CN116987020A - Protease inhibitor and preparation method and application thereof - Google Patents

Protease inhibitor and preparation method and application thereof Download PDF

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Publication number
CN116987020A
CN116987020A CN202310476208.XA CN202310476208A CN116987020A CN 116987020 A CN116987020 A CN 116987020A CN 202310476208 A CN202310476208 A CN 202310476208A CN 116987020 A CN116987020 A CN 116987020A
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China
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protease inhibitor
alkyl
pharmaceutically acceptable
independently selected
cycloalkyl
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CN202310476208.XA
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Chinese (zh)
Inventor
何伟
吴彩
李彬
李昊翔
郑济青
宛世璋
徐立谦
王玫景
刘凯
徐晨淏
梁锷
刘磊
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Tsinghua University
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Tsinghua University
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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Abstract

The invention discloses a protease inhibitor, a preparation method and application thereof, which can be used as PLpro inhibitor in combination with one or more pharmaceutically acceptable auxiliary materials or one or more other active ingredients for treating diseases or symptoms caused by or related to virus infection. The auxiliary materials can be carriers, diluents, binders, lubricants, wetting agents and the like. The protease inhibitor has high inhibition activity, and can be used for broad-spectrum antiviral, especially coronavirus.

Description

Protease inhibitor and preparation method and application thereof
Technical Field
The invention relates to the field of biological medicine, in particular to a PLPro protease inhibitor and a preparation method and application thereof.
Background
Coronaviruses mainly attack respiratory tract, gastrointestinal tract, nervous system and the like, often cause respiratory tract and intestinal tract diseases, nervous system symptoms and myocarditis, and the infection of the viruses seriously affects human health. While there have been some advances in the development of vaccines and antibody drugs against coronaviruses, the development of antiviral drugs would provide a new means for combating coronaviruses.
Disclosure of Invention
The present invention provides a protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, the protease inhibitor having the structure of formula (I):
wherein,,
m is independently selected from: C. n, O, S;
n is independently selected from integers of 1-5 (e.g., 1, 2, 3, 4, 5);
L 1 absent or selected from: c (C) 1 -C 6 Alkylene, -CO-, -SO 2 -；
L 2 Absent or selected from: c (C) 1 -C 6 Alkylene, C 1 -C 6 A heteroalkylene group; a is that 1 -A 5 Any one of the groups being CR 1 Other groups being independently selected from CR 1 ' or N;
R 1 selected from: substituted or unsubstituted nitrogen-containing heterocyclic ring,-R L -OR'；
R A Is C 1 -C 6 An alkyl group;
R 1 ' is selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si (C) 1 -C 6 Alkyl) -NO 2 -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -n=cr' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, C 1 -C 6 Alkylene, C 3 -C 6 Heteroalkylene, C 3 -C 6 Cycloalkylene, C 3 -C 6 Heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -which may be optionally substituted;
r 'and R' are independently selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, which may be optionally substituted.
In an embodiment, M is C.
In an embodiment, n is independently selected from integers from 1 to 3.
In an embodiment, n is 1.
In an embodiment, n is 2.
In an embodiment, said L 1 Absent or selected from: c (C) 1 -C 6 Alkylene, -CO-.
In an embodiment, said L 2 Absent or selected from: c (C) 1 -C 6 An alkylene group.
In embodiments, said R 1 Is a substituted or unsubstituted nitrogen-containing heterocycle.
In embodiments, said R 1 Selected from: -R L -OR'、
Preferably, the saidSelected from the following structures:
in embodiments, said R A Is methyl.
In embodiments, said R A Is tert-butyl.
In embodiments, said R 1 ' is selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -R L -OR', which may be optionally substituted.
In embodiments, said R 1 ' is selected from: H. -CH 3 、-OH。
In an embodiment, the a 1 -A 5 In A of 1 Is N;
in an embodiment, the a 1 -A 5 In A of 2 Is N;
in an embodiment, the a 1 -A 5 In A of 3 Is N;
in an embodiment, the a 1 -A 5 In A of 4 Is N;
in an embodiment, the a 1 -A 5 In A of 5 Is N;
in an embodiment, the a 1 -A 5 Any one of the groups being CR 1 Other radicals being CR 1 ’。
In embodiments, the protease inhibitor is selected from the group consisting of structures having the formula (I-1), (I-2), (I-3), (I-4), as follows:
In an embodiment, the protease inhibitor is selected from the group consisting of those having the structure of formula (I-1), as follows:
wherein,,
A 1 -A 5 any one of the groups being CR 1 Other groups being independently selected from CR 1 ' or N;
R 1 is a substituted or unsubstituted nitrogen-containing heterocycle;
R 1 ' is selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-Si(C 1 -C 6 Alkyl) -NO 2 -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -n=cr' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, C 1 -C 6 Alkylene, C 3 -C 6 Heteroalkylene, C 3 -C 6 Cycloalkylene, C 3 -C 6 Heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -which may be optionally substituted;
r 'and R' are independently selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, which may be optionally substituted;
R 4 selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy.
In embodiments, the protease inhibitor is selected from the group consisting of structures having formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), as follows:
in an embodiment, the protease inhibitor has the structure of formula (II-1):
In embodiments, the protease inhibitor is selected from the group consisting of structures having the formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), as follows:
in an embodiment, the protease inhibitor has the structure of formula (III-1):
in embodiments, said R 1 Selected from:-OH、/>
wherein R is 2 、R 2 ’、R 4 Independently selected from H, (=O), C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”；
Z 1 Selected from NR 3 ' or O;
m 1 1 or 2;
R 3 、R 3 ' independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
In embodiments, R 4 Selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy.
In embodiments, said R 1 Selected from: -OH,
In embodiments, said R 1 is-OH.
In embodiments, said R 1 Selected from:
in embodiments, said R 1 Selected from:
wherein Z is 2 Is O or
m is 1, 2 or 3;
R 45 、R 46 independently selected from H, (=O), C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
R 41 、R 42 Independent selection Self H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
In embodiments, said R 3 、R 3 ’、R 41 、R 42 Independently selected from H, -C 1 -C 6 Alkyl, -OH, - (C) 1 -C 6 Alkylene) -COOH, - (C 1 -C 6 Alkylene) -OH, - (C 1 -C 6 Alkylene) -CONH 2 。
In embodiments, said R 2 、R 2 ’、R 4 、R 41 、R 42 Independently selected from: -H, (=o), F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -CF 3 、-OH、-N 3 、-B(OH) 2 、
-CN、/>
In an embodiment, the protease inhibitor has the following structure:
in an embodiment, the protease inhibitor has the following structure:
the invention also provides a pharmaceutical composition comprising the protease inhibitor or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, and one or more pharmaceutically acceptable excipients.
The pharmaceutical composition may also include one or more additional active ingredients in combination.
For example, the adjuvant may be a carrier, diluent, binder, lubricant, wetting agent, or the like.
The pharmaceutical composition of the present invention may be formulated in the following form: syrups, elixirs, suspensions, powders, granules, tablets, capsules, troches, solutions, creams, ointments, lotions, gels, emulsions and the like.
The invention also provides the use of the protease inhibitors described above and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, the pharmaceutical compositions described above as PLpro inhibitors, for example as antiviral agents.
The invention also provides the use of the protease inhibitors and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, and the pharmaceutical compositions described above in medicaments for reducing and/or inhibiting coronavirus replication.
The invention also provides application of the protease inhibitor, pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof and the pharmaceutical composition in preparing medicines for preventing and/or treating diseases or symptoms caused by or related to virus infection.
In one embodiment of the invention, the virus is a coronavirus, e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, MERS-CoV, etc.
In particular, the disease or condition is a disease or condition caused by or associated with a coronavirus infection, such as covd-19, SARS, MERS, etc.
