WO2023051657A1 - 一类氰基化合物、其制备方法及用途 - Google Patents
一类氰基化合物、其制备方法及用途 Download PDFInfo
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- WO2023051657A1 WO2023051657A1 PCT/CN2022/122384 CN2022122384W WO2023051657A1 WO 2023051657 A1 WO2023051657 A1 WO 2023051657A1 CN 2022122384 W CN2022122384 W CN 2022122384W WO 2023051657 A1 WO2023051657 A1 WO 2023051657A1
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- Prior art keywords
- alkyl
- compound
- formula
- halogenated
- aryl
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- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 50
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- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000008720 membrane thickening Effects 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 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
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 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
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000565 sealant Substances 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the invention belongs to the field of medicinal chemistry and chemical synthesis, in particular, the invention relates to a class of cyano compounds, their preparation method and application.
- Coronaviruses are single-stranded positive-sense RNA viruses, and some coronaviruses can spread widely among people and cause severe symptoms.
- coronaviruses that can infect humans, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV and SARS-CoV-2.
- Most functional proteins of coronaviruses are encoded by the ORF1ab gene, which are first translated into a polyprotein, and then cleaved into multiple active proteins by 3CL protease and PL protease. Therefore, inhibiting the activity of 3CL protease can effectively inhibit the replication of the virus.
- Different coronavirus 3CL proteases have a high degree of structural homology, so 3CL protease inhibitors have broad-spectrum anti-coronavirus activity.
- Enterovirus 71 is a small RNA virus, which is one of the common viruses that cause hand, foot and mouth disease, and may also cause meningitis, brainstem encephalitis, myocarditis and other diseases. In recent years, enterovirus 71 has repeatedly broken out in infants and young children, and there is still a lack of effective therapeutic drugs in clinical practice.
- RNA/picornaviruses including coronavirus/enterovirus 71.
- the inventors Based on the crystal structure of 3CL protease, the inventors rationally designed a class of cyano compounds, which can effectively inhibit the 3CL protease activity of coronaviruses and/or picornaviruses, and can effectively inhibit multiple viruses including enterovirus 71 in vitro.
- the 3CL protease activity of a picorna virus can effectively inhibit the replication of the picorna virus at the cellular level, and can be used to prepare drugs for coronavirus and/or picorna virus-induced diseases.
- the inventors have completed the present disclosure on the basis of this.
- the primary object of the present invention is to provide the cyano compound represented by general formula I, its racemate, enantiomer, diastereoisomer and pharmaceutically acceptable salt thereof.
- the second object of the present invention is to provide a preparation method of such compounds.
- the third object of the present invention is to provide a pharmaceutical composition containing the compound.
- the fourth object of the present invention is the use of this type of compound in the preparation of 3CL protease inhibitors.
- the fifth object of the present invention is the use of such compounds in the preparation of drugs for preventing or treating diseases induced by coronaviruses and/or picornaviruses.
- the present invention provides a cyano compound represented by general formula I, its racemate, enantiomer, diastereoisomer and pharmaceutically acceptable salt thereof.
- the present invention provides a process for the preparation of compounds of general formula I.
- the compound of the present invention has 3CL protease inhibitory activity, can inhibit the hydrolysis of the protein complex of gene expression of coronavirus and picorna virus, and then inhibit virus replication and development, and can be used for the prevention and treatment of diseases caused by coronavirus or picorna virus infection.
- the present invention relates to cyano compound shown in general formula I, its racemate, enantiomer, diastereomer or pharmaceutically acceptable salt:
- R 1 is selected from -COR 8 and -SO 2 R 9 ;
- R 2 and R 3 are each independently selected from H, D, C 1 -C 10 alkyl, adamantyl and C 3 -C 7 cycloalkyl, or, R 2 forms with R 3 and the carbon atom connected to it 3-8 membered carbon rings;
- R 4 is selected from H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 20 aryl, C 6 -C 20 aryl substituted by C 1 -C 10 alkyl, C 1 ⁇ C 10 alkoxy substituted C 6 ⁇ C 20 aryl and halogenated C 6 ⁇ C 20 aryl;
- R 5 is selected from H, C 1 -C 10 alkyl and C 3 -C 7 cycloalkyl;
- R 4 and R 5 are connected to each other to form a C 2 -C 6 alkylene group, thereby connecting X and Y;
- R 6 is selected from
- R is selected from H and D;
- R 8 is selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 7 cycloalkyl, halogenated C 1 -C 10 alkyl, halogenated C 3 -C 7 ring Alkyl, -NR 13 R 14 , C 6 ⁇ C 20 aryl, halogenated C 6 ⁇ C 20 aryl, C 1 ⁇ C 10 alkyl substituted C 6 ⁇ C 20 aryl, halogenated C 1 ⁇ C 10 alkyl substituted C 6 -C 20 aryl, 5-20 membered heteroaryl and halogenated 5-20 membered heteroaryl;
- R 9 is selected from C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, halogenated C 1 -C 10 alkyl, halogenated C 3 -C 7 cycloalkyl, -NR 15 R 16 , C 6 ⁇ C 20 aryl, halogenated C 6 ⁇ C 20 aryl, C 1 ⁇ C 10 alkyl substituted C 6 ⁇ C 20 aryl, halogenated C 1 ⁇ C 10 alkyl substituted C 6 ⁇ C 20 aryl Base, 5-20 membered heteroaryl and halogenated 5-20 membered heteroaryl;
- R 13 and R 14 are each independently selected from H and C 1 -C 10 alkyl
- R 15 and R 16 are each independently selected from H and C 1 -C 10 alkyl groups.
- R 2 and R 3 are each independently selected from H, D, C 1 -C 6 alkyl, adamantyl, and C 3 -C 7 cycloalkyl, or, R 2 and R 3 and The connected carbon atoms form a 3-8 membered carbon ring.
- R 2 and R 3 are each independently selected from H, isopropyl, tert-butyl, cyclopentyl, and adamantyl, or, R 2 and R 3 and the carbon atom connected to it form a ring Propyl and Cyclopentyl.
