EA045400B1 - PYRIDONE DERIVATIVE, ITS COMPOSITION AND APPLICATION AS AN ANTI-VIRAL MEDICINE - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to the field of medicinal chemistry and, in particular, relates to a new pyridone derivative or its stereoisomer, pharmaceutically acceptable salt, solvate or crystalline form, a pharmaceutical composition containing the specified pyridone derivative or its stereoisomer, pharmaceutically acceptable salt, solvate or crystalline form, and its use as an antiviral drug, in particular its use in the preparation of a drug as a cap-dependent endonuclease inhibitor for the prevention and/or treatment of influenza infection, in particular, for example its use in the preparation of a drug for the prevention and/or treatment of virus infection influenza type A and/or influenza virus type B infection.

Prior Art

Influenza is an acute respiratory infection caused by the influenza virus. Influenza causes thousands of deaths each year, and large-scale influenza epidemics can cause millions of deaths worldwide. Although influenza vaccines and antiviral drugs such as amantadine can be used to prevent and treat influenza, their preventive and therapeutic effectiveness is very limited, and the development of a wider range of vaccines and more effective anti-influenza drugs is required.

The neuraminidase inhibitors oseltamivir and zanamivir can inhibit active viral replication and release, but in clinical settings, the effectiveness of neuraminidase inhibitors in critically ill patients is questionable, and widespread resistance is also a neuraminidase inhibitor problem that needs to be considered. Due to the fear of a new highly lethal influenza pandemic, anti-influenza drugs with new mechanisms of action are urgently needed.

Transcription of 8 RNA fragments is a critical step in the life cycle of influenza viruses. RNA polymerase plays a key role in this stage. RNA polymerase is a trimer composed of three subunits PA, PB1 and PB2, which are responsible for the replication and transcription of viral RNA in the nucleus of infected host cells. Transcription of influenza virus RNA has a special cap-interception mechanism; the PB2 subunit is responsible for recognizing and binding to the cap structure of the host mRNA precursor, and the PA subunit cleaves the host mRNA as a primer to initiate the transcription process. The cleaved mRNA primers are used in the PB1 subunit to synthesize viral mRNA. Since the cap-dependent endonuclease of the PA subunit is very conserved among influenza virus variations and is necessary for the life cycle of the virus, and the binding site is specific, the binding domain is well suited as a target for the development of new anti-influenza drugs. Because the endonuclease binding sites of influenza A viruses and influenza B viruses are very similar, cap-dependent endonuclease inhibitors show activity against both influenza A and B. The marketed influenza drug Baloxavir marboxil is an inhibitor cap-dependent endonuclease, which has clinically proven high therapeutic efficacy against influenza type A/B. CN 102803260A describes a substituted polycyclic carbamoyl pyridone derivative which has cap-dependent endonuclease inhibitory activity and can be used as a therapeutic and/or prophylactic agent against influenza infection.

Brief description of the invention

One of the objects of the present invention is to provide a new pyridone derivative that can be used as a cap-dependent endonuclease inhibitor and that is superior to existing pyridone derivatives in at least one of the following aspects: activity, pharmacokinetic properties such as bioavailability, and cytotoxicity.

A second object of the present invention is to provide a pyridone derivative which not only has excellent cap-dependent endonuclease inhibitory activity and low cytotoxicity, but also has significantly improved pharmacokinetic properties, in particular bioavailability.

To achieve these goals, the following technical solutions are used in the present invention.

A pyridone derivative having formula (I), or a pharmaceutically acceptable salt thereof,

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W 'o o o—L. o ^%N ^R 6

III (I) where (1) A is selected from N or CR1, and R1 is selected from hydrogen, halogen or C _1-6 hydrocarbyl;

(2) M is selected from N or CR ₂ , and R ₂ is selected from hydrogen atom, hydroxy group, C _1-6 hydrocarbyl or C _1-6 hydrocarbyloxy;

(3) Q is selected from N or CR ₃ , and R ₃ is selected from hydrogen atom or C _1-6 hydrocarbyl;

(4) R is selected from NH or CR ₄ R ₅ , R4 and R ₅ are independently selected from hydrogen or C _1-6 hydrocarbyl;

(5) R ₆ and R are connected and form a sixth ring together with the nitrogen atom to which they are both connected, and the sixth ring is a spiro ring or a 4-, 5-, 6- or 7-membered monocyclic, and optionally contains 1, 2 , 3 or more groups independently selected from a heteroatom and C=O, in addition to the nitrogen atom to which R and R ₆ are both connected, where the heteroatom is independently selected from N, O or S; or