The present invention also provides a method for preventing and/or treating a disease or condition caused by or associated with a viral infection comprising the step of administering to a subject an effective amount of a protease inhibitor of the invention described above or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, or a pharmaceutical composition of the invention described above.
In particular, the disease or condition is a disease or condition caused by or associated with a coronavirus infection, such as MERS, and the like.
Specifically, the subject is an animal; in one embodiment of the invention, the subject is a mammal, such as a human, monkey, cat, dog, mouse, bat, or the like.
Drawings
FIG. 1 shows the inhibition curves of compound C1.
FIG. 2 shows the inhibition curves of compound C2.
FIG. 3 shows the inhibition curves of compound C3.
FIG. 4 shows the inhibition curves of compound C5.
FIG. 5 shows the inhibition curves of compound C8.
FIG. 6 shows the inhibition curves for Compound C12.
FIG. 7 shows the inhibition ratio curve of Compound C13.
Detailed Description
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates.
The term "alkyl" refers to a hydrocarbon chain radical that is straight or branched and contains no unsaturation, and is attached to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. If the alkyl group is substituted with a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. If the alkyl group is substituted with an aryl group, it is correspondingly an "aralkyl" radical, such as benzyl, benzhydryl, or phenethyl. If an alkyl group is substituted with a heterocyclic group, then it is correspondingly a "heterocyclylalkyl" radical. "alkylene" generally refers to an alkanediyl group having two free valences, typically alkylene groups containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, and the like.
The term "alkoxy" refers to a substituent formed upon substitution of a hydrogen in a hydroxy group with an alkyl group, typically alkoxy groups having 1 to 12 (e.g., 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.
The term "cycloalkyl" refers to a saturated or partially saturated (especially saturated) monocyclic or polycyclic group which may contain 1 to 4 monocyclic and/or fused rings, 3 to 18 carbon atoms, preferably 3 to 10 (e.g. 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl and the like.
The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing from 1 to 3 monocyclic or fused rings and from 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, and typically aryl is an aryl containing from 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, and the like. "arylene" refers to a divalent group derived from an aromatic hydrocarbon by removal of two hydrogen atoms.
The term "heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing from 1 to 3 monocyclic and/or fused rings and from 3 to about 18 ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the invention contain 1,2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroaryl groups include, for example, but are not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, and the like. Suitable heteroalicyclic groups in the compounds of the present invention contain 1,2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroalicyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, thiiranyl, azepanyl, oxazepanyl, diazepinyl, triazepinyl, 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, quinolizine, and the like.
The above groups may be substituted at one or more available positions with one or more suitable groups such as: OR ',= O, SR ', SOR ', SO 2 R'、OSO 2 R'、OSO 3 R'、NO 2 、NHR'、N(R') 2 、＝N-R'、N(R')COR'、N(COR') 2 、N(R')SO 2 R'、N(R')C(＝NR')N(R')R'、N 3 CN, halogen, COR ', COOR', OCOR ', OCOOR', OCONHR ', OCON (R') 2 、CONHR'、CON(R') 2 、CON(R')OR'、CON(R')SO 2 R'、PO(OR') 2 、PO(OR')R'、PO(OR')(N(R')R')、C 1 -C 12 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, aryl, and heterocyclyl, wherein each R' group is independently selected from: hydrogen, OH, NO 2 、NH 2 SH, CN, halogen, COH, COalkyl, COOH, C 1 -C 12 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, aryl, and heterocyclyl. Wherein these groups themselves are substituted, and the substituents may be selected from the list previously described.
"halogen" means bromine, chlorine, iodine or fluorine.
"haloalkyl" means a radical in which a hydrogen atom on the alkyl group is replaced by a halogen atom (F, cl, br, I), e.g. -CH 2 Rh、-CHRh 2 、-CRh 3 Wherein Rh is F, cl, br or I; such as-CF 3 。
The term "pharmaceutically acceptable salt" refers to an acidic or basic salt that is theoretically non-toxic, irritating and allergic and is capable of achieving or providing clinically acceptable pharmacokinetic, absorption, distribution and metabolic properties of the drug molecule for its intended purpose. The salts of the invention include pharmaceutically acceptable acidic or basic salts of acidic groups, basic groups or amphoteric groups of the compounds. A list of suitable salts can be found in S.M. bire, et al, J.Pharm.Sci.,66,1-19 (1977).
Pharmaceutically acceptable salts described herein include acid addition salts and base addition salts.
The acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate, and salts of amino acids such as arginine, gluconate, galacturonate, and the like. The acid addition salts may be prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form the salt. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
The base addition salts described herein refer to salts formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or with organic amines. Examples of metals for use as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1, 2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
The term "solvate" is understood to mean any form of the compound of the invention, wherein the compound is linked to another molecule (usually a polar solvent) by a non-covalent bond, including in particular hydrates and alcoholates, such as methanolate. The preferred solvate is a hydrate.
The term "prodrug" is used in its broad sense and encompasses derivatives which can be converted in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Preferably, the prodrug having a carboxyl functionality is a lower alkyl ester of a carboxylic acid. The carboxylic acid esters are readily esterified from any carboxylic acid moiety present in the molecule.
Any reference herein to a compound is intended to represent such specific compound, as well as certain variations or forms thereof. In particular, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein represents any one of the racemates, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomers or geometric isomers of the double bonds may also be present, whereby in some cases the molecules may be present as (E) -isomers or (Z) -isomers (trans and cis isomers). If a molecule contains multiple double bonds, each double bond will have its own stereoisomers, which may be the same or different from those of the other double bonds of the molecule. Furthermore, the compounds referred to herein may exist as atropisomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the present invention.
Example 1:
C1: 1 H NMR(600MHz,DMSO-d 6 )δ9.16(s,1H),9.05(s,1H),8.67(d,J＝8.5Hz,1H),7.94(d,J＝8.1Hz,1H),7.82(dd,J＝15.5,7.6Hz,2H),7.61–7.55(m,1H),7.53(dd,J＝8.1,6.7Hz,1H),7.50–7.44(m,1H),6.98(d,J＝8.4Hz,1H),6.81(dd,J＝8.2,2.7Hz,1H),6.56(d,J＝2.9Hz,1H),4.09(d,J＝4.8Hz,2H),3.48(s,2H),2.97(d,J＝12.3Hz,2H),1.95(dd,J＝8.8,4.6Hz,2H),1.91(s,3H),1.87(q,J＝7.0,6.1Hz,2H),1.36(d,J＝5.1Hz,2H),1.19(d,J＝5.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.01,147.94,138.32,138.01,132.25,131.28,128.94,128.87,128.11,126.14,125.88,125.62,125.53,115.79,113.61,54.22,51.11,34.58,25.82,18.31,14.55.MS(ESI,m/z):C27H29N3O,[M+H]+412.239.
FIG. 1 shows the inhibition curves of compound C1.
Example 2
C2： 1 H NMR(600MHz,DMSO-d 6 )δ11.08(d,J＝10.1Hz,1H),9.08(s,1H),8.67(d,J＝8.4Hz,1H),7.93(d,J＝8.0Hz,1H),7.82(dd,J＝13.5,7.6Hz,2H),7.60–7.55(m,1H),7.52(dd,J＝8.0,6.6Hz,1H),7.47(t,J＝7.6Hz,1H),6.98(d,J＝8.3Hz,1H),6.80(dd,J＝8.5,2.7Hz,1H),6.56(d,J＝2.7Hz,1H),4.02–3.97(m,2H),3.53(dd,J＝12.9,2.7Hz,2H),3.24(d,J＝12.3Hz,2H),2.70(d,J＝4.9Hz,3H),2.15(tt,J＝8.2,5.4Hz,2H),1.89(d,J＝7.5Hz,5H),1.36(q,J＝4.3Hz,2H),1.18(q,J＝4.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.04,147.64,138.38,138.03,133.94,132.26,131.25,128.93,128.86,128.10,126.13,125.87,125.64,125.51,115.72,113.53,62.33,51.50,38.59,34.57,23.89,18.27,14.55.MS(ESI,m/z):C28H31N3O,[M+H]+426.254.