- one of R 2 and R 3 is selected from H, and the other is selected from isopropyl, tert-butyl, cyclopentyl, and adamantyl, or, R 2 and R 3 and the The carbon atoms form cyclopropyl and cyclopentyl.
- R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 6 -C substituted by C 1 -C 6 alkyl 10 aryl, C 1 -C 6 alkoxy substituted C 6 -C 10 aryl and halogenated C 6 -C 10 aryl;
- R 5 is selected from H, C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl;
- R 4 and R 5 are connected to each other to jointly form a C 2 -C 6 alkylene group, thereby connecting X and Y.
- R 4 is selected from C 1 -C 6 alkyl and C 6 -C 10 aryl group, R 5 is selected from H; or, R 4 and R 5 are connected to each other to form a C 2 -C 6 alkylene group, thereby connecting X and Y.
- R 4 and R 5 are linked together to form CH 2 CH 2 and CH 2 CH 2 CH 2 , thereby linking X and Y.
- X and Y are independently selected from O and S, and R 4 and R 5 are connected to each other to form CH 2 CH 2 , thereby connecting X and Y.
- both X and Y are selected from S, or both X and Y are selected from O, and R 4 and R 5 are connected to each other to form CH 2 CH 2 , thereby connecting X and Y.
- X is selected from S
- Y is absent
- R is selected from phenyl and isopropyl
- R is selected from H.
- R is selected from
- R7 is selected from H.
- R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, halogenated C 1 -C 6 alkyl, halogenated C 3 ⁇ C 7 cycloalkyl, -NR 13 R 14 , C 6 ⁇ C 10 aryl, halogenated C 6 ⁇ C 10 aryl, C 1 ⁇ C 6 alkyl substituted C 6 ⁇ C 10 aryl, C 6 -C 10 aryl substituted by halogenated C 1 -C 6 alkyl, 5-10 membered heteroaryl and halogenated 5-10 membered heteroaryl.
- R 8 is selected from C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NR 13 R 14 , C 3 -C 7 cycloalkane group, halogenated C 3 ⁇ C 7 cycloalkyl, phenyl, halogenated phenyl, C 1 ⁇ C 6 alkyl substituted phenyl, halogenated C 1 ⁇ C 6 alkyl substituted phenyl and 5 ⁇ 6 Metaheteroaryl.
- R 9 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, halogenated C 1 -C 6 alkyl, halogenated C 3 -C 7 cycloalkyl, -NR 15 R 16 , C 6 ⁇ C 10 aryl, halogenated C 6 ⁇ C 10 aryl, C 1 ⁇ C 6 alkyl substituted C 6 ⁇ C 10 aryl, halogenated C 1 ⁇ C 6 alkyl substituted C 6 -C 10 aryl, 5-10-membered heteroaryl and halogenated 5-10-membered heteroaryl.
- R 9 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, C 1 -C 6 alkyl substituted phenyl and halogenated C 1 -C 6 alkane Substituted phenyl groups.
- each of R 13 and R 14 is independently selected from H and C 1 -C 6 alkyl.
- each of R 15 and R 16 is independently selected from H and C 1 -C 6 alkyl.
- R 8 is selected from CH 3 , CF 3 , CH 2 CF 3 , CF 2 CF 3 , methoxy, Cyclopropyl, phenyl, and pyridin-3-yl.
- R9 is selected from CH3 , cyclopropyl, phenyl, p-methylphenyl, and p-trifluoromethylphenyl.
- the cyano compound shown in general formula I is selected from the cyano compound shown in general formula IA:
- R 1 , R 2 , R 3 , R 4 , R 5 , X and Y are as defined above.
- the cyano compound shown in general formula I is selected from the cyano compound shown in general formula IB:
- the cyano compound shown in general formula I is selected from any one of the cyano compounds shown in the following general formula:
- R 1 , R 2 , R 3 and R 6 are as defined above.
- the compound represented by general formula I of the present invention is selected from the following compounds:
- the present invention provides the method for preparing the compound shown in general formula I, and described method is one of following methods:
- the step ia) is: the compound represented by the formula II is reacted with the compound represented by the formula III through the action of a condensing agent and a base in a solvent at a temperature of -20°C to 50°C for 0.1-12h to obtain the compound represented by the formula Compound shown in IV;
- the solvent is one or more of the following mixtures, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate and 1,4-bis Oxyhexane;
- the condensing agent is one or more of the following mixtures: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid, 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-hydroxypyridine-N-oxide, 1-propylphosphoric anhydride, 1H - Benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, N,N'-carbonyldiimidazole and O-benzotriazole-tetramethyluronium hexafluorophosphate;
- the base is N,N-diisopropylethylamine, triethylamine and N-methylmorpholine;
- the step ib) is: reacting the compound represented by formula IV with a dehydrating agent in an anhydrous solvent at a temperature of -20°C to 50°C for 1-24 hours to obtain the compound represented by general formula I;
- the anhydrous solvent is one or more of the following mixtures, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane and pyridine;
- the dehydrating agent is trifluoroacetic anhydride and N-(triethylammoniumsulfonyl) methyl carbamate; or
- the compound shown in formula VI is obtained by condensing the compound shown in formula V and the compound shown in formula III, wherein PG in the compound shown in formula V is an amino protecting group;
- the step iia) is: the compound represented by the formula V is reacted with the compound represented by the formula III through the action of a condensing agent and a base in a solvent at a temperature of -20°C to 50°C for 0.1-12h, so as to obtain the compound represented by the formula Compound shown in VI,
- the solvent is one or more of the following mixtures, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate and 1,4-bis Oxyhexane,
- the condensing agent is one or more of the following mixtures, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid, 1-ethyl -(3-Dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-hydroxypyridine-N-oxide, 1-propyl phosphoric anhydride, 1H-benzotri Azol-1-yloxytripyrrolidinyl hexafluorophosphate, N,N'-carbonyldiimidazole and O-benzotriazole-tetramethyluronium hexafluorophosphate;
- the base is N,N-diisopropylethylamine, triethylamine and N-methylmorpholine;
- the protecting group PG of the amino group is tert-butoxycarbonyl, benzyl and p-methoxybenzyl;
- the step iib) is: reacting the compound represented by formula VI with trifluoroacetic acid or an organic solution of hydrogen chloride or Pd/C/ H2 at a temperature of -20°C to 50°C to obtain the compound represented by formula VII;
- the compound shown in formula VII is obtained by aminoacylation, sulfonylation or condensation reaction to the compound shown in formula IV;
- the step iic) is:
- the compound represented by formula VII is subjected to aminoacylation reaction with acid chloride or acid anhydride under the condition of adding a base to obtain the compound represented by formula IV; or,
- the compound represented by formula VII is subjected to sulfonylation reaction with sulfonyl chloride or sulfonic anhydride under alkaline conditions to obtain the compound represented by formula IV; or,
- the compound shown in formula VII is condensed with the carboxyl compound under the conditions of a condensing agent and a base to obtain a compound shown in formula IV;
- the base is N,N-diisopropylethylamine, triethylamine and N-methylmorpholine;
- the condensing agent is one or more of the following mixtures, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid, 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-hydroxypyridine-N-oxide, 1-propylphosphoric anhydride, 1H -Benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, N,N'-carbonyldiimidazole and O-benzotriazole-tetramethyluronium hexafluorophosphate,
- the step iid) is: reacting the compound represented by formula IV with a dehydrating agent in an anhydrous solvent at a temperature of -20°C to 50°C for 1-24h to obtain the compound represented by general formula I;
- the anhydrous solvent is one or more of the following mixtures, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane and pyridine;
- the dehydrating agent is trifluoroacetic anhydride and methyl N-(triethylammoniumsulfonyl)carbamate,
- Another aspect of the present invention also provides a pharmaceutical composition, which comprises a cyano compound selected from the general formula I, its racemate, enantiomer and diastereomer, and their pharmaceutically acceptable One or more of the accepted salts.
- the pharmaceutical composition may also include one or more pharmaceutically acceptable adjuvants, diluents, carriers, excipients or adjuvants.
- Another aspect of the present invention also provides a pharmaceutical composition, which comprises a cyano compound selected from the general formula I, or its racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients; optionally, the pharmaceutical composition further comprises ritonavir or a pharmaceutically acceptable salt thereof.
- Another aspect of the present invention also provides a pharmaceutical combination, which comprises a cyano compound selected from the general formula I, its racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt, and ritonavir or a pharmaceutically acceptable salt thereof.
- Another aspect of the present invention also provides a pharmaceutical composition, which comprises a cyano compound selected from general formula I or a pharmaceutically acceptable salt thereof, ritonavir or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Accepted excipients.
- the compound of the present invention has the inhibitory activity of coronavirus 3CL protease and picornavirus 3CL protease.
- another aspect of the present invention provides a coronavirus 3CL protease inhibitor and/or a picornavirus 3CL protease inhibitor, which comprises a cyano compound selected from the general formula I, its racemate, enantiomer Isomers and diastereoisomers, and one or more of their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions.
- the present invention also provides the above-mentioned cyano compound, its racemate, enantiomer, diastereomer, its pharmaceutically acceptable salt, or their mixture, or the above-mentioned pharmaceutical composition in the preparation of medicine purposes, the drug is selected from drugs for inhibiting coronavirus 3CL protease activity, drugs for preventing and/or treating coronavirus infection, drugs for inhibiting picornavirus 3CL protease activity, and drugs for preventing and and/or drugs to treat picornavirus infections.
- the present invention also provides a method of inhibiting 3CL protease, said method comprising administering to a subject in need of treatment a cyano compound selected from the general formula I of the present invention, its racemates, enantiomers and diastereomers. Enantiomers, and one or more of their pharmaceutically acceptable salts, or the pharmaceutical composition according to the present invention.
- the present invention also provides a method of preventing and/or treating a disease or condition, the method comprising administering to a subject in need of treatment a cyano compound selected from the general formula I of the present invention, its racemate, enantiomer Conformers and diastereoisomers, and one or more of their pharmaceutically acceptable salts, or according to the pharmaceutical composition of the present invention, the disease or disorder is a disease or disorder mediated by 3CL protease , especially diseases or conditions associated with coronavirus infection and/or picornavirus infection.
- the present invention also provides one or more of the cyano compounds represented by the above general formula I, their racemates, enantiomers and diastereomers, and their pharmaceutically acceptable salts, Use of the pharmaceutical composition thereof in the preparation of medicines for preventing or treating related diseases caused by coronavirus and/or picornavirus infection.
- the present invention also provides a method for preventing or treating related diseases caused by coronavirus and/or picornavirus infection.
- the coronavirus is selected from SARS-CoV, MERS-CoV, H229E-CoV, HKU1-CoV, NL63-CoV, OC43-CoV or SARS-CoV-2.
- the related diseases caused by the coronavirus infection are selected from respiratory tract infection, pneumonia or complications thereof.
- C 1 -C 10 alkyl means a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl
- Alkylene can be understood to mean a straight-chain or branched saturated divalent hydrocarbon group.
- C 2 ⁇ C 6 alkylene can be understood as a straight-chain or branched saturated divalent hydrocarbon group with 2-6 carbon atoms, including but not limited to CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 etc.
- C 3 -C 8 cycloalkyl means a cyclic alkyl group containing 3-8 ring carbon atoms.
- C 3 ⁇ C 7 cycloalkyl means a cyclic alkyl group containing 3-7 ring carbon atoms.
- the cycloalkyl group in this disclosure includes but not limited to cyclopropyl, methylcyclopropyl, ethylcyclopropyl , Dimethylcyclopropyl, cyclobutyl, methylcyclobutyl, ethylcyclobutyl, cyclopentyl, cyclohexyl, etc.
- C 1 -C 10 alkoxy means a linear, branched or cyclic alkoxy group containing 1-10 carbon atoms.
- C 1 ⁇ C 6 alkoxy means a straight chain, branched or cyclic alkoxy group containing 1-6 carbon atoms.