R ₆ represents a fifth ring and the fifth ring is an unsubstituted or substituted carbocyclic ring, continuous or interrupted by 1, 2, 3 or more members independently selected from a heteroatom and C=O, and the fifth ring is a spiro or bridged ring, wherein the heteroatom is independently selected from N, O or S;

when the sixth ring is a spiro ring, the common carbon atom of the spiro ring and the nitrogen atom common to the spiro ring and the mother ring are adjacent or separated by one atom; and the ring in the spiro ring that shares a nitrogen atom with the mother ring contains an oxygen atom or a nitrogen atom in a position opposite that nitrogen atom;

when the sixth ring is a 4-, 5-, 6-, or 7-membered monocyclic ring, formula (I) is further subject to the following condition: the sixth ring contains an endocyclic carbon-carbon ethylene bond or the sixth ring contains an exocyclic carbon-carbon ethylene bond having one common carbon atom with the sixth ring;

(6) m is 0, 1, 2, 3, 4 or 5 and R7 is selected from hydrogen, hydroxy, cyano, halogen, carboxyl or C _1-6 hydrocarbyl, C _1-6 halohydrocarbyl or C _{1- 6} hydrocarbyloxy;

(7) X is selected from -CH(OCH3), -CH(8CH3) or S;

(8) W represents a hydrogen atom or W is selected from the following groups:

(a) -C(=O)-R8;

(b) -C(=O)-(CH ₂ ) _k -R ₈ , where k is selected from 0-3;

(c) -C(=O)-O-(CH ₂ ) _k -R ₈ , where k is selected from 0-3;

(d) -CH2-O-R8;

(e) -CH ₂ -OC(=O)-R ₈ ;

(f) -CH2-O-C(=O)-O-R8;

(g) -CH(-CH3)-O-C(=O)-R8;

(h) -CH(-CH3)-O-C(C=O)-O-(CH2)k-R8, where k is selected from 0-3;

(i) -CH2-O-P(=O)(OH)2;

(j) -CH2-OP(=O)(OPh)(NHR8); or (k) -CH ₂ -OP(=O)(OCH ₂ OC(=O)OR ₈ ) ₂ , wherein R ₈ is selected from C _1-6 hydrocarbyl or C _1-6 hydrocarbyloxy;

(9) Ar1 and Ar2 are both phenyl rings.

In the context of the present invention, when multiple R7s are present (ie m greater than 1), these R7s may be the same or different.

In accordance with another preferred aspect of the present invention, R1 is selected from hydrogen, halogen or C _1-6 alkyl.

In accordance with another preferred aspect of the present invention, R ₂ is selected from hydrogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy.

In accordance with another preferred aspect of the present invention, R3 is selected from hydrogen or C _1-6 alkyl.

In accordance with another preferred aspect of the present invention, R4 and R5 are independently selected from hydrogen or C _1-6 alkyl.

In accordance with another preferred aspect of the present invention, R7 is selected from hydrogen, hydroxy, cyano, halogen, carboxyl, C _1-6 alkyl or C _1-6 alkoxy.

In accordance with another preferred aspect of the present invention, R8 is selected from

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C1-6 alkyl or _C1-6 alkoxy.

In accordance with another preferred aspect of the present invention, m is 0, 1, 2 or 3.

According to another preferred aspect of the present invention, A is CR1, R1 is hydrogen.

According to another preferred aspect of the present invention, M is CR ₂ and R ₂ is hydrogen.

According to another preferred aspect of the present invention, Q is N.

According to another preferred aspect of the present invention, when R ₆ represents the fifth ring, R is CR4R5, R4 and R5 are both hydrogen.

According to another preferred aspect of the present invention, X is S.

According to another preferred aspect of the present invention, m is 0, 1, 2 or 3, A is CR1, R1 is hydrogen, M is _CR2 , _R2 is hydrogen, Q is N, X is S.

In another preferred aspect of the present invention, when the sixth ring is a spiro ring, the ring in the spiro ring that shares a nitrogen atom with the parent ring is a 5-, 6-, 7-, or 8-membered ring, and the other ring is is a 3-, 4-, 5- or 6-membered carbocyclic, oxygen-containing heterocyclic or sulfur-containing heterocyclic ring, unsubstituted or having a substituent selected from halogen, C _1-3 hydrocarbyl, C _1-3 halohydrocarbyl, hydroxymethyl, methoxymethyl or methoxyethyl.

More preferably, when the other ring has a substituent, the substituent is selected from methyl, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methoxyethyl, or chloromethyl.