FIG. 2 shows the inhibition curves of compound C2.
Example 3
C3： 1 H NMR(600MHz,DMSO-d 6 )δ9.08(d,J＝2.4Hz,1H),8.66(d,J＝8.4Hz,1H),7.94(d,J＝8.1Hz,1H),7.82(dd,J＝13.0,7.6Hz,2H),7.60–7.55(m,1H),7.52(dd,J＝8.1,6.7Hz,1H),7.47(t,J＝7.6Hz,1H),6.99(d,J＝8.3Hz,1H),6.80(dd,J＝8.4,2.6Hz,1H),6.56(d,J＝2.6Hz,1H),4.29–4.25(m,2H),2.99–2.88(m,4H),2.01(ddt,J＝16.9,8.1,4.6Hz,4H),1.90(s,3H),1.37(s,2H),1.18(t,J＝3.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.96,143.25,139.04,138.05,133.94,132.26,131.90,128.93,128.88,128.12,126.13,125.89,125.63,125.54,124.53,116.60,114.31,52.55,43.70,34.59,26.13,18.36,14.58.MS(ESI,m/z):C27H29N3O,[M+H]+412.238.
FIG. 3 shows the inhibition curves of compound C3.
Example 4
C4: 1 H NMR(600MHz,DMSO-d 6 )δ9.00(s,1H),8.68(d,J＝8.4Hz,1H),7.93(dd,J＝8.1,2.8Hz,1H),7.83(dd,J＝8.5,2.8Hz,1H),7.80(d,J＝7.1Hz,1H),7.57(d,J＝7.2Hz,1H),7.55–7.49(m,1H),7.46(td,J＝7.7,2.4Hz,1H),6.90(dd,J＝8.5,2.6Hz,1H),6.70(dd,J＝8.4,2.9Hz,1H),6.44(d,J＝2.4Hz,1H),4.06(d,J＝4.6Hz,2H),3.33(t,J＝1.7Hz,2H),2.38(dd,J＝10.9,3.0Hz,2H),2.16(d,J＝10.7Hz,2H),2.02(d,J＝2.9Hz,3H),1.90(s,3H),1.86–1.81(m,2H),1.74(dd,J＝8.0,4.3Hz,2H),1.36(s,2H),1.17(d,J＝4.9Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ144.94,138.09,133.96,132.26,131.63,128.91,128.79,128.07,126.06,125.84,125.65,125.49,122.93,116.51,114.23,56.86,55.01,45.63,34.61,28.13,18.40,14.47.MS(ESI,m/z):C28H31N3O,[M+H]+426.254.
Example 5
C5： 1 H NMR(600MHz,DMSO-d 6 )δ9.05(d,J＝3.0Hz,1H),8.66(d,J＝8.4Hz,1H),7.94(d,J＝8.1Hz,1H),7.83(dd,J＝10.9,7.6Hz,2H),7.58(dd,J＝8.4,6.8Hz,1H),7.53(t,J＝7.4Hz,1H),7.47(t,J＝7.6Hz,1H),6.98(d,J＝8.2Hz,1H),6.41(dd,J＝8.2,2.6Hz,1H),6.19(d,J＝2.5Hz,1H),4.14(s,1H),3.99(t,J＝8.0Hz,2H),3.82(dd,J＝8.8,5.2Hz,2H),2.82–2.66(m,6H),1.92(s,3H),1.36(t,J＝5.6Hz,2H),1.19(t,J＝5.4Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.91,148.96,138.36,138.00,133.93,132.26,131.21,128.93,128.12,126.16,125.89,125.62,125.54,124.44,113.13,110.85,55.58,54.45,34.50,18.45,14.64.MS(ESI,m/z):C26H29N3O,[M+H]+400.237.
FIG. 4 shows the inhibition curves of compound C5.
Example 6:
C6： 1 H NMR(600MHz,DMSO-d 6 )δ9.01(s,1H),8.67(d,J＝8.4Hz,1H),7.93(d,J＝8.1Hz,1H),7.82(dd,J＝17.7,7.6Hz,2H),7.57(t,J＝7.6Hz,1H),7.52(t,J＝7.4Hz,1H),7.46(p,J＝6.8,6.3Hz,1H),6.90(d,J＝8.2Hz,1H),6.33(dd,J＝8.2,2.5Hz,1H),6.11(d,J＝2.6Hz,1H),5.56(d,J＝6.4Hz,1H),4.50(h,J＝5.9Hz,1H),3.95(t,J＝7.0Hz,2H),3.36(dd,J＝7.6,5.1Hz,2H),1.90(s,3H),1.37–1.32(m,2H),1.17(d,J＝5.7Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.11,150.17,138.09,133.95,132.26,131.10,128.91,128.81,128.09,126.10,125.87,125.63,125.50,123.24,112.95,110.71,62.24,61.24,34.54,18.43,14.50.MS(ESI,m/z):C24H24N2O2,[M+H]+373.191.
example 7:
C7： 1 H NMR(600MHz,DMSO-d 6 )δ9.02(s,1H),8.66(d,J＝8.4Hz,1H),7.93(dd,J＝8.2,1.4Hz,1H),7.85–7.78(m,2H),7.57(ddd,J＝8.4,6.7,1.4Hz,1H),7.54–7.43(m,3H),6.91(d,J＝8.2Hz,1H),6.33(dd,J＝8.2,2.5Hz,1H),6.11(d,J＝2.6Hz,1H),4.35(h,J＝6.9Hz,1H),3.95(t,J＝7.3Hz,2H),3.42(t,J＝6.8Hz,2H),1.89(s,3H),1.39(s,9H),1.37–1.32(m,2H),1.16(q,J＝4.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.06,155.25,149.92,138.12,138.05,133.94,132.26,131.10,128.91,128.81,128.09,126.10,125.87,125.63,125.50,123.48,112.96,110.68,78.59,59.37,41.24,34.54,28.66,18.44,14.51.MS(ESI,m/z):C29H33N3O3,[M+H]+472.259.
example 8:
C8： 1 H NMR(600MHz,DMSO-d 6 )δ9.00(s,1H),8.66(d,J＝8.4Hz,1H),7.93(dd,J＝8.2,1.4Hz,1H),7.83(d,J＝8.2Hz,1H),7.80(dd,J＝7.1,1.3Hz,1H),7.55(dddd,J＝27.6,8.0,6.7,1.3Hz,2H),7.46(dd,J＝8.2,7.1Hz,1H),6.90(d,J＝8.2Hz,1H),6.32(dd,J＝8.1,2.5Hz,1H),6.10(d,J＝2.5Hz,1H),3.92(t,J＝7.0Hz,2H),3.73(p,J＝6.6Hz,1H),3.24–3.19(m,2H),1.90(s,3H),1.37–1.29(m,2H),1.16(q,J＝4.7Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.14,150.36,138.06,133.94,132.26,131.05,128.91,128.80,128.08,126.09,125.87,125.64,125.50,123.06,112.94,110.67,62.63,43.84,40.53,34.54,18.44,14.50.MS(ESI,m/z):C24H25N3O,[M+H]+372.207.
