方案中描述了制备式I所示化合物的方法。在某些情况下,可以改变执行反应方案的步骤的顺序,以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基、烯丙基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基、9-芴基甲氧基羰基、苄基、对甲氧基苄基、烯丙基、烯丙基氧羰基、对甲苯磺酰基、特戊酰基、三氟乙酰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃-150℃,优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
优选地,所述式I化合物可通过如下方法制备:
(1)化合物a与b发生反应生成化合物c;
(2)在还原剂存在下,化合物c发生还原反应生成化合物d,所述还原剂选自下组:氢气、硼氢化钠、硼氢化锂、硼氢化钾、二异丁基氢化铝、氢化铝锂、二氢双(2-甲氧乙氧基)铝酸钠、或其组合;
(3)在碱存在下,化合物d与化合物e反应生成化合物f,其中,所述碱选自下组:氢化钠、叔丁醇钾、氢氧化钠、氢氧化钾、正丁基锂、二异丙基氨基锂、六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、碳酸钾、碳酸铯、碳酸钠、三乙胺、二异丙基乙基胺、1.8-二氮杂二环[5.4.0]十一烷-7-烯、或其组合;
(4)在缩合剂存在下,化合物f与g发生缩合反应生成化合物h;
(5)在缩合剂存在下,化合物h与i发生缩合反应生成化合物I;
以上所述缩合剂选自下组:二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基-7-偶氮苯并三氮唑、1-羟基苯并三唑、N-羟基丁二酰亚胺、N,N,N,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲、苯并三氮唑-N,N,N,N'-四甲基脲六氟磷酸盐、1H-苯并三唑-1-基氧代三(二甲氨基)磷鎓六氟磷酸盐、丙基磷酸酐、2-羟基吡啶氮氮化物、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐或其组合;
其中,R1、R2、R3、A的定义如上所述。
相对于现有技术,本发明具有以下有益效果:
(1)本发明提供了一种结构新颖的如式I所示的化合物或其药学上可接受的盐;
(2)本发明化合物可有效抑制Mpro,其可用于制备预防和/或治疗包括SARS-CoV-2、SARS-CoV-1、MERS-CoV、HCoV、TGEV、MHV、BCoV、IBV等冠状病毒感染引起的疾病的药物。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
各实施例中,1H NMR由BRUKER AVANCE NEO 400MHz型核磁共振仪记录,化学位移以δ(ppm)表示;液质联用(LCMS)由Shimadzu LC-20AD,SIL-20A,CTO-20AC,SPD-M20A,CBM-20A,LCMS-2020型质谱仪记录;制备HPLC分离使用Gilson-281型号液相色谱仪。
实施例
中间体的制备
1、中间体A的制备
中间体A合成路线如下所示:
(1)向化合物A-1(50.0g,387mmol)的丙酮(500mL)溶液中加入三乙胺(45.0g,445mmol),和溴化苄(69.5g,406mmol,48.3mL),反应液在25℃下搅拌6小时。反应液减压浓缩,加入冰水(300mL),用乙酸乙酯(200mL×3)萃取,合并有机相用水(300mL×1)和饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,得到化合物A-2。
(2)0℃下,向化合物A-2(68.0g,310mmol)的二氯甲烷(800mL)溶液中加入4-二甲氨基吡啶(7.58g,62.0mmol),和碳酸二叔丁酯(74.4g,341mmol),反应液在25℃下搅拌16小时。加入冰水(500mL)淬灭反应,用二氯甲烷(200mL×1)萃取,合并有机相用水(200mL×1)和饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,得到化合物A-3。
(3)向化合物A-3(50.0g,156mmol)的乙二醇二甲醚(800mL)溶液中加入叔丁氧基双(二甲胺基)甲烷(40.9g,234mmol),反应液在氮气保护下于85℃搅拌12小时。反应液减压浓缩,加入乙酸乙酯(30.0mL×1),有机相用水(30.0mL×2)和饱和食盐水(20.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:1到1:4)分离,得到化合物A-4。
MS-ESI[M+H-Boc]+,计算值275,实测值275。