In one specific and preferred aspect of the present invention, in formula (I), the sixth ring is selected from the following groups:

or .

In a preferred embodiment of the present invention, the pyridone derivative has formula IIa or formula IIb:

Pa Пь where in formula IIa and formula IIb

G represents O;

Z is selected from CH ₂ , O or S;

p and q are respectively 0, 1 or 2 and cannot both be equal to O, and when Z is O or S then p+q is greater than or equal to 2;

the definitions of W, R ₇ and m respectively are the same as above.

More preferably, in Formula IIa and Formula IIb, p+q=1 or 2 or 3, and Z is CH ₂ or p=1 or 2, q=1 or 2, and Z is O or S.

More preferably, in Formula IIa and Formula IIb, Z is CH ₂ and p=0, q=1, or p=0, q=2, or p=1, q=0, or p=1, q=1, or p=1, q=2, or p=2, q=0, or p=2, q=1; or

Z represents O and p=1, q=1, or p=1, q=2, or p=2, q=1, or p=2, q=2; or

Z represents S and p=1, q=1, or p=1, q=2, or p=2, q=1, or p=2, q=2.

Pyridone derivatives having formula IIa or formula IIb shown above show the best activity, the metabolic stability of the drug is significantly improved, and it is expected to have a positive effect on glucuronidation in phase II metabolism.

In another aspect of the present invention, the pyridone derivative has Formula IIc shown below:

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-s

Hc where in formula IIc a, b, c and d are equal to 0, 1, 2 or 3 respectively, and a and b are not equal to 0 or 3 at the same time, and c and d are not equal to 0 or 3 at the same time the same time;

E represents CH ₂ or O;

K represents CH ₂ or O;

the definitions of W, R ₇ and m respectively are the same as above.

Preferably in formula IIc a+b=1, or 2, or 3 and c+d=1, or 2, or 3.

Compounds having formula IIc have a new structure and are compounds highly active against influenza viruses type A and type B.

In one aspect of the present invention, when the fifth ring is a bridge ring, the bridge ring is bicyclic or tricyclic, and a bridge head carbon atom or a non-bridge head carbon atom of the bridge ring is bonded to a corresponding nitrogen atom of the mother ring.

In certain particular embodiments of the present invention, when the fifth ring is a bridged ring, the bridged ring is selected from bicyclo[1.1.1]pentane, bicyclo[2.1.0]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.0 ]hexane, bicyclo[3.1.1]heptane, bicyclo[3.2.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.0]octane.

In addition, when the fifth ring is a bridged ring, the bridged ring is unsubstituted or substituted with 1,2, 3 or more substituents selected from fluorine, chlorine, bromine, trifluoromethyl, _-CH2OH or _-CH2OCH3 .

In another aspect of the present invention, the pyridone derivative has Formula IId or Formula IIe shown below:

where in formula IId and formula IIe

R ₁₂ is selected from hydrogen atom, hydroxy group, cyano group, halogen, C _1-6 hydrocarbyl, C _1-6 halohydrocarbyl, C ₁ . ₆ alkoxy C _1-6 hydrocarbyl, hydroxy-C _1-6 hydrocarbyl, C _1-6 hydrocarbyloxy, carboxyl;

the definitions of W, R ₇ and m respectively are the same as above.

Preferably R ₁₂ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, methoxymethyl or hydroxymethyl.

Compounds having Formula IId and Formula IIe are significantly optimized in terms of group size and spatial arrangement compared to existing compounds, and therefore have the potential to inhibit the activity of the influenza A virus, have a significant metabolic advantage (metabolic stability) and have good development prospects.

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According to another aspect of the present invention, R ₆ is selected from the following groups:

or

According to another aspect of the present invention, when the sixth ring is a 4-, 5-, 6-, or 7-membered monocyclic ring, the sixth ring contains 1 heteroatom, which is a nitrogen atom bonded to both R and R ₆ .

According to another aspect of the present invention, in formula (I), the sixth ring is selected from the following groups:

F

OR .

According to another aspect of the present invention, R ₇ is connected to a phenyl ring.

In accordance with another aspect of the present invention, R ₇ is selected from hydrogen, hydroxy, cyano, halogen, C _1-6 hydrocarbyl, C _1-6 halohydrocarbyl, or C _1-6 hydrocarbyloxy.

In accordance with another aspect of the present invention, R ₇ is connected to a phenyl ring, wherein R ₇ is selected from F, Cl, Br, trifluoromethyl or methyl, and m is 0, 1, 2 or 3.