- the alkoxy group in this disclosure includes but not limited to methoxy, ethoxy, Propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, cyclopentyloxy, hexyloxy, cyclohexyloxy and the like.
- Aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
- the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
- C 6 -C 20 aryl can be understood as an aryl group having 6-20 carbon atoms.
- C aryl rings with 6 carbon atoms
- C aryl such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 a ring of 3 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
- C 6 -C 10 aryl can be understood as an aryl group having 6-10 carbon atoms.
- C aryl rings with 6 carbon atoms
- C aryl such as phenyl
- C aryl rings with 9 carbon atoms
- C aryl such as indanyl or indenyl
- C 10 aryl rings with 10 carbon atoms
- Heteroaryl is an aromatic ring group containing 5-20 ring atoms, one or more of which is a heteroatom selected from N, O or S, and the rest of the ring atoms are carbon.
- “5-20 membered heteroaryl” can be understood as having 5-20 ring atoms, especially 5 or 6 or 9 or 10 or 13 or 14 ring atoms, and it contains 1-7 independently selected from N, O and the heteroaryl of the heteroatom of S.
- “5-10 membered heteroaryl” can be understood as having 5-10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5 heteroaryls independently selected from N, O and S atom heteroaryl.
- 5-6 membered heteroaryl can be understood as a heteroaryl group having 5 or 6 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S.
- the heteroaryl group described in the present invention can be selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl Or thiadiazolyl and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo Triazolyl, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl,
- Halogen is selected from fluorine, chlorine, bromine, iodine.
- Halo includes monohalo, polyhalo or perhalo, ie one, more or all hydrogen atoms are replaced by halogen.
- Substituted means that one or more hydrogen atoms on a group are replaced by one or more substituents.
- “Therapeutically effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the invention for the onset of one or more symptoms of a particular disease, condition or disorder.
- the amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
- “Pharmaceutically acceptable salt” refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
- pharmaceutical combination refers to a combination comprising two or more active ingredients or pharmaceutically acceptable salts thereof.
- the active ingredients in the pharmaceutical combination or their pharmaceutically acceptable salts can be administered at the same time, in some embodiments of the present invention, the active ingredients in the pharmaceutical combination or their pharmaceutically Acceptable salts may also be administered separately or sequentially.
- “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention or their salts and pharmaceutically acceptable auxiliary materials. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the invention to an organism.
- “Pharmaceutically acceptable excipients” refer to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
- Figure 1 is a graph of the inhibitory rate-concentration of compound 2 on the in vitro activity of the WIV04 strain of SARS-CoV-2.
- Figure 2 is a graph of the inhibitory rate-concentration of compound 2 on the in vitro activity of SARS-CoV-2 strain B.1.351.
- Fig. 3 is a graph showing the inhibitory effect of Compound 2 on the virus titer in the lungs of mice in Example 26 after 2 days of infection (Fig. A) and 4 days after infection (Fig. B).
- FIG. 4 is a graph showing the body weight changes of mice in Example 26.
- Fig. 5 is a graph showing the inhibitory effect of compound 2 on the virus titer in the brain of mice after 4 days of infection in Example 26.
- Step 1 Add the starting material SMA (2.74g, 11.85mmol), 35ml of dichloromethane and 35ml of DMF into the reaction flask, cool down to 0°C, add the starting material SMB (3.56g, 11.86mmol), benzotri Azolazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 6.29g, 14.22mmol) and N-methylmorpholine (NMM, 3.91ml, 35.56mmol), heated to room temperature for reaction 10h, after the reaction was completed, an appropriate amount of dichloromethane was added, and the organic phase was washed successively with 1N aqueous hydrochloric acid solution and saturated brine.
- SMB benzotri Azolazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
- NMM N-methylmorpholine
- Step 2 Add INT-1 (3.71g, 8.58mmol), 37ml of THF and 37ml of purified water and lithium hydroxide monohydrate (0.72g, 17.16mmol) into the reaction flask, and react at room temperature for 2h.
- Embodiment 24 Compound inhibits SARS-CoV-2 3CLpro activity test
- the inhibitory activity of the tested compounds on SARS-CoV-2 3CL pro enzyme activity was evaluated by fluorescence resonance energy transfer method.
- the volume of the entire enzymatic reaction system is 120 ⁇ L, the final concentration of protease is 30 nM, and the final concentration of substrate is 20 ⁇ M.
- the buffer of the reaction system includes 50mM Tris pH7.3, 1mM EDTA.
- the test time is 3.5min, and the fluorescence value is read every 35s. For the final result, the reading value of the first 2 minutes was used to fit the reaction rate, and compared with the control group (DMSO), the inhibition rate was calculated.
- the IC50 value and the inhibition rate curve were obtained by fitting with the
- the experimental results are shown in Table 1.
- the results show that the compound of the present invention has a potent inhibitory effect on SARS-CoV-2 3CL pro .
- the range of IC50 values is: A means ⁇ 0.1 ⁇ M, B means 0.1-1 ⁇ M, C means 1-10 ⁇ M.
- Example 24-2 Compound 2 was tested for the inhibitory activity of the mutant 3CL protease of the SARS-CoV-2 Omicron strain
- a reaction buffer was prepared containing 20 mM Tris-HCl, 1 mM EDTA, 0.01% BSA, 1 mM DTT and 100 mM NaCl.
- the compounds to be tested were diluted to different concentrations in dimethyl sulfoxide (DMSO) with the Echo pipetting system and transferred to 384-well plates.
- DMSO dimethyl sulfoxide
- the mutant 3CL protease was diluted with reaction buffer, and added to a 384-well plate at an amount of 10 ⁇ L/well, centrifuged at 1000 rpm for 1 min, and then incubated at room temperature for 30 minutes. Then add 10 ⁇ L/well of substrate, and centrifuge at 1000 rpm for 30 s to start the enzyme reaction.
- the final concentration of the enzyme is 50 nM
- the final concentration of the substrate is 20 ⁇ M
- the concentration of the compound ranges from 10000 nM to 0.51 nM.