FIG. 5 shows the inhibition curves of compound C8. Example 9:
C9： 1 H NMR(600MHz,DMSO-d 6 )δ9.03(s,1H),8.66(d,J＝8.4Hz,1H),7.93(d,J＝8.1Hz,1H),7.85–7.79(m,2H),7.77(d,J＝8.5Hz,1H),7.57(ddd,J＝8.4,6.8,1.4Hz,1H),7.52(ddd,J＝8.0,6.8,1.3Hz,1H),7.48–7.44(m,1H),6.93(d,J＝8.2Hz,1H),6.36(dd,J＝8.2,2.5Hz,1H),6.14(d,J＝2.5Hz,1H),4.28–4.19(m,1H),4.06(t,J＝7.3Hz,2H),3.55–3.45(m,2H),2.91(s,3H),1.90(s,3H),1.42–1.32(m,2H),1.17(q,J＝4.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.00,149.80,138.15,138.04,133.94,131.15,128.92,128.10,126.12,125.62,125.51,123.80,113.08,110.84,59.92,43.34,40.74,40.53,34.55,18.45,14.52.MS(ESI,m/z):C25H27N3O3S,[M+H]+450.184.
example 10:
C10: 1 H NMR(400MHz,DMSO-d 6 )δ9.00(s,1H),8.67(d,J＝8.3Hz,1H),8.43(d,J＝6.9Hz,1H),7.94(d,J＝7.9Hz,1H),7.85–7.78(m,2H),7.60–7.44(m,3H),6.92(d,J＝8.1Hz,1H),6.35(d,J＝7.3Hz,1H),6.14(s,1H),4.52(dd,J＝12.9,6.4Hz,1H),3.98(t,J＝7.3Hz,2H),3.45(t,J＝6.5Hz,2H),1.91(s,3H),1.81(s,3H),1.38–1.32(m,2H),1.21–1.13(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ170.02,169.43,149.81,138.10,138.04,133.94,132.25,131.12,128.89,128.80,128.07,126.08,125.85,125.61,125.48,123.56,112.90,110.63,59.38,34.56,22.96,18.44,14.52.MS(ESI,m/z):C26H27N3O2,[M+H]+414.213.
example 11:
C11： 1 H NMR(600MHz,DMSO-d 6 )δ9.00(s,1H),8.67(d,J＝8.4Hz,1H),7.93(d,J＝8.0Hz,1H),7.85–7.78(m,2H),7.57(ddd,J＝8.4,6.7,1.5Hz,1H),7.55–7.51(m,1H),7.51–7.44(m,1H),6.91(d,J＝8.2Hz,1H),6.34(dd,J＝8.1,2.5Hz,1H),6.12(d,J＝2.5Hz,1H),3.80(t,J＝7.1Hz,2H),3.57(t,J＝4.7Hz,4H),3.49–3.44(m,2H),3.23–3.18(m,1H),2.30(s,4H),1.90(s,3H),1.34(q,J＝4.4Hz,2H),1.17(q,J＝4.7Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.10,149.99,138.07,133.94,132.25,131.10,128.91,128.85,128.08,126.11,125.86,125.64,125.51,112.68,110.46,66.40,56.11,55.02,49.99,40.53,34.53,18.42,14.54.MS(ESI,m/z):C25H27N3O3S,[M+H]+442.249.
example 12:
C12： 1 H NMR(400MHz,Methanol-d4)δ8.61(d,J＝8.5Hz,1H),7.91(d,J＝7.6Hz,2H),7.82(d,J＝8.3Hz,1H),7.58(t,J＝7.6Hz,1H),7.51(t,J＝7.5Hz,1H),7.46(t,J＝7.7Hz,1H),6.99(d,J＝8.2Hz,1H),6.46(dd,J＝8.3,2.5Hz,1H),6.25(d,J＝2.6Hz,1H),3.73(q,J＝8.0Hz,4H),2.60(s,6H),1.97(s,3H),1.58(s,3H),1.46(d,J＝7.3Hz,2H),1.32(d,J＝6.0Hz,2H). 13 C NMR(101MHz,Methanol-d4)δ172.36,148.61,137.33,136.79,134.16,132.10,130.78,128.37,127.85,125.58,125.09,124.70,124.49,124.44,112.86,110.00,60.56,59.51,36.64,34.15,16.81,14.65,13.54.MS(ESI,m/z):C27H31N3O,[M+H]+414.258.
FIG. 6 shows the inhibition curves for Compound C12. Example 13:
C13: 1 H NMR(400MHz,Methanol-d4)δ8.61(d,J＝8.5Hz,1H),7.96–7.86(m,2H),7.82(d,J＝8.3Hz,1H),7.58(t,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.41(dd,J＝8.2,2.5Hz,1H),6.20(d,J＝2.5Hz,1H),3.97(t,J＝7.1Hz,2H),3.62(p,J＝6.1Hz,1H),3.46(t,J＝6.4Hz,2H),2.35(d,J＝1.5Hz,3H),1.96(s,3H),1.45(d,J＝5.6Hz,2H),1.32(d,J＝6.7Hz,2H).MS(ESI,m/z):C25H27N3O,[M+H]+386.223.
FIG. 7 shows the inhibition ratio curve of Compound C13.
Example 14:
C14： 1 H NMR(400MHz,DMSO-d 6 )δ9.10(s,1H),8.29–8.18(m,1H),7.93(dt,J＝6.8,3.4Hz,1H),7.80(d,J＝8.2Hz,1H),7.72(dd,J＝7.3,1.2Hz,1H),7.53–7.43(m,3H),6.92(d,J＝8.2Hz,1H),6.34(dd,J＝8.2,2.6Hz,1H),6.10(d,J＝2.5Hz,1H),3.80(t,J＝7.0Hz,2H),3.40(dd,J＝7.3,5.7Hz,2H),3.12(p,J＝6.1Hz,1H),2.92(q,J＝9.2,6.3Hz,2H),2.75(d,J＝9.6Hz,2H),2.25–2.12(m,1H),2.08(s,6H),1.94(s,3H),1.89–1.75(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ168.96,149.96,140.79,138.44,134.58,131.01,130.26,129.37,127.69,126.17,125.98,125.46,125.43,125.09,123.29,112.51,110.77,60.56,56.73,56.31,41.98,34.09,31.41,18.38,16.77.MS(ESI,m/z):C27H31N3O,[M+H]+414.2540.
example 15
C15： 1 H NMR(400MHz,DMSO-d 6 )δ9.78(s,1H),8.87(s,1H),8.70(d,J＝8.3Hz,1H),8.12(s,1H),7.93(d,J＝7.9Hz,1H),7.82(d,J＝7.6Hz,2H),7.63–7.56(m,1H),7.53(d,J＝7.5Hz,1H),7.51–7.42(m,3H),7.00(t,J＝7.8Hz,3H),6.72(s,1H),6.70(s,1H),2.09(s,3H),2.00(s,3H),1.38–1.32(m,2H),1.19–1.13(m,2H).MS(ESI,m/z):C29H27N3O2,[M+H]+450.210.
Example 16
C16： 1 H NMR(400MHz,DMSO-d 6 )δ9.82(s,1H),8.92(s,1H),8.70(d,J＝8.4Hz,1H),8.28(s,1H),7.93(d,J＝8.0Hz,1H),7.83(d,J＝7.6Hz,2H),7.62–7.57(m,1H),7.57–7.43(m,3H),7.12(t,J＝8.0Hz,1H),7.03(d,J＝8.0Hz,1H),6.98(d,1H),6.81(s,1H),6.79(s,1H),6.70(d,J＝7.8Hz,1H),2.10(s,3H),2.02(s,3H),1.39–1.33(m,2H),1.19–1.13(m,2H).MS(ESI,m/z):C29H27N3O2,[M+H]+450.210.
Example 17
C17： 1 H NMR(400MHz,DMSO-d 6 )δ9.74(s,1H),9.07(s,1H),8.64(d,J＝8.3Hz,1H),7.96–7.89(m,2H),7.81(t,J＝7.2Hz,2H),7.59–7.50(m,2H),7.50–7.44(m,1H),7.44–7.38(m,2H),7.00–6.84(m,4H),6.68(s,1H),2.02(s,3H),1.95(s,3H),1.36–1.31(m,2H),1.19–1.14(m,2H).MS(ESI,m/z):C29H27N3O2,[M+H]+450.210.