According to another aspect of the present invention, W is hydrogen or W is selected from the following groups:

(e) -CH2-O-C(=O)-R8;

(f) -CH2-O-C(=O)-O-R8;

(g) -CH(-CH3)-O-C(=O)-R8;

(h) -CH(-CH3)-O-C(C=O)-O-(CH2)k-R8, where k is selected from 0-3;

(i) -CH2-O-P(=O)(OH)2;

g) -CH2-O-P(=O)(OPh)(NHR8); or (k) -CH2-O-P(=O)(OCH2OC(=O)OR8)2.

In accordance with another aspect of the present invention, R8 is selected from methyl, ethyl, isopropyl or butyl.

In the context of the present invention, the pyridone derivative is preferably selected from the following compounds:

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According to the present invention, the pyridone derivative represented by formula (I) is

The present invention also describes a pharmaceutical composition containing a pyridone derivative having formula (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and a pharmaceutically acceptable carrier.

Preferably, the acceptable carrier is selected from the group consisting of a pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, adsorption enhancer, surfactant, lubricant, flavoring agent, sweetener.

This pharmaceutical composition is an antiviral pharmaceutical composition, further optionally containing one or more therapeutic agents selected from the group consisting of a neuraminidase inhibitor, a nucleoside drug, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor or other anti-influenza drugs.

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Preferably, the antiviral pharmaceutical composition further contains at least one therapeutic agent.

The present invention also relates to the use of a pyridone derivative having formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the preparation of a medicament for the treatment of a viral infectious disease, wherein the viral infectious disease is preferably infectious diseases caused by influenza A and/or viruses. or influenza B viruses.

The present invention also relates to the use of a pyridone derivative having formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the preparation of an antiviral drug, wherein the antiviral drug is preferably a drug or agent that inhibits the activity of influenza virus cap-dependent endonuclease.

In the present application, for convenience of description, in some places, the pyridone derivative having formula (I) or a pharmaceutically acceptable salt thereof is collectively referred to as the compound of the present invention.

In the pharmaceutical composition of the present invention, the compound of the present invention is preferably present in a therapeutically effective amount.

The pharmaceutical composition may be administered in any dosage form, which may include, but is not limited to, tablet, powder, capsule, granule, oral liquid, injectable, suppository, pill, cream, paste, gel, inhalant, suspension, dry suspension, patch, lotion, nanopreparation, etc. The dosage form of the pharmaceutical composition of the present invention is preferably a tablet, capsule or injectable preparation.

The dosage forms of the drug listed above can be prepared by methods known in the field of pharmacology.

In a particular embodiment, the pharmaceutical composition of the present invention may have, for example, the following ratios of ingredients (ratio by weight):

compound of the present invention 5-95%;

lactose 1-60%;

starch 0-20%;

microcrystalline cellulose 1-40%;

sodium carboxymethyl starch 1-5%;

polyethylene glycol (PEG6000) 0-10%;

Magnesium stearate 1-5%.

The present invention also describes a method for preparing a pyridone derivative, i.e. compounds having formula (I) according to the present invention, proceeding according to the following scheme:

In a particular embodiment of the present invention, the synthesis depicted above can be carried out according to the following steps.

Step-1: A and B are dissolved in 50% ethyl acetate solution of T3P and reacted at 60-100°C for 1-10 hours to obtain Intermediate C.

Step-2: Intermediate C is reacted with lithium chloride in DMA solution at 100°C for 12 hours and the resulting mixture is purified to obtain compound D.

Step-3: React the resulting compound D and an acyl chloride or halide in the presence of a base to obtain a hydroxy-protected prodrug (I), wherein the base is an organic base and an inorganic base, wherein the organic base is selected from triethylamine, DIPEA, DBU and pyridine and etc.; and the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium bicarbonate, etc.

By using the technical solutions described above, the present invention has the following advantages over the prior art.

The present invention describes a new pyridone derivative which has high inhibitory activity against influenza A virus and influenza B virus and can be used in clinical treatment alone or in combination with other anti-influenza drugs such as neuraminidase inhibitors, nucleoside drugs and PB2 inhibitors. 15 045400 ry, and is capable of quickly curing patients suffering from influenza in the clinic. These compounds are superior to existing pyridone derivatives in at least one of the following aspects: activity, pharmacokinetic properties (such as bioavailability) and cytotoxicity.

Definitions of terms

Unless otherwise specified, all technical and scientific terms used herein have the meanings commonly known to those skilled in the art to which the present invention relates.