- select the Kinetic Reduction Vmax mode on the Flexstation 3 microplate reader read the fluorescence value of 490nm wavelength continuously every 75 seconds, a total of 35 times, obtain the reaction rate value (V), calculate the inhibition rate, and use XLfit software to perform four-parameter Fitting obtains the half maximal inhibitory concentration ( IC50 ).
- the inhibition rate calculation method is as follows:
- Inhibition rate (V max -V compound )/(V max -V min )*100%
- V max is the reaction rate value of wells containing only enzyme and substrate
- V min is the reaction rate value of wells containing only substrate
- V Compound is the reaction rate value of wells containing test compound, enzyme and substrate .
- Example 24-3 Compound 2 was tested for the inhibitory activity of coronavirus 3CL protease from different sources
- 3CL protease self-recombined full-length coronavirus 3CL protease based on the coronavirus genome sequence, the genome GenBank numbers of SARS-CoV, MERS-CoV, H229E-CoV, HKU1-CoV, NL63-CoV and OC43-CoV are AAP13442.1, MT387202.1, AF304460.1, AY597011.2, AY567487.2 and AY903459.1, the DNA sequences required for the expression of six coronavirus 3CL protease proteins were purchased from Nanjing GenScript Biotechnology Co., Ltd.
- 3CL protease substrate was purchased from Nanjing GenScript Biotechnology Co., Ltd.
- Chymotrypsin substrate was purchased from Jill Biochemical Co., Ltd.
- reaction buffer (containing 50mM Tris and 1mM EDTA).
- the compound to be tested was dissolved in DMSO to form a 100 mM stock solution, and was further diluted with a 2-fold gradient with a reaction buffer, with a total of 11 concentrations.
- the volume of the entire enzymatic reaction system is 120 ⁇ L, and the final concentrations of SARS-CoV, MERS-CoV, H229E-CoV, HKU1-CoV, NL63-CoV and OC43-CoV proteases are 30nM, 80nM, 30nM, 20nM, 30nM and 10nM, respectively , with a final substrate concentration of 10 ⁇ M.
- the wavelengths of excitation light and emission light during reading are 340nm and 490nm, respectively.
- the test time is 10 minutes, and the fluorescence value is read every 1 minute.
- the final result is obtained by fitting the reading value of the first 5 minutes to obtain the reaction rate, and the inhibition rate is calculated.
- 3CL protease source Compound 2 IC 50 ( ⁇ M) HKU1-CoV 0.0049 OC43-CoV 0.010 SARS-CoV-1 0.024 MERS-CoV 0.060 H229E-CoV 0.13 NL63-CoV 0.85
- Example 25-1 Compound 2 has inhibitory effect on SARS-CoV-2 WIV04, B.1.351 strain cell level
- Vero E6 cells were used in the test, and Vero E6 cells (50,000 cells/well) were added to a 48-well plate, 100 ⁇ L/well of medium containing gradient concentration compounds was added, and SARS-CoV-2 was added one hour later, the multiplicity of infection (MOI) is 0.01. After co-incubating for 1 hour, the supernatant was aspirated, washed and re-added with 200 ⁇ L/well of medium containing gradient concentrations of compounds, and incubated at 37°C for 24 hours. After 24 hours, the cell supernatant was collected, viral RNA was extracted from the supernatant, and the virus copy number of the supernatant was detected by real-time fluorescent quantitative PCR. The compound inhibition rate was calculated according to the virus copy number, and the EC 50 of the compound was calculated by Prism 6.0.
- Example 25-2 Compound 2 inhibits the cell level of SARS-CoV-2 Vero E6 original strain (WIV04), Delta strain (B.1.617.2), and Omicron strain (B.1.1.529)
- Vero E6 cells the method of detecting the virus copy number in the culture supernatant by real-time fluorescent quantitative PCR method in Vero E6 cells was used to study the effect of compound 2 on the original strain of SARS-CoV-2 (WIV04 strain), Delta strain (B.1.617 .2) and Omicron strain (B.1.1.529) inhibited replication in cells. Since Vero E6 cells highly express the efflux transporter P-gp, 0.5 ⁇ M P-gp inhibitor CP-100356 was added to incubate with the compound.
- Vero E6 was purchased from ATCC (Product No. CRL-1586), original strain of SARS-CoV-2 (SARS-CoV-2-WIV04 strain), Delta strain (B.1.617.2), Omicron strain ((B.1.1.529)
- the virus comes from the Microbial Bacteria (Virus) Species Collection Center of Wuhan Institute of Virology, Chinese Academy of Sciences.
- StepOne Plus Real-time PCR system (4376600, ABI, USA)
- the Vero E6 cells were digested with trypsin and placed in medium (90% DMEM, 10% fetal bovine serum), seeded into a 48-well plate with 50,000 cells per well, and cultured overnight.
- the compound to be tested was dissolved in DMSO to prepare a 40 mM stock solution, and further diluted with a medium containing 0.5 ⁇ M Pgp inhibitor to obtain the concentration required for the test.
- the final concentration of the compound to be tested in the experiment ranged from 1 ⁇ M to 0.004 ⁇ M.
- Vero E6 cells were digested and placed in culture medium (90% DMEM, 10% fetal calf serum), seeded into a 96-well plate with 20,000 cells per well, and cultured overnight. Dissolve the compound to be tested in DMSO to prepare a 40mM stock solution, and further use culture medium or medium containing 0.5 ⁇ M Pgp inhibitor for gradient dilution to obtain the concentration required for the test. The final concentration of the test compound in the experiment ranges from 500 ⁇ M to 1.95 ⁇ M .
- Test results As shown in Table 4, after being combined with the P-gp inhibitor CP-100356, Compound 2 can dose-dependently inhibit the replication of the Delta strain in Vero E6 cells, with an IC 50 of 0.040 ⁇ M. In the original strain, compound 2 combined with P-gp inhibitor also exerted a strong inhibitory effect, with an IC 50 of 0.027 ⁇ M. In addition, compound 2 combined with P-gp inhibitors could significantly inhibit the replication of Omicron strain in Vero E6 cells, with an IC 50 of 0.12 ⁇ M. Compound 2 alone and in combination with P-gp inhibitors had no obvious cytotoxicity on the proliferation of Vero E6 cells, with CC 50 >500 ⁇ M.