Example 18
C18： 1 H NMR(400MHz,DMSO-d 6 )δ9.05(s,1H),9.01(s,1H),8.69–8.61(m,1H),8.04(s,1H),7.95–7.91(m,1H),7.86–7.80(m,2H),7.55–7.48(m,3H),7.12–7.05(m,2H),7.01–6.98(m,1H),6.80(s,1H),6.68–6.61(m,1H),2.51(s,6H),1.99(s,3H),1.39–1.34(m,2H),1.23(s,9H),1.20–1.15(m,2H).MS(ESI,m/z):C32H33N3O2,[M+H]+492.257.
Example 19
C19： 1 H NMR(400MHz,CDCl 3 )δ8.13–8.06(m,1H),7.90–7.86(m,1H),7.85–7.81(m,1H),7.77(d,J＝8.2Hz,1H),7.52–7.46(m,2H),7.46–7.40(m,1H),6.84(d,J＝8.1Hz,1H),6.26(dd,J＝8.1,2.4Hz,1H),6.19(d,J＝2.1Hz,1H),6.07(s,1H),4.02–3.97(m,2H),3.70–3.64(m,2H),3.29(s,2H),2.26(s,6H),1.74(s,3H),1.29–1.26(m,2H),1.26–1.23(m,2H).MS(ESI,m/z):C27H31N3O,[M+H]+414.247.
Example 20
C20： 1 H NMR(400MHz,CDCl 3 )δ8.14–8.08(m,1H),7.91–7.86(m,1H),7.86–7.82(m,1H),7.80–7.75(m,1H),7.52–7.41(m,3H),6.88(d,J＝8.1Hz,1H),6.36–6.31(m,1H),6.19–6.11(m,2H),3.90–3.84(m,2H),3.61–3.55(m,2H),3.32(s,2H),3.26–3.18(m,1H),2.23(s,6H),1.68(s,3H),1.33–1.29(m,2H),1.27–1.23(m,2H).MS(ESI,m/z):C27H31N3O,[M+H]+414.247.
Example 21
C21： 1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝8.1Hz,1H),7.91(d,J＝7.7Hz,1H),7.80(d,J＝8.1Hz,1H),7.59–7.48(m,3H),7.47–7.41(m,1H),6.94(d,J＝8.4Hz,2H),6.60(d,J＝8.4Hz,2H),3.51(s,2H),1.28–1.20(m,2H),1.06–0.97(m,2H).MS(ESI,m/z):C20H19NO,[M+H]+290.147.
Example 22
C22： 1 H NMR(400MHz,CDCl 3 )δ8.39(d,J＝8.2Hz,1H),7.91(d,J＝7.8Hz,1H),7.79(d,J＝8.1Hz,1H),7.58–7.53(m,1H),7.53–7.46(m,2H),7.44–7.39(m,1H),6.68(d,J＝8.1Hz,1H),5.96(d,J＝2.0Hz,1H),5.80(dd,J＝8.1,2.1Hz,1H),3.47(s,2H),3.06(s,3H),1.40–1.27(m,2H),1.06–0.97(m,2H).MS(ESI,m/z):C21H21NO2,[M+H]+320.157.
Preparation of the compound:
(1) Preparation of cyclopropylamine intermediate (1- (naphthalen-1-yl) cyclopropylamine), the synthetic route is as follows:
the specific operation is as follows:
1-Naphthol (1, 5mmol,1.0 e.q.) was placed in a round bottom flask, 10mL of dry tetrahydrofuran was added as a solvent, then tetraisopropyl titanate (5.5 mmol,1.0 e.q.) was added, the reaction system was cooled to-78 ℃, and then ethyl grignard reagent (11 mmol,2.2 e.q.) was slowly added dropwise to the reaction system. After the completion of the dropwise addition, the reaction system was warmed to room temperature and reacted for 1.5 hours. Boron trifluoride diethyl etherate (10 mmol,2.0 e.q.) was then added dropwise to the reaction system, and the reaction was stirred at room temperature for three hours after completion of the dropwise addition. After the completion of the reaction, 20mL of 2N hydrochloric acid was added dropwise to the reaction system, followed by quenching with stirring for 20 minutes, and then an excessive amount of saturated sodium hydroxide solution was added. Ethyl acetate is added for extraction, the organic phase is collected and is separated by silica gel column chromatography after spin drying, and the cyclopropylamine intermediate 2 can be obtained.
(2) The compounds of examples 1-4 were prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 2mmol,1.0 e.q.) was placed in a 50mL vial, and nitrogen-hydrogen containing amine compound 4 (3 mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.04 mmol,0.02 e.q.), X-PHOS ligand (0.08 mmol,0.04 e.q.), and cesium carbonate (4 mmol,2.0 e.q.) were added. Toluene solvent (10 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin, and the intermediate 5 is obtained by column chromatography separation and purification.
Intermediate 5 (1.0 e.q.) was placed in a round bottom flask and tetrahydrofuran was added: water=2:1 as solvent, then lithium hydroxide (4.0 e.q.) was added to the reaction system, the reaction system was acidified with 2N hydrochloric acid after stirring at 60 ℃ for 6 hours, and after adding ethyl acetate, a white solid was precipitated, and the solid was suction filtered off and dried to obtain intermediate 6.
The reaction between 6 and the previously obtained tricyclic amine intermediate 2 was carried out by adding DMF solvent in a ratio equivalent, adding HATU (1.5 e.q.) and DIPEA (2.0 e.q.), reacting at 70 ℃ for 12h, extracting the reaction solution with ethyl acetate, washing with saturated ammonium chloride solution three times, and purifying the organic phase by silica gel column chromatography to obtain the product 7.
When Boc (t-butoxycarbonyl) protection is present in amine compound 6, the final product is obtained after final removal of t-butoxycarbonyl from compound 7 by hydrochloric acid.
Methyl 2-methyl-5-bromobenzoate (3, 2mmol,1.0 e.q.) was placed in a 50mL vial, and nitrogen-hydrogen containing amine compound 4 (3 mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.04 mmol,0.02 e.q.), X-PHOS ligand (0.08 mmol,0.04 e.q.), and cesium carbonate (4 mmol,2.0 e.q.) were added. Toluene solvent (10 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin, and the intermediate 5 is obtained by column chromatography separation and purification.
Intermediate 5 (1.0 e.q.) was placed in a round bottom flask and tetrahydrofuran was added: water=2:1 as solvent, then lithium hydroxide (4.0 e.q.) was added to the reaction system, the reaction system was acidified with 2N hydrochloric acid after stirring at 60 ℃ for 6 hours, and after adding ethyl acetate, a white solid was precipitated, and the solid was suction filtered off and dried to obtain intermediate 6.
The reaction between 6 and the previously obtained tricyclic amine intermediate 2 was carried out by adding DMF solvent in a ratio equivalent, adding HATU (1.5 e.q.) and DIPEA (2.0 e.q.), reacting at 70 ℃ for 12h, extracting the reaction solution with ethyl acetate, washing with saturated ammonium chloride solution three times, and purifying the organic phase by silica gel column chromatography to obtain the product 7.
When Boc (t-butoxycarbonyl) protection is present in amine compound 6, the final product is obtained after final removal of t-butoxycarbonyl from compound 7 by hydrochloric acid.