1H NMR(400MHz,CDCl3)δ7.31-7.36(m,5H),7.12(s,1H),5.13-5.23(m,2H),4.57(dd,J=3.6,10.4H,1H),3.19-3.26(m,1H),2.99(s,6H),2.83-2.88(m,1H),1.42(s,9H)。
(4)-65℃下,向化合物A-4(43.0g,114mmol)的四氢呋喃(4.0L)溶液中加入二异丁基氢化铝(1mol/L,172mL),反应液在氮气保护下于-65℃搅拌1小时。升温至0℃继续反应1小时。加入水(6.88mL)淬灭反应,加入氢氧化钠(15%,6.88mL),水(20.6mL)和硫酸镁(40.0g),继续搅拌30分钟,反应液过滤,加入水(600mL),用乙酸乙酯(200mL×2)萃取,有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=10:1)分离,得到化合物A-5。
1H NMR(400MHz,CDCl3)δ7.32-7.37(m,5H),6.23(t,J=2.4H,1H),5.50(t,J=2.4H,1H),5.19(dd,J=12.0,28.4H,2H),4.65(dd,J=3.2,6.0H,1H),3.01-3.10(m,1H),2.66-2.72(m,1H),1.44(s,9H)。
(5)向化合物A-5(12.0g,36.2mmol)的四氢呋喃(120mL)溶液中加入1.8-二氮杂二环[5.4.0]十一烷-7-烯(551mg,3.62mmol),化合物A-6(15.9g,72.4mmol),反应液在25℃下搅拌16小时。反应液加入水(200mL),用乙酸乙酯(100mL×2)萃取,有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到6:1)分离,得到化合物A。
MS-ESI[M+H]+,计算值552,实测值552。
1H NMR(400MHz,CDCl3)δ7.46-7.81(m,6H),7.29-7.38(m,7H),7.15-7.22(m,2H),5.14-5.24(m,2H),4.51-4.62(m,2H),2.78-3.05(m,1H),2.33-2.49(m,2H),2.08-2.14(m,2H),1.40-1.44(m,9H)。
实施例1化合物1
化合物1的合成路线如下所示:
(1)向化合物A(5.00g,9.06mmol)的异丙醇(20.0mL)溶液中加入钯碳(500mg,10%),反应液在氢气氛(15psi)25℃下搅拌12小时。反应液过滤,减压浓缩,得到化合物1-1。
MS-ESI[M+H]+,计算值462,实测值462。
1H NMR(400MHz,CDCl3)δ7.78-7.84(m,1H),7.60(d,J=7.2Hz,1H),7.42-7.53(m,3H),7.28-7.38(m,4H),7.20-7.24(m,1H),5.03-5.28(m,1H),4.49-4.60(m,1H),2.73-3.02(m,1H),2.43-2.57(m,1H),2.19-2.37(m,1H),1.90-2.09(m,2H),1.42-1.52(m,9H)。
(2)向化合物1-1(300mg,650μmol)的乙腈(6.0mL)溶液中加入碳酸钾(200mg,1.45mmol)和碘代异丙烷(331mg,1.95mmol,195μL),反应液在25℃氮气保护下搅拌16小时。反应液减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到0:1)分离得到化合物1-2。
MS-ESI[M+H]+,计算值504,实测值504。
1H NMR(400MHz,CDCl3)δ7.59-7.65(m,2H),7.51-7.56(m,3H),7.35-7.39(m,3H),7.22(d,J=7.6Hz,2H),5.00-5.21(m,2H),4.51-4.55(m,1H),2.92-3.13(m,1H),2.75-2.90(m,1H),2.40-2.52(m,2H),2.08-2.16(m,1H),1.49(d,J=3.2Hz,9H),1.37-1.44(m,3H),1.27-1.31(m,3H)。
(3)向化合物1-2(220mg,436μmol)的四氢呋喃(3.0mL)溶液中加入盐酸水溶液(1mol/L,300μL),反应液在25℃下搅拌1小时。反应液用饱和碳酸氢钠水溶液调节pH值到7,用二氯甲烷(15.0mL×3)萃取,有机相用无水硫酸钠干燥,过滤,有机相减压浓缩.粗品经硅胶柱层析法(二氯甲烷/甲醇=5:1)分离得到化合物1-3。
MS-ESI[M-Boc+H]+,计算值240,实测值240。
1H NMR(400MHz,CDCl3)δ5.02-5.11(m,1H),4.36-4.48(m,1H),2.87-3.03(m,1H),2.30-2.38(m,2H),1.87(m,2H),1.63-1.74(m,1H),1.39-1.48(m,9H),1.26-1.29(m,6H)。