The term unsubstituted, when used in the definition of a group, means that the group being defined has no substituents other than hydrogen, in which case the group is of a form generally known to those skilled in the art to which the present invention relates. For example, unsubstituted C _1-6 alkyl is a group commonly known to those skilled in the art, such as methyl, ethyl and the like.

The term substituted, when used in a group definition, means that 1, 2, 3 or more hydrogen atoms in the group in question are replaced by a substituent, and that the definition of that group must be understood in conjunction with that substituent. In this application, unless otherwise indicated, when the term substituted is used, it is understood that the hydrogen atoms in the group to which the definition is given are replaced by 1, 2, 3 or more substituents selected from the group consisting of the following: cyano group, halogen, hydroxy group, carboxyl, ester, sulfonyl, sulfonyl amide, amide, carbonyl (-C(=O)-), C _1-6 hydrocarbyl S(=O)(=NH)-, amino, carbonyl hydrazide, C _{1 -6} hydrocarbyl, halogenated C _1-6 hydrocarbyl, hydroxyl-substituted C _1-6 hydrocarbyl, acylamino-substituted C _1-6 hydrocarbyl, C _1-6 hydrocarbyloxy, halogenated C _1-6 hydrocarbyloxy, C _1-6 hydrocarbyloxy C _{1- 6} hydrocarbyl, C _1-6 hydrocarbyloxy, C _1-6 hydrocarbyloxy, C _1-6 hydrocarbylamino, C _1-6 hydrocarbyl sulfhydryl, C _1-6 hydrocarbyl carbonyl, C _1-6 hydrocarbylamino carbonyl, C _1-6 hydrocarbyl amide, halogenated C _{1 -6} hydrocarbyl amide, C _1-6 hydrocarbyloxy acyl, C _1-6 hydrocarbylamino acylamino, C _1-6 hydrocarbyl sulfonyl, C _1-6 hydrocarbyl sulfonyl amide, C _3-6 cycloalkyl, halogenated C _3-6 cycloalkyl, C _{3- 6} cycloalkoxy, halogenated C _3-6 cycloalkoxy, C _3-6 cycloalkyl C _1-6 hydrocarbyl, C _3-6 cycloalkoxy C _1-6 hydrocarbyl, C _3-6 cycloalkyl C _1-6 hydrocarbyloxy, C _3-6 cycloalkyl C _{1 -6} hydrocarbyloxy C _1-6 hydrocarbyloxy, C _3-6 cycloalkylamino, C _3-6 cycloalkyl C _1-6 hydrocarbylamino, C _3-6 cycloalkyl sulfhydryl, halogenated C _3-6 cycloalkylsulfhydryl, C _3-6 cycloalkyl C _1-6 hydrocarbyl sulfhydryl, C _3-6 cycloalkyl sulfonyl, C _3-6 cycloalkyl, C _1-6 hydrocarbylsulfonyl, C _3-6 cycloalkyl sulfonyl amide, C _3-6 cycloalkyl, C _1-6 hydrocarbyl sulfonyl amide, C _3-6 cycloalkylcarbonyl, C _3-6 cycloalkyl C _1-6 hydrocarbonyl, C _3-6 cycloalkylamino carbonyl, C _3-6 cycloalkyl C1-6 hydrocarbylamino carbonyl, C3-6 cycloalkyl amide, C3-6 cycloalkyl C1-6 hydrocarbyl amide, C3-6 cycloalkylamino amide, C _4-8 heterocycloalkyl, C _4-8 heterocycloalkoxy, halogenated C _4-8 heterocycloalkoxy, C _4-8 heterocycloalkoxy C _1-6 hydrocarbyl, halogenated C _4-8 heterocycloalkoxy C _1-6 hydrocarbyl, C _4-8 heterocycloalkyl C _1-6 hydrocarbyloxy, halogenated C _4-8 heterocycloalkyl C _1-6 hydrocarbyloxy, C _4-8 heterocycloalkyl C _1-6 hydrocarbyl, C _4-8 heterocycloalkyl C _1-6 hydrocarbyloxy C _1-6 hydrocarbyl, C _4-8 heterocycloalkylamino, C _4-8 heterocycloalkyl sulfhydryl , C _4-8 heterocycloalkyl C _1-6 hydrocarbyl sulfhydryl, C _4-8 heterocycloalkyl sulfonyl, C _4-8 heterocycloalkyl C _1-6 hydrocarbyl sulfonyl, C _4-8 heterocycloalkyl sulfonyl amide, C _4-8 heterocycloalkyl C _1-6 hydrocarbyl sulfonyl amide, C _4-8 heterocycloalkyl carbonyl, C _4-8 heterocycloalkyl C _1-6 hydrocarbyl carbonyl, carbonyl-substituted C _4-8 heterocycloalkyl, C _4-8 heterocycloalkylamino carbonyl, C _4-8 heterocycloalkyl amide, C _4-8 heterocycloalkyl C _{1- 6} hydrocarbyl amide, C _5-10 aryl, C _5.1 aryloxy, C _5-10 aryloxy C _1-6 hydrocarbyl, C _5-10 aryl C _1-6 hydrocarbyl, C _5-10 aryl C _1-6 hydrocarbyloxy, C _5-10 arylamino, C _5-10 aryl sulfhydryl, C _5-10 aryl C _1-6 hydrocarbyl sulfhydryl, C _5.1 aryl sulfonyl, C _5.1 aryl C _1-6 hydrocarbyl sulfonyl, C5.10 aryl sulfonamide, C _5-10 aryl C _1-6 hydrocarbyl sulfonyl amide, C _5-10 aryl carbonyl, C 5-10 aryl C _1-6 hydrocarbyl carbonyl, C _5-10 arylamino carbonyl, C _5-10 aryl amide or C _5-10 arylamino amide.