(3) The compound of example 5 was prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 10mmol,1.0 e.q.) was placed in a 350mL vial and 3-dimethylaminoazetidine (19, 15mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.2 mmol,0.02 e.q.), X-PHOS ligand (0.4 mmol,0.04 e.q.), and cesium carbonate (50 mmol,5.0 e.q.) were added. Toluene solvent (60 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is finished, the organic solvent is dried by spin-drying, and the intermediate 20 is obtained by column chromatography separation and purification.
Placing the intermediate 20 (1.0 e.q.) in a round-bottom flask, adding tetrahydrofuran, water=2:1 as a solvent, then adding potassium hydroxide (4.0 e.q.) into the reaction system, stirring and reacting for 6 hours at 60 ℃, spin-drying the organic solvent, then adding 2N hydrochloric acid into the rest aqueous solution for acidification, adjusting the pH to=1, spin-drying the aqueous solution, adding a methanol solution to extract organic matters, filtering and removing filter residues, collecting filtrate, and spin-drying to obtain white solid which is the intermediate 21.
The reaction of 21 with the previously obtained tricyclic amine intermediate 2 was carried out by adding DMF solvent in a ratio equivalent to HATU (1.5 e.q.) and DIPEA (2.0 e.q.), reacting at 70 ℃ for 12h, extracting the reaction solution with ethyl acetate, washing with saturated ammonium chloride solution three times, and purifying the organic phase by silica gel column chromatography to obtain the product 22. The end product 22 is C5.
(4) The compound of example 6 was prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 10mmol,1.0 e.q.) was placed in a 350mL vial and azetidin-3-ol (47, 15mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.2 mmol,0.02 e.q.), X-PHOS ligand (0.4 mmol,0.04 e.q.), and cesium carbonate (50 mmol,5.0 e.q.) were added. Toluene solvent (60 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin-drying and separated and purified by column chromatography to obtain an intermediate 48.
Intermediate 48 (1.0 e.q.) was placed in a round bottom flask, tetrahydrofuran: water=2:1 was added as a solvent, then potassium hydroxide (4.0 e.q.) was added to the reaction system, stirred at 60 ℃ for reaction for 6 hours, then the organic solvent was dried by spinning, then 2N hydrochloric acid was added to the remaining aqueous solution for acidification, the ph=1 was adjusted, then the aqueous solution was dried by spinning, the organic matter was extracted by adding methanol solution, suction filtration and removal of filter residues, the filtrate was collected, and a white solid was obtained after spinning as intermediate 49.
49 and the previously obtained ternary cyclic amine intermediate 2 are added with DMF solvent according to a ratio of one equivalent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) are added, the reaction is carried out for 12h at 70 ℃, the reaction solution is extracted with ethyl acetate, the solution is washed three times with saturated ammonium chloride solution, and after the organic phase is dried by spin-drying, the product 50 is obtained by silica gel column chromatography. The final product 50 is C6.
(5) The compounds of examples 7, 8, 9, 10, etc. were prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 10mmol,1.0 e.q.) was placed in a 350mL vial and 3-N-t-butoxycarbonylaminocyclobutylamine (51, 15mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.2 mmol,0.02 e.q.), X-PHOS ligand (0.4 mmol,0.04 e.q.), and cesium carbonate (50 mmol,5.0 e.q.) were added. Toluene solvent (60 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin and separated and purified by column chromatography to obtain an intermediate 52.
Intermediate 52 (1.0 e.q.) was placed in a round bottom flask, tetrahydrofuran: water=2:1 was added as solvent, then potassium hydroxide (4.0 e.q.) was added to the reaction system, stirred at 60 ℃ for reaction for 6 hours, then the organic solvent was dried by spinning, extracted once with ethyl acetate, the organic phase was discarded, then 2N hydrochloric acid was added to the remaining aqueous solution for acidification, the pH was adjusted to=1, extracted once with ethyl acetate, the organic phase was collected, and a white solid was obtained after spinning, namely intermediate 53.
The reaction mixture was reacted with the previously obtained ternary cyclic amine intermediate 2 in a one-to-one equivalent ratio with the addition of DMF solvent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) at 70 ℃ for 12h, extraction of the reaction mixture with ethyl acetate, washing three times with saturated ammonium chloride solution, and purification of the organic phase by silica gel column chromatography to give the product 54. The final product 54 is C7.
Intermediate 54 (4 mmol,1.0 e.q.) was dissolved in 20mL of dichloromethane solvent, 2mL of 4N-strength hydrochloric acid-dioxane solution was added, and the reaction was stirred at room temperature for 2 hours, a white solid was precipitated, and the solid was suction-filtered off and dried to obtain final product 55. Final product 55 is example C8.
Intermediate 55 (1 mmol,1.0 e.q.) was dissolved in 5mL of dichloromethane solvent, triethylamine (2 mmol,2.0 e.q.) was added followed by dropwise addition of methylsulfonic anhydride (1.5 mmol,1.5 e.q.). The reaction was stirred at room temperature for 4 hours, and then the organic solvent was dried by spin-drying and separated and purified by column chromatography to obtain the final product 56. Final product 56 is example C9.
Intermediate 55 (1 mmol,1.0 e.q.) was dissolved in 5mL of dichloromethane solvent, triethylamine (2 mmol,2.0 e.q.) was added followed by dropwise addition of acetyl chloride (1.5 mmol,1.5 e.q.). The reaction was stirred at room temperature for 4 hours, and then the organic solvent was dried by spin-drying and separated and purified by column chromatography to obtain the final product 57. Final product 57 is example C10.
(6) The compound of example 11 was prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 10mmol,1.0 e.q.) was placed in a 350mL vial and 4- (azetidin-3-yl) morpholine (58, 15mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.2 mmol,0.02 e.q.), X-PHOS ligand (0.4 mmol,0.04 e.q.), and cesium carbonate (50 mmol,5.0 e.q.) were added. Toluene solvent (60 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin-drying and separated and purified by column chromatography to obtain an intermediate 59.
Intermediate 59 (1.0 e.q.) was placed in a round bottom flask, tetrahydrofuran: water=2:1 was added as a solvent, then potassium hydroxide (4.0 e.q.) was added to the reaction system, stirred at 60 ℃ for reaction for 6 hours, then the organic solvent was dried by spin, then 2N hydrochloric acid was added to the remaining aqueous solution for acidification, the ph=1 was adjusted, then the aqueous solution was dried by spin, the organic matter was extracted by adding methanol solution, suction filtration and removal of the filter residue, the filtrate was collected, and a white solid was obtained after spin drying, which was intermediate 60.
The reaction mixture was reacted with the previously obtained ternary cyclic amine intermediate 2 in a ratio equivalent to DMF solvent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) at 70 ℃ for 12h, ethyl acetate was extracted, the reaction mixture was washed three times with saturated ammonium chloride solution, and the organic phase was dried by spin-drying, followed by purification by silica gel column chromatography to obtain the product 61. The final product 61 is C11.
(7) The compound of example 12 was prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 10mmol,1.0 e.q.) was placed in a 350mL vial and N, 3-trimethylazetidin-3-amine (62, 15mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.2 mmol,0.02 e.q.), X-PHOS ligand (0.4 mmol,0.04 e.q.), and cesium carbonate (50 mmol,5.0 e.q.) were added. Toluene solvent (60 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin and separated and purified by column chromatography to obtain an intermediate 63.
Intermediate 63 (1.0 e.q.) was placed in a round bottom flask, tetrahydrofuran: water=2:1 was added as solvent, then potassium hydroxide (4.0 e.q.) was added to the reaction system, stirred at 60 ℃ for reaction for 6 hours, then the organic solvent was dried by spin, then 2N hydrochloric acid was added to the remaining aqueous solution for acidification, the ph=1 was adjusted, then the aqueous solution was dried by spin, the organic matter was extracted by adding methanol solution, suction filtration and removal of the filter residue, the filtrate was collected, and a white solid was obtained after spin drying as intermediate 64.