(4)向化合物1-4(66.2mg,259μmol)的二氯甲烷(3.0mL)溶液中加入6-氯-1-羟基苯并三唑(38.2mg,282μmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(54.2mg,282μmol),二异丙基乙基胺(91.4mg,707μmol)和化合物1-3(80.0mg,235μmol),应液在氮气保护25℃下搅拌16小时。反应液加入水(20.0mL),用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇=5:1)分离得到化合物1-5。
MS-ESI[M+H]+,计算值577,实测值577。
1H NMR(400MHz,CDCl3)δ4.95-5.18(m,2H),4.27-4.64(m,1H),3.58-3.79(m,1H),3.40-3.56(m,1H),2.73-3.20(m,1H),2.51-2.72(m,1H),2.31-2.49(m,1H),2.06-2.29(m,1H),1.85-2.03(m,1H),1.60-1.72(m,1H),1.58(s,2H),1.50(s,3H),1.39-1.46(m,13H),1.22-1.32(m,8H),1.02-1.09(m,4H),0.86-0.95(m,2H)。
(5)化合物1-5(80.0mg,138μmol)溶于甲酸(1.0mL),反应液在30℃下搅拌1小时。反应液用饱和碳酸氢钠水溶液调节pH值到7,用二氯甲烷(60.0mL×2)萃取,有机相用无水硫酸钠干燥,过滤,有机相减压浓缩,得到化合物1-6。
MS-ESI[M+H]+,计算值377,实测值377。
(6)向化合物1-6(30.0mg,79.6μmol)的N,N-二甲基甲酰胺(2.0mL)溶液中加入丙基磷酸酐(126mg,199μmol,118μL,50%),二异丙基乙基胺(30.9mg,239μmol)和化合物1-7(36.2mg,159μmol),反应液在氮气保护25℃下搅拌12小时。反应液加入水(150mL),用乙酸乙酯(150.0mL×2)萃取,合并有机相用饱和食盐水(150.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,经高效液相色谱法分离(Welch Xtimate C18,150mm×25mm 5μm,A:水(0.225%甲酸);B:乙腈,30%-70%:30分钟)得到化合物1的甲酸盐。
MS-ESI[M+H]+,计算值586,实测值586。
1H NMR(400MHz,MeOD)δ4.97-5.08(m,2H),4.56(d,J=4.8Hz,1H),4.13-4.22(m,1H),3.98-4.06(m,1H),3.81-3.89(m,1H),2.66-2.75(m,1H),2.36-2.52(m,1H),2.15-2.31(m,2H),1.92-2.00(m,1H),1.60-1.65(m,1H),1.40-1.42(m,1H),1.28(d,J=6.0Hz,6H),1.07-1.09(m,3H),1.04-1.07(m,9H),0.95-0.97(m,1H),0.91-0.94(m,3H)。
试验例化合物对SARS-COV-2 3CLpro靶点的抑制效果
实验目的:检测待测化合物对SARS-COV-2 3CLpro靶点的抑制效果。
实验材料:试验药品为本发明实施例化合物自制;SARS-COV-2 3CLpro由上海润诺生物科技有限公司提供,FRET多肽购自GL-China(货号为787985);二甲亚砜购自Sigma(货号为D4540);OptiPlate-384购自PerkinElmer(货号为6007270);离心机购自Eppendorf(型号为5430);酶标仪购自Biotek(型号为Synergy2);Echo 550购自Labcyte(型号为Echo550)。
实验方法:将待测化合物溶解在二甲亚砜中,配制成浓度为10mM的储备液,测试终浓度为10μM起始,3倍稀释,10个浓度。使用Echo 550转移20nL1000倍终浓度待测化合物溶液到384孔反应板中。在空白孔和阴性对照孔中加入20nL二甲亚砜。在空白孔中加入10μL的1倍终浓度的反应溶液(50mM三羟甲基氨基甲烷盐酸盐(Tris-HCI)pH 7.5,1M硫酸钠,1mM乙二胺四乙酸,0.01%胎牛血清),其余孔中加入10μL的10nM的SARS-COV-2 3CLpro溶液。1000rpm离心1分钟,室温孵育15分钟。在反应板各孔中加入10μL的30μM的FRET多肽,开始反应。将反应板在1000rpm离心1分钟,使用Synergy 2连续读取荧光信号。采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物抑制酶活性的IC50值。检测结果如表1。
表1
实施例 | IC50(nM) |
1的甲酸盐 | 18 |