Preferably, the above substituent is selected from cyano, halogen (preferably F, C1, Br), hydroxy, carboxyl, ester, sulfonyl, sulfonylamino, carbonylamino, carbonyl, C _1-6 hydrocarbyl sulfinylamino, amino, carbonyl hydrazide, C _1-6 hydrocarbyl, halogenated C _1-6 hydrocarbyl, hydroxyl-substituted C _1-6 hydrocarbyl, amide-substituted C _1-6 hydrocarbyl, C _1-6 hydrocarbyloxy, halogenated C _1-6 hydrocarbyloxy, C _1-6 hydrocarbyloxy C _{1 -6} hydrocarbyl or C _1-6 hydrocarbyloxy C _1-6 hydrocarbyloxy.

More preferably, the above substituent is selected from cyano, F, C1, Br, hydroxy, carboxyl, ester, sulfonyl, sulfonylamino, amide, carbonyl, methylsulfinylamino, ethylsulfinylamino, isopropylsulfinylamino, tert-butylsulfinylamino, amino, acylhydrazino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, halomethyl (particularly, for example, trifluoromethyl), haloethyl, halo-n-propyl, halo- isopropyl, halocyclopropyl, halogen-nbutyl, halogen-isobutyl, halogen-tert-butyl, halocyclobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxycyclopropyl, hydroxy-n-butyl, hydroxyisobutyl, hydroxy-tert- butyl, hydroxycyclobutyl, hydroxy-n-pentyl, hydroxyisopentyl, hydroxy neopentyl, hydroxycyclohexyl, methoxy, ethoxy, propoxy.

The substituent is usually indicated before the substituted group when creating names, for example Ci-3 alkoxy C _3-8 cycloalkyl C _1-6 alkyl means that C _1-6 alkyl is substituted with C _3-8 cycloalkyl and C _3-8 cycloalkyl is further substituted with C _{1- 3} alkoxy group, for example, the structural formula of methoxycyclobutylmethyl is:

The term continuous, when used in the definition of a group, means that the covalent bond of the group is not interrupted by another group, in which case the group is of a form generally known to those skilled in the art to which the present invention relates. For example, unsubstituted cycloalkyl is a group commonly known to those skilled in the art, such as cyclobutyl, cyclopentyl, and the like.

The term interruptible or interruptible, when used in the definition of a group, means that one or more covalent bonds in a given group are interrupted by interrupting atoms or groups, and that the definition of a given group must be understood in conjunction with these interrupting atoms or groups. In this application, unless otherwise indicated, when the term interruptible is used, it means that the covalent bonds in the specified group are replaced by 1, 2, 3 or more members selected from heteroatoms (O, N, S), C=O, S =O or SO ₂ . The location of the interruption may be any chemically feasible position, and when multiple interrupting atoms or groups are present, the relative relative positions of the multiple interrupting atoms or groups are not limited, provided they are chemically feasible.

The term stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, and it includes cis/trans isomers, enantiomers and conformers. All stereoisomers are included within the scope of the present invention. The compounds of the present invention may be a single stereoisomer or a mixture of other isomers, such as a racemate, or a mixture of all other stereoisomers.

The term salt means the pharmaceutically acceptable salt that the compound of the present invention forms with an acid, which may be an organic or inorganic acid, particularly selected, for example, from the following: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid or analogues thereof.