The reaction mixture was reacted with the previously obtained ternary cyclic amine intermediate 2 in a ratio equivalent to DMF solvent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) at 70 ℃ for 12 hours, extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was dried by spin-drying, followed by purification by silica gel column chromatography to give the product 65. The final product 65 is C12.
(8) The compound of example 13 was prepared as follows:
methyl 2-methyl-5-bromobenzoate (3, 10mmol,1.0 e.q.) was placed in a 350mL vial and tert-butyl azetidin-3-yl (methyl) carbamate (66, 15mmol,1.5 e.q.), tris (dibenzylideneacetone) dipalladium (0.2 mmol,0.02 e.q.), X-PHOS ligand (0.4 mmol,0.04 e.q.), and cesium carbonate (50 mmol,5.0 e.q.) were added. Toluene solvent (60 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin, and the intermediate 67 is obtained by column chromatography separation and purification.
Intermediate 67 (1.0 e.q.) was placed in a round bottom flask, tetrahydrofuran: water=2:1 was added as solvent, then potassium hydroxide (4.0 e.q.) was added to the reaction system, after stirring and reacting for 6 hours at 60 ℃, the organic solvent was dried by spinning, extracted once with ethyl acetate, the organic phase was discarded, then 2N hydrochloric acid was added to the remaining aqueous solution for acidification, the pH was adjusted to=1, extracted once with ethyl acetate, the organic phase was collected, and a white solid was obtained after spinning as intermediate 68.
The reaction mixture was reacted with the previously obtained ternary cyclic amine intermediate 2 in a one-to-one equivalent ratio with the addition of DMF solvent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) at 70 ℃ for 12h, extraction of the reaction mixture with ethyl acetate, washing three times with saturated ammonium chloride solution, and purification of the organic phase by silica gel column chromatography gave product 69.
Intermediate 54 (4 mmol,1.0 e.q.) was dissolved in 20mL of dichloromethane solvent, trifluoroacetic acid (8 mmol,2.0 e.q.) was added, the reaction was stirred at room temperature for 2 hours, the organic solution was dried by spin, then saturated sodium bicarbonate solution was added in excess, the organic phase was extracted with ethyl acetate, and then the organic phase was separated and purified by silica gel column chromatography to obtain the final product 70. The final product 70 is C13.
(9) The compound of example 14 was prepared as follows:
methyl 1-naphthyetate 31 (10 mmol,1.0 e.q.) and 1, 3-dibromopropane (10 mmol,1.0 e.q.) were placed in a round bottom flask and dissolved in 50mL DMF. Sodium hydride (60%dispersion in mineral oil,40mmol,4.0e.q) was added in portions while stirring under ice bath, then the ice bath was removed and stirred at ambient temperature for 12h. After the reaction was completed, an appropriate amount of water was added to quench, and ethyl acetate was added to extract, and the organic phase was washed 1 with saturated ammonium chloride solution, and the remaining organic phase was dried over anhydrous sodium sulfate. Column chromatography purification gives product intermediate 32.
Intermediate 32 (6.25 mmol,1.0 eq) was dissolved in a tetrahydrofuran/methanol/water mixed solvent (3:1:1, 50 mL) and potassium hydroxide (25 mmol,4.0 eq) was added. The reaction was carried out at 50℃for 8 hours. After detecting that the reaction has been completely converted, the solvent is dried by spinning, the ph=1 is adjusted by adding 2N HCl solution, extraction is performed by adding ethyl acetate, the organic phase is washed 1 time with saturated brine, the organic phase is collected, and the white solid product 33 is obtained by spinning.
Intermediate 33 (6.25 mmol,1.0 eq) was dissolved in 25mL of ultra-dry toluene, triethylamine (13.75 mmol,2.2 eq) was added and DPPA (7.5 mmol,1.2 eq) was added under argon. Stirring at normal temperature for 30min until all carboxylic acid raw materials are converted into acyl azide, heating to 75 ℃, reacting for 4h until most of acyl azide is converted into isocyanate, adding excessive hydrochloric acid (2M aqueous solution, > 4.0 eq), cooling to 60 ℃ and reacting overnight. Adding sodium bicarbonate solution to adjust pH to alkaline, adding ethyl acetate for extraction, collecting organic phase, spin-drying, and separating by silica gel column chromatography to obtain intermediate 34.
Intermediate 34 and the previously obtained carboxylic acid intermediate 6 were added in one equivalent to DMF solvent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) were added, reacted at 50 ℃ for 12h, the reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was dried by spin-drying, followed by purification by silica gel column chromatography to obtain product 35. Final product 35 is the compound of example 14.
(10) The compounds of examples 15, 16, 17, 18, 19 and 20 were prepared as follows:
(11) Route step 1 was prepared as follows:
1-Naphthol (1, 5mmol,1.0 e.q.) was placed in a round bottom flask, 10mL of dry tetrahydrofuran was added as a solvent, then tetraisopropyl titanate (5.5 mmol,1.0 e.q.) was added, the reaction system was cooled to-78 ℃, and then ethyl grignard reagent (11 mmol,2.2 e.q.) was slowly added dropwise to the reaction system. After the completion of the dropwise addition, the reaction system was warmed to room temperature and reacted for 1.5 hours. Boron trifluoride diethyl etherate (10 mmol,2.0 e.q.) was then added dropwise to the reaction system, and the reaction was stirred at room temperature for three hours after completion of the dropwise addition. After the completion of the reaction, 20mL of 2N hydrochloric acid was added dropwise to the reaction system, followed by quenching with stirring for 20 minutes, and then an excessive amount of saturated sodium hydroxide solution was added. Ethyl acetate is added for extraction, the organic phase is collected and is separated by silica gel column chromatography after spin drying, and the cyclopropylamine intermediate 2 can be obtained.
(12) Route step 2 was prepared as follows:
2-methyl-5-bromobenzoic acid (3 a) and the previously obtained tricyclic amine intermediate 2 were added in a ratio equivalent to DMF solvent, HATU (1.5 e.q.) and DIPEA (2.0 e.q.) were added, the reaction was carried out at 25 ℃ for 3 hours, the reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and after the organic phase was spin-dried, the intermediate 4a was obtained by silica gel column chromatography purification.
(13) Route step 3 was prepared as follows:
the compound of example 17 was prepared as follows:
380mg of intermediate 4 (1 mmol,1.0 e.q.) was placed in a 50mL vial and 225mg of amine compound 5a (1.5 mmol,1.5 e.q.), 18mg of tris (dibenzylideneacetone) dipalladium (0.02 mmol,0.02 e.q.), 19mgX-PHOS ligand (0.04 mmol,0.04 e.q.), and 651mg of cesium carbonate (2 mmol,2.0 e.q.) were added. Toluene solvent (5 mL) was then added, the reaction was capped with argon and the tube was heated to 110℃and stirred overnight. After the conversion of the substrate is detected by the spot plate, the organic solvent is dried by spin, and the final product XCH-65, namely the compound of the example 17, is obtained by column chromatography separation and purification.
EXAMPLE 15 preparation of Compounds
The preparation of the compound of example 15 was identical to the preparation of the compound of example 17, except that 2-methyl-5-bromobenzoic acid (3 a) was changed to 2-methyl-4-bromobenzoic acid (3 b).
EXAMPLE 16 preparation of Compounds
The preparation of the compound of example 16 was the same as the preparation of the compound of example 15, except that the amine compound 5a was changed to 5b.
EXAMPLE 18 preparation of Compounds
The preparation of the compound of example 16 was the same as that of the compound of example 17, except that the amine compound 5a was changed to 5c.
Example 19 preparation of Compounds
The preparation of the compound of example 19 was the same as that of the compound of example 17, except that 2-methyl-5-bromobenzoic acid (3 a) was changed to 3d and amine compound 5a was changed to 5d.