- Example 26 In vivo antiviral effect of compound 2 on SARS-CoV-2 delta strain on hACE2-K18 transgenic mice
- Vero E6 cells were purchased from ATCC (Cat. No. CRL-1586).
- StepOne Plus Real-time PCR system (4376600, ABI, USA)
- K18-hACE2 transgenic mice were infected with the delta strain of SARS-CoV-2 by intranasal drops, and this day was Day 0.
- the vehicle 50 mg/kg or 200 mg/kg compound 2 (combined with 50 mg/kg cytochrome P450 inhibitor ritonavir) were administered by intragastric administration, and BID was administered for 2 days (dose on day 0 1 time, 2 times on the 1st day, 1 time on the 2nd day) or 4 days (one time on the 0th day, 2 times on the 1st, 2nd and 3rd day respectively).
- the body weight changes of the mice were recorded, and lung and brain tissues were collected at the end point.
- the left lung was fixed in formaldehyde, and then used for histopathological examination after embedding, sectioning and H&E staining.
- the right lung and brain tissues were each divided into two parts. One part was ground and the homogenate was taken to extract RNA and reverse-transcribed, and the virus copy number was detected by real-time fluorescent quantitative PCR. Another part of the homogenate was taken after grinding to detect the virus titer by plaque test.
- the plaque test method is as follows: Vero E6 cells were seeded in a 24-well plate, with 12,000 cells per well, and cultured overnight. The stock solution of tissue homogenate was serially diluted 10 times in DMEM medium for later use.
- Test result as shown in table 5, after infecting 2 days, compare with model group (virus average copy number is 9.19 ⁇ 0.30 log 10copies/g), under the situation of joint ritonavir, compound 2 50mg/kg and 200mg/kg significantly reduced the viral load in the lungs, the average copy number was 7.66 ⁇ 0.27 log10 copies/g and 6.79 ⁇ 0.30 log10 copies/g, and the virus copy number decreased by 2.4 log10 copies at the dose of 200mg/kg /g. After 4 days of infection, a sustained inhibitory effect of compound 2 on viral copy number was observed. In terms of virus titer, as shown in Figure 3, a significant inhibitory effect of compound 2 was observed.
- the virus replication was completely inhibited at a dose of 200 mg/kg, and no titer was detected.
- the virus titer decreased by more than 3 log10 PFU/g, and compound 2 showed a sustained inhibitory effect on the virus titer after 4 days of infection.
- body weight as shown in Figure 4, after 4 days of infection, the body weight of the mice in the model group lost about 10%, while the body weight of the compound 2 administration group did not decrease significantly, indicating that compound 2 did not appear obvious toxicity under continuous administration.
- compound 2 After 4 days of infection, compared with the model group, compound 2 can significantly reduce the virus copy number in the brain of mice at the dose of 50mg/kg and 200mg/kg, especially the virus copy number in the brain at the dose of 200mg/kg Comparable to the uninfected normal group.
- compound 2 had no virus titer at both doses, showing a strong inhibitory effect of compound 2 .
- Example 27 Selectivity of compound 2 for kinases
- Full Human Panel[10uM ATP]KinaseProfiler is a test product provided by Eurofins, article number: 50-005KP10, this product contains 413 kinases.
- Example 28 Selectivity of compound 2 to safety targets
- Safety47 Panel Dose Response SAFETYscan is a test product provided by Eurofins, article number: 87-1003DR. This product contains 78 tests related to 47 safety targets.
- the experimental methods used include: cAMP test, calcium flow test, hormone nuclear receptor test, kinase binding test, enzyme activity test, neurotransmitter transporter test, ion channel test and transport experiments. Specific methods for each experiment are available on the eurofins website at: https://www.eurofinsdiscoveryservices.com/catalogmanagement/viewItem/Safety47-Panel-Dos e-Response-SAFETYscan-DiscoverX/87-1003DR.
- Human plasma was purchased from BioIVT, anticoagulated with EDTA K2, and stored at -80°C.
- 96-well equilibrium dialysis plates were purchased from HTDialysis LLC.
- Equilibrium dialysis membranes were purchased from Gales Ferry.
- the dialysis membrane was soaked in ultrapure water for 60 minutes to separate the membrane into two pieces, then soaked in 20% ethanol for 20 minutes, and finally soaked in the buffer used for dialysis for 20 minutes.
- the ratio of sample peak area to internal standard peak area The buffer side represents the free concentration of the compound, the ratio of sample peak area to internal standard peak area
- the plasma side represents the sum of the free and bound concentrations of the compound, the ratio of the sample peak area to the internal standard peak area is initially Plasma samples represent the total concentration of compound at the beginning of the sample incubation.
- mice There were 60 Balb/c mice (purchased from Shanghai Minchang Biotechnology Co., Ltd.), half male and half male, weighing 18-25 g.
- Balb/c mice were intragastrically administered Compound 2 at a dose of 100 mg/kg and a volume of 10 mL/kg.
- Example 31 Safety pharmacological test on the effect of compound 2 on the cardiovascular system of cynomolgus monkeys by intragastric administration
- SBP systolic blood pressure
- DBP diastolic blood pressure
- MBP mean arterial blood pressure
- mice 32 cynomolgus monkeys (groups 1 and 4, 5 animals/sex/group, groups 2 and 3, animals/sex/group, 4 groups in total) were randomly divided into groups, administered by nasal feeding Administration of compound 2 (40, 160 and 600mg/kg/day) or control preparation (98.9% vehicle preparation+1.1%MTBE, 0mg/kg/day) was administered twice a day for a total of 14 days. sky. All animals were included in this study to evaluate the effect of drug administration on ECG parameters (including heart rate, PR interval, QRS duration, QT interval, and QTcF) and blood pressure during the pre-dose phase, dosing period, and recovery period .