The term solvate means a form of a compound of the present invention that forms a solid or liquid complex when coordinated with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water molecules. In the context of the present invention, the solvate is preferably a hydrate.

The term crystalline form refers to the various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.

The term hydrocarbyl means alkyl or alkenyl.

The term alkyl means a linear, branched or cyclic saturated substituent consisting of carbon and hydrogen. It contains preferably 1-20 carbon atoms, more preferably 1-12 carbon atoms. The term alkyl means a linear, branched or cyclic saturated hydrocarbyl group. The alkyl group particularly includes, for example, methyl, ethyl, npropyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2,2- methylbutyl and 2,3-dimethylbutyl, 16-alkyl, 18-alkyl. The term C1-20 alkyl means a linear, branched or cyclic saturated hydrocarbyl group containing 1-20 carbon atoms. When the alkyl group is substituted, the substituent may be in any substitutable position, and the substitution may be mono-substitution or poly-substitution. For example, the substituent may be selected from alkyl, alkenyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group or oxo group.

The term alkenyl means a linear, branched or cyclic unsaturated hydrocarbyl group containing a double bond, preferably containing 2-20 carbon atoms, more preferably 2-12 carbon atoms. When substituted, the substituent may be in any position available for substitution, and the substitution may be a mono-substitution or a poly-substitution. For example, the substituent may be selected from alkyl, alkenyl, alkoxy group, alkylthio group, alkylamino group, deuterium, halogen, thiol, hydroxy group, nitro group, carboxy group, ester group, cyano group, cycloalkyl, aryl, heteroaryl, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group or oxo group.

The term cycloalkyl means a saturated monocyclic cyclohydrocarbyl group. One cycle usually contains 3-10 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, and the like. In this application, spiro-cycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups are collectively referred to as polycyclic cycloalkyl groups.

The term ring, unless otherwise indicated, means any cyclic structure and is not limited to any forms or compositions, and can mean any form of monocyclic ring, bridged ring, spiro ring, fused ring and polycyclic ring, and can be carbocyclic or heterocyclic ring or other ring forms, such as a carbocyclic ring interrupted by a carbonyl, and may be unsubstituted or substituted. When a ring containing a particular atom or group is indicated, it means that the particular atom or group is a member of the ring itself. For example, the sixth ring contains C=O means that the ring member of the sixth ring itself contains C=O, and if only the substituent on the ring contains C=O, then this case is not covered.

The term carbocyclyl or carbocyclic ring means a carbocyclic group containing 3-20 carbon atoms, preferably 3-16 carbon atoms, more preferably 4-12 carbon atoms, and includes cycloalkyl, cycloalkenyl, aryl, bicyclic carbocyclyl, polycyclic carbocyclyl and the like. The term heterocyclyl or heterocyclic ring means that the ring structurally contains at least one heteroatom and may in particular be, for example, heteroaryl, non-aromatic heterocyclyl, bicyclic heterocyclyl and polycyclic heterocyclyl containing one or more identical or different heteroatoms selected from O , S and N, etc.

The term aryl should be understood in a broad sense and includes not only carbocyclic aryl but also heteroaryl.

The term carbocyclic aryl means a 6-10 membered all carbon monocyclic or polycyclic aromatic group including phenyl, naphthyl, biphenyl and the like. The carbocyclic aryl group may be substituted or unsubstituted. The substituent is independently selected from alkyl, cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, etc.), alkenyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro group, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, alkylsilyl, etc.

The term heteroaryl means a heteroaromatic system containing 1-10 heteroatoms, including monocyclic aryl and fused-ring aryl. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Monoheterocyclic groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2, 4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline and the like.

Fused heterocyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromenone, fluorenone, quinoxaline, 3,4-dihydronaphthalinone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc. P. Heteroaryl groups may be substituted or unsubstituted. The substituent is selected, for example, from alkyl, cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, etc.), alkenyl, azide, amino group, deuterium, alkoxy group, alkylthio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, alkylsilyl, etc.

The term hydrogen, unless specifically stated otherwise, includes all isotopes of hydrogen, in particular may be protium (H), deuterium (D) or tritium (T), and preferably hydrogen at various positions is independently selected from protium or deuterium. Hydrogen in the active hydrogen position is protium. The term deuterium refers to an isotope of protium, which has twice the atomic mass of protium and binds stronger to carbon. The terms deuterated and deuterium mean that protium is replaced by deuterium at the specified position.