Example 19 preparation of Compounds
The preparation of the compound of example 20 was the same as that of the compound of example 17, except that 2-methyl-5-bromobenzoic acid (3 a) was changed to 3c and amine compound 5a was changed to 5d.
The compound of example 22 was prepared as follows:
183mg 1a (1 mmol,1.0 eq), 122mg 2d (1 mmol,1.0 eq), 33. Mu.L (1 mmol,1 eq) AcOH,635mg NaBH (OAc) are weighed out 3 (3 mmol,3.0 eq) was dissolved in 10mL THF and placed in a flask and stirred under Ar protection overnight. Saturated aqueous sodium bicarbonate and ethyl acetate were added to wash, leaving the organic phase. Column chromatography gives the final product XCH-190, the compound of example 22.
Experimental example 1: the PLpro inhibitory Activity of the Compounds prepared in the above examples was examined
Biological test conditions:
1. reaction buffer 20mM HEPEs,pH 7.5,100mM NaCl,1mM TCEP
2. Preparing mother solution:
(1) 20. Mu.M Ub-AMC (Ub-AMC dry powder is directly dissolved by a reaction buffer, and is used after centrifugation to remove sediment);
(2) 400nM PLpro (frozen to-80℃after molecular sieve purification, thawed on pre-ice, diluted with reaction buffer);
(3) 40. Mu.M test compound (test compound dry powder dissolved in DMSO to 40mM; diluted in 50% DMSO to 400. Mu.M; and diluted in reaction buffer to 40. Mu.M);
3. for single point inhibition test reaction systems: 10. Mu.M Ub-AMC,100nM PLpro,1. Mu.M test compound, total volume 20. Mu.L, 384 well plate;
mu.L PLpro mother liquor and 5 mu.L test compound mother liquor are added into 384-well plates and incubated for 30min at 4 ℃;
10. Mu.L of Ub-AMC mother liquor was added to 384-well plates, and after 30min reaction at 37℃AMC fluorescence intensity was measured (extraction: 360nm; emission:460 nm);
4. control (+control): DMSO corresponding dilution factor replaced test compound;
blank (Blank) Reaction buffer replaces PLpro;
5. and (3) data processing: subtracting the Blank value from the measured value, and normalizing by taking the DMSO value as a reference;
6、IC 50 and (3) measuring:
test compound concentration gradient (nM): 10000, 5000, 1000, 500, 250, 125, 62.5, 31.25, 15.625,10,5,2,1,0.5,0.1,0.01
Measuring fluorescence value after 15min of reaction (about 15min of enzyme reaction rate is in a linear interval and 30min of non-linear interval);
7. fitting data: the data were normalized and then processed with Sigmaplot (fitting equation: logistic,3 Parameter).
The results are shown in the following table.
Table 1 experimental results
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Wherein GRL0617 is a positive reference (Ghosh et al, 2009; ghosh et al, 2010; ratia et al, 2008).

Claims (16)

1. A protease inhibitor, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, the protease inhibitor having the structure of formula (I):
wherein,,
m is independently selected from: C. n, O, S;
n is independently selected from integers of 1-5 (e.g., 1, 2, 3, 4, 5);
L 1 absent or selected from: c (C) 1 -C 6 Alkylene, -CO-, -SO 2 -；
L 2 Absent or selected from: c (C) 1 -C 6 Alkylene, C 1 -C 6 A heteroalkylene group; a is that 1 -A 5 Any one of the groups being CR 1 Other groups being independently selected from CR 1 ’ Or N;
A 1 -A 5 any one of the groups being CR 1 Other groups being independently selected from CR 1 ’ Or N;
R 1 selected from: substituted or unsubstituted nitrogen-containing heterocyclic ring,-R L -OR'；
R A Is C 1 -C 6 An alkyl group;
R 1 ’ selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si (C) 1 -C 6 Alkyl) -NO 2 -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -n=cr' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, C 1 -C 6 Alkylene, C 3 -C 6 Heteroalkylene, C 3 -C 6 Cycloalkylene, C 3 -C 6 Heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -which may be optionally substituted;
r 'and R' are independently selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, which may be optionally substituted;
R 4 selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy.
2. The protease inhibitor according to claim 1 selected from the group consisting of structures having the formula (I-1), (I-2), (I-3), (I-4), or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds thereof, as follows:
3. the protease inhibitor according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, having the structure of formula (I-1):
wherein,,
A 1 -A 5 any one of the groups being CR 1 Other groups being independently selected from CR 1 ' or N;
R 1 is a substituted or unsubstituted nitrogen-containing heterocycle;
R 1 ' is selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-Si(C 1 -C 6 Alkyl) -NO 2 -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -n=cr' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, C 1 -C 6 Alkylene, C 3 -C 6 Heteroalkylene, C 3 -C 6 Cycloalkylene, C 3 -C 6 Heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -which may be optionally substituted;
r 'and R' are independently selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, which may be optionally substituted;
R 4 selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy.
4. The protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof according to claim 1, wherein a is 1 -A 5 In A of 1 Is N; alternatively, said A 1 -A 5 In A of 2 Is N; alternatively, said A 1 -A 5 In A of 3 Is N; alternatively, said A 1 -A 5 In A of 4 Is N; alternatively, said A 1 -A 5 In A of 5 Is N; alternatively, said A 1 -A 5 Any one of the groups being CR 1 Other radicals being CR 1 ’ 。
5. The protease inhibitor or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds thereof according to claim 1 having the structure of formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6) as follows:
6. The protease inhibitor or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds thereof according to claim 5 having the structure of formula (II-1):
7. the protease inhibitor according to claim 1 having the structure of formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds thereof, as follows:
8. the protease inhibitor according to claim 7 having the structure of formula (III-1):
9. the protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound of any one of claims 1-8, wherein R 1 Selected from:
-OH、
wherein R is 2 、R 2 ’ 、R 4 Independently selected from H, (=O), C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, ringAlkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”；
Z 1 Selected from NR 3 ’ Or O;
m 1 1 or 2;
R 3 、R 3 ’ Independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
10. The protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound of any one of claims 1-8, wherein R 1 Selected from:
wherein R is 2 、R 2 ’ 、R 5 Independently selected from H, (=O), C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”；
Z 1 Selected from NR 3 ’ Or O;
m 1 1 or 2;
R 3 、R 3 ’ independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
11. The protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof according to claim 10 wherein R 1 Selected from: -OH,
12. The protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof according to claim 10 wherein R 1 The method comprises the following steps:
wherein R is 41 、R 42 Independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
13. The protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof according to claim 10 wherein R 1 The method comprises the following steps:
wherein Z is 2 Is O orm 2 1, 2 or 3;
R 45 、R 46 independently selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -N 3 、-B(OH) 2 、-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N＝CR'R”。
14. The protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound of any one of claims 6-13, wherein R 3 、R 3 ’ 、R 41 、R 42 Independently selected from H, -C 1 -C 6 Alkyl, -OH, - (C) 1 -C 6 Alkylene) -COOH, - (C 1 -C 6 Alkylene) -OH, - (C 1 -C 6 Alkylene) -CONH 2 。
15. The protease inhibitor or pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound of any one of claims 6-13, wherein R 2 、R 2 ’ 、R 4 、R 41 、R 42 Independently selected from: -H, (=o), F, cl, br, I, methyl, ethylN-propyl, isopropyl, n-butyl, t-butyl, -CF 3 、-OH、-N 3 、-B(OH) 2 、
16. The protease inhibitor or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof according to claim 1, wherein the protease inhibitor has the structure:
CN202310476208.XA 2022-04-29 2023-04-28 Protease inhibitor and preparation method and application thereof Pending CN116987020A (en)

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