由表1测试数据可知,本发明化合物对SARS-COV-2 3CLpro具有显著的抑制效果,具有用于制备治疗和预防包括SARS-CoV-2、SARS-CoV-1、MERS-CoV、HCoV、TGEV、MHV、BCoV、IBV等冠状病毒感染引起的疾病的药物的潜力。
申请人声明,本发明通过上述实施例来说明所述化合物、包含其药物组合物及其应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (9)
1.一种式I所示的化合物、或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,
其中,
R1选自:C1-C3烷基、-COORa、-CONRaRb;优选地,R1为-COORa;
Ra和Rb各自独立地选自:H、任选取代的C1-C4烷基、任选取代的3-8元碳环基或任选取代的4-8元杂环基,或Ra和Rb与它们相连的N原子形成任选取代的4-8元杂环,其中,所述杂环包含1-3个选自N、O、S、P的杂原子,所述取代是指被选自下组的1-3个取代基取代:卤素、C3-C8碳环基、3-8元杂环基、C1-C4烷基和C1-C4卤代烷基;
A为C3-C6碳环基,其中,所述碳环基可任选地被1-3个选自下组的取代基取代:卤素、C1-C3烷基和C1-C3烷氧基;
R2选自:C1-C6烷基、C2-C6烯基、C2-C6炔基或C3-C8碳环基,其中,所述烷基、烯基、炔基、碳环基可任选地被1-3个R’取代;
每个R’独立地选自:卤素、氧代(=O)、C1-C6烷基、C1-C4烷氧基、或C3-C8碳环基;
R3选自:H、C1-C6烷基、C1-C6卤代烷基、-(CH2)m-R、-C(=O)-C1-C6烷基、-C(=O)-C1-C6卤代烷基、-C(=O)O-C1-C6烷基、-C(=O)NRcRd、-SO2-C1-C6烷基、-SO2-C1-C6卤代烷基;
R选自:任选取代的3-8元碳环基或任选取代的4-8元杂环基,其中,所述取代是指被选自下组的1-3个取代基取代:卤素、氧代(=O)、C3-C8碳环基、4-8元杂环基、C1-C4烷基、C1-C4卤代烷基和C1-C3烷氧基;
Rc、Rd各自独立地选自:H、任选取代的C1-C6烷基,或Rc和Rd与它们相连的N原子形成任选取代的4-8元杂环,其中,所述杂环包含1-3个选自N、O、S、P的杂原子,所述取代是指被选自下组的1-3个取代基取代:卤素、C1-C4烷基和C1-C4卤代烷基;
m为0、1、2、3或4。
2.如权利要求1所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,
选自:/>
3.如权利要求1或2中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R1选自:COORa;Ra选自:H、C1-C6烷基或C1-C6卤代烷基;优选地,Ra为甲基、乙基或异丙基。
4.如权利要求1-3中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R2为C1-C6烷基或C3-C8碳环基;优选地,R2为叔丁基、异丙基或环丙基。
5.如权利要求1-4中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R3选自:三氟乙酰基、三氟甲磺酰基、甲磺酰基、特戊酰基、新戊酰基、叔丁氧羰基、甲氧基羰基和乙氧基羰基。
6.根据权利要求1-5中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,所述化合物选自下组:
7.一种药物组合物,其特征在于,所述药物组合物包括根据权利要求1-6中任一项所述的化合物和药学上可接受的载体。
8.根据权利要求1-6中任一项所述的化合物或权利要求7所述的药物组合物的用途,其特征在于,所述用途选自下述(a)-(c)中的任意一种:
(a)制备用于预防和/或治疗与主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)有关的病毒感染相关疾病的药物;
(b)制备用于体外非治疗性与主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)的活性有关的抑制剂;或
(c)制备用于体外非治疗性冠状病毒的增殖抑制剂。
9.一种抑制主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)活性的方法,包括步骤:将权利要求1-6中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合或权利要求7所述的药物组合物与主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)接触,从而抑制主蛋白酶(Mpro)或3C样蛋白酶(3CLpro)的活性,优选地,所述方法是非治疗性和非诊断性,更优选地,所述方法是体外的。
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