The term haloalkyl means an alkyl group substituted with at least one halogen atom.

The term heterocyclic group means a cyclic group containing at least one heteroatom, where the heteroatom is nitrogen, oxygen, sulfur, etc. Heterocyclic groups include monoheterocyclic groups and polyheterocyclic groups.

The term heteroatom, unless otherwise specified, generally includes nitrogen, oxygen and sulfur.

The term halogen, unless otherwise specified, generally includes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, and more preferably fluorine.

- 18 045400

The terms many, several, or more, when used to define the number of substituents or interrupting atoms/groups, generally do not exceed the number of chemically substitutable groups or the number of bonds that can be interrupted. More specifically, the terms many, several or more preferably mean a number equal to 6 or less, more preferably equal to or less, and even more preferably equal to 4 or less.

The term optionally or optionally includes two parallel circuits: selected and not selected. For example, the sixth ring optionally contains C=O means that the sixth ring contains C=O or does not contain C=O.

Detailed Description of Illustrative Embodiments

The embodiments described below are provided for a more complete understanding of the present invention and are not intended to limit the present invention in any way. The structures of all compounds were determined by 1H NMR and mass spectrometry (MS).

Below is a list of abbreviated names of some compounds used in embodiments of the present invention.

DCM: dichloromethane;

EA: ethyl acetate;

DMF: dimethylformamide;

THF: tetrahydrofuran;

TEA: triethylamine;

T3P: 1-propanephosphonic anhydride;

Boc-hydrazine: tert-butoxycarbonyl hydrazine;

HATU: 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

TFA: trifluoroacetic acid;

DMA: N,N-dimethylacetamide;

DPPP: 1,3-bis(diphenylphosphino)propane;

DPPA: diphenylphosphoryl azide;

DBU: 1,8-diazabicyclobicyclo(5,4,0)-7-undecene;

DIPEA: N,N-diisopropylethylamine.

The present invention is described in more detail below in connection with particular embodiments.

Embodiment 1: Preparation of Compound I-1.

Preparation of compound 1b. In 20 ml of DMF, compound 1a (2.0 g, 8.1 mmol), DBU (1.85 g, 12.2 mmol) and ethyl iodide (2.28 g, 14.6 mmol) were reacted at room temperature for 16 h. The resulting mixture was then diluted with 100 ml of water and extracted with ethyl acetate . The organic phases were combined and washed successively with a solution of sodium thiosulfate, 0.5 N. HCl solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give 2.1 g of an oily product as compound 1b.

Receiving connection 1s. In N,N-dimethylacetamide (20 ml), compound 1b (2.1 g, 7.7 mmol), Boc-hydrazine (1.53 g, 11.6 mmol) and pyridinium p-toluenesulfonate (5.78 g, 23.1 mmol) was reacted at 60°C for 16 hours After completion of the reaction, 100 ml of water was added to the mixture and then extracted with ethyl acetate (50 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give the crude product, which was purified by column chromatography to give 1.9 g of a yellow oily product representing

- 19 045400 is connection 1c.

ESI-MS m/z 389.2 (M+H)+.

Preparation of compound 1d. Compound 1c (1.9 g, 4.9 mmol) was dissolved in 10 ml of ethanol, 1N was added. aqueous NaOH solution (14.7 ml, 14.7 mmol), and the mixture was kept at 60°C for 24 hours. The resulting mixture was acidified with 3 N. HCl solution and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated. The resulting crude product was triturated in dichloromethane/petroleum ether (5 ml/50 ml) to give 1.1 g of a white solid as compound 1d.

ESI-MS m/z 361.2 (M+H) ⁺ .

Obtaining connection 1f. 1d (360 mg, 1 mmol), 1e (133 mg, 1.2 mmol), TEA (303 mg, 3.0 mmol) and HATU (570 mg, 1.5 mmol) were stirred in DCM at room temperature overnight, then diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated, then purified by column chromatography to give 350 mg of a white solid as compound 1f.

ESI-MS m/z 454.2 (M+H) ⁺ .

Preparation of compound 1g. Compound 1f (350 mg, 0.77 mmol) was dissolved in 4 ml of DCM, 1 ml of TFA was added, and the reaction was carried out at 0°C for 6 hours. The mixture was evaporated, 1 N was added. NaOH solution until the medium was alkaline, and the resulting mixture was extracted with a mixture of dichloromethane/iPrOH. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to obtain 210 mg of an oily product, which was directly used in the next step.

Obtaining connection 1h. Compound 1g (210 mg, 0.59 mmol) was dissolved in