- ECG parameters including heart rate, PR interval, QRS duration, QT interval, and QTcF
- Test results Under the conditions of this test, cynomolgus monkeys were given compound 2 (40, 160 and 600 mg/kg/day) by nasal feeding for 14 days, twice a day, and there was no change in the cardiovascular system related to the test product; Arrhythmia related to the test product; no changes in ECG parameters or blood pressure related to the test product were seen throughout the test.
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Abstract
Description
仪器名称 | 品牌 | 型号 |
Echo纳升级声波移系统 | Labcyte | Echo 650 |
Flexstation 3酶标仪 | MolecMar Devices | FLEX3 |
离心机 | Eppendorf | 5810 |
3CL蛋白酶 | 化合物2 IC 50(μM)(n=3*) |
SARS-CoV-2(奥密克戎株) | 0.022±0.00090 |
试剂材料 | 品牌 | 货号 |
牛胰腺来源的糜蛋白酶 | Sigma | C4129 |
Tris | Sigma | BCBX3837 |
EDTA | Sigma | 0001434776 |
3CL蛋白酶来源 | 化合物2 IC 50(μM) |
HKU1-CoV | 0.0049 |
OC43-CoV | 0.010 |
SARS-CoV-1 | 0.024 |
MERS-CoV | 0.060 |
H229E-CoV | 0.13 |
NL63-CoV | 0.85 |
Claims (12)
- 一种通式I所示的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐:其中,R 1选自-COR 8和-SO 2R 9;R 2与R 3各自独立地选自H、D、C 1~C 10烷基、金刚烷基和C 3~C 7环烷基,或者,R 2与R 3和与之相连的碳原子形成3~8元碳环;X选自O、S、S(=O) 2和S=O;Y不存在或选自O、S、S(=O) 2和S=O;R 4选自H、C 1~C 10烷基、C 3~C 8环烷基、C 6~C 20芳基、C 1~C 10烷基取代的C 6~C 20芳基、C 1~C 10烷氧基取代的C 6~C 20芳基和卤代C 6~C 20芳基;R 5选自H、C 1~C 10烷基和C 3~C 7环烷基;或者,R 4与R 5彼此相连共同形成C 2-C 6亚烷基,从而连接X和Y;R 7选自H和D;R 8选自H、C 1~C 10烷基、C 1~C 10烷氧基、C 3~C 7环烷基、卤代C 1~C 10烷基、卤代C 3~C 7环烷基、-NR 13R 14、C 6~C 20芳基、卤代C 6~C 20芳基、C 1~C 10烷基取代的C 6~C 20芳基、卤代C 1~C 10烷基取代的C 6~C 20芳基、5~20元杂芳基和卤代5~20元杂芳基;R 9选自C 1~C 10烷基、C 3~C 7环烷基、卤代C 1~C 10烷基、卤代C 3~C 7环烷基、-NR 15R 16、C 6~C 20芳基、卤代C 6~C 20芳基、C 1~C 10烷基取代的C 6~C 20芳基、卤代C 1~C 10烷基取代的C 6~C 20芳基、5~20元杂芳基和卤代5~20元杂芳基;R 13和R 14各自独立地选自H和C 1~C 10烷基;R 15和R 16各自独立地选自H和C 1~C 10烷基。
- 根据权利要求1所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,其中,R 2与R 3各自独立地选自H、D、C 1~C 6烷基、金刚烷基和C 3~C 7环烷基,或者,R 2与R 3和与之相连的碳原子形成3~8元碳环;或者R 2与R 3各自独立地选自H、异丙基、叔丁基、环戊基和金刚烷基,或者,R 2与R 3和与之相连的碳原子形成环丙基和环戊基;或者R 2与R 3中的一个选自H,另一个选自异丙基、叔丁基、环戊基和金刚烷基,或者,R 2与R 3和与之相连的碳原子形成环丙基和环戊基。
- 根据权利要求1或2所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,其中,R 4选自H、C 1~C 6烷基、C 3~C 8环烷基、C 6~C 10芳基、C 1~C 6烷基取代的C 6~C 10芳基、C 1~C 6烷氧基取代的C 6~C 10芳基和卤代C 6~C 10芳基;R 5选自H、C 1~C 6烷基和C 3~C 7环烷基;或者,R 4与R 5彼此相连共同形成C 2-C 6亚烷基,从而连接X和Y;或者,R 4与R 5彼此相连共同形成CH 2CH 2和CH 2CH 2CH 2,从而连接X和Y。
- 根据权利要求1-3任一项所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,其中,R 8选自H、C 1~C 6烷基、C 1~C 6烷氧基、C 3~C 7环烷基、卤代C 1~C 6烷基、卤代C 3~C 7环烷基、-NR 13R 14、C 6~C 10芳基、卤代C 6~C 10芳基、C 1~C 6烷基取代的C 6~C 10芳基、卤代C 1~C 6烷基取代的C 6~C 10芳基、5~10元杂芳基和卤代5~10元杂芳基,R 13和R 14各自独立地选自H和C 1~C 6烷基;或者R 8选自C 1~C 6烷基、卤代C 1~C 6烷基、C 1~C 6烷氧基、-NR 13R 14、C 3~C 7环烷基、卤代C 3~C 7环烷基、苯基、卤代苯基、C 1~C 6烷基取代的苯基、卤代C 1~C 6烷基取代的苯基和5~6元杂芳基,R 13和R 14各自独立地选自H和C 1~C 6烷基;或者R 9选自C 1~C 6烷基、C 3~C 7环烷基、卤代C 1~C 6烷基、卤代C 3~C 7环烷基、-NR 15R 16、C 6~C 10芳基、卤代C 6~C 10芳基、C 1~C 6烷基取代的C 6~C 10芳基、卤代C 1~C 6烷基取代的C 6~C 10芳基、5~10元杂芳基和卤代5~10元杂芳基,R 15和R 16各自独立地选自H和C 1~C 6烷基;或者R 9选自C 1~C 6烷基、C 3~C 7环烷基、苯基、C 1~C 6烷基取代的苯基和卤代C 1~C 6烷基取代的苯基;或者R 9选自CH 3、环丙基、苯基、对甲基苯基和对三氟甲基苯基。
- 根据权利要求1-4任一项所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,其中,X选自O、S、S(=O) 2和S=O;Y不存在或选自O、S和S=O;R 4选自C 1~C 6烷基和C 6~C 10芳基,R 5选自H;或者,R 4与R 5彼此相连共同形成C 2~C 6亚烷基,从而连接X和Y;或者X、Y各自独立地选自O、S和S=O,R 4与R 5彼此相连共同形成CH 2CH 2和CH 2CH 2CH 2,从而连接X和Y;或者X、Y各自独立地选自O和S,R 4与R 5彼此相连共同形成CH 2CH 2,从而连接X和Y。
- 一种制备通式I所示化合物的方法,所述方法为以下方法之一:方法i:ia)由式II所示化合物与式III所示化合物通过缩合反应得到式IV所示化合物;优选地,所述步骤ia)为:式II所示化合物在-20℃~50℃温度下,在溶剂中,通过缩合剂和碱的作用与式III所示化合物反应0.1-12h,从而得到式IV所示化合物,任选地,所述溶剂为以下的一种或几种混合,四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙酸乙酯、1,4-二氧六环;任选地,所述缩合剂为以下的一种或几种混合,2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑、2-羟基吡啶-N-氧化物、1-丙基磷酸酐、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、N,N'-羰基二咪唑、O-苯并三氮唑-四甲基脲六氟磷酸盐;任选地,所述碱为N,N-二异丙基乙胺、三乙胺、N-甲基吗啉;ib)式IV所示化合物通过脱水得到通式I所示化合物;优选地,所述步骤ib)为:式IV所示化合物在-20℃~50℃温度下,在无水溶剂中,与脱水剂反应1-24h得到通式I所示化合物;任选地,所述无水溶剂为以下的一种或几种混合,四氢呋喃、二氯甲烷、甲苯、1,4-二氧六环和吡啶;任选地,所述脱水剂为三氟醋酸酐或N-(三乙基铵磺酰)氨基甲酸甲酯;或者方法ii:iia)由式V所示化合物与式III所示化合物缩合得到式VI所示化合物,其中式V所示化合物中的PG为氨基的保护基团;优选地,所述步骤iia)为:式V所示化合物在-20℃~50℃温度下,在溶剂中,通过缩合剂和碱的作用与式III所示化合物反应0.1-12h,从而得到式VI所示化合物;任选地,所述溶剂为以下的一种或几种混合,四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙酸乙酯和1,4-二氧六环;任选地,所述缩合剂为以下的一种或几种混合,2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑、2-羟基吡啶-N-氧化物、1-丙基磷酸酐、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、N,N'-羰基二咪唑和O-苯并三氮唑-四甲基脲六氟磷酸盐;任选地,所述碱为N,N-二异丙基乙胺、三乙胺和N-甲基吗啉;任选地,所述氨基的保护基团PG为叔丁氧羰基、苄基和对甲氧基苄基;iib)式VI所示化合物脱保护得到式VII所示化合物;优选地,所述步骤iib)为:在-20℃~50℃温度下,将式VI所示化合物与三氟醋酸或氯化氢的有机溶液或Pd/C/H 2反应得到式VII所示化合物;iic)式VII所示化合物通过氨基酰化、磺酰化或缩合反应得到式IV所示化合物;优选地,所述步骤iic)为:在-20℃~50℃温度下,将式VII所示化合物与酰氯或酸酐在加入碱的条件下进行氨基酰化反应得到式IV所示化合物;在-20℃~50℃温度下,将式VII所示化合物与磺酰氯或磺酸酐在碱的条件下进行磺酰化反应得到式IV所示化合物;在-20℃~50℃温度下,将式VII所示化合物与羧基化合物在缩合剂与碱的条件下进行缩合反应得到式IV所示化合物;任选地,所述碱为N,N-二异丙基乙胺、三乙胺和N-甲基吗啉;任选地,所述缩合剂为以下的一种或几种混合,2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑、2-羟基吡啶-N-氧化物、1-丙基磷酸酐、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、N,N'-羰基二咪唑和O-苯并三氮唑-四甲基脲六氟磷酸盐;iid)式IV所示化合物通过脱水得到通式I所示化合物;优选地,所述步骤iid)为:式IV所示化合物在-20℃~50℃温度下,在无水溶剂中,与脱水剂反应1-24h得到通式I所示化合物;任选地,所述无水溶剂为以下的一种或几种混合,四氢呋喃、二氯甲烷、甲苯、1,4-二氧六环和吡啶;任选地,所述脱水剂为三氟醋酸酐或N-(三乙基铵磺酰)氨基甲酸甲酯;其中,R 1、R 2、R 3、R 4、R 5、R 6、R 7、X和Y的定义如权利要求1-8任一项中所述。
- 一种药物组合物,其包含选自如权利要求1-8任一项所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,以及药学上可接受的辅料;任选地,所述药物组合物还进一步包含利托那韦或其药学上可接受的盐。
- 一种药物组合,其包含选自如权利要求1-8任一项所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,以及利托那韦或其药学上可接受的盐。
- 根据权利要求1-8任一项所述的氰基化合物,或其外消旋体、对映异构体、非对映异构体或药学上可接受的盐,或者根据权利要求10或11所述的药物组合物或药物组合在制备药物中的用途,所述药物选自用于抑制冠状病毒3CL蛋白酶活性的药物,用于预防和/或治疗冠状病毒感染的药物,用于抑制小RNA病毒的3CL蛋白酶活性的药物,和用于预防和/或治疗小RNA病毒感染的药物;任选地,所述冠状病毒选自SARS-CoV、MERS-CoV、H229E-CoV、HKU1-CoV、NL63-CoV、OC43-CoV和SARS-CoV-2。
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CA3230035A1 (en) | 2023-04-06 |
AU2022357033A1 (en) | 2024-03-21 |
CN117209556A (zh) | 2023-12-12 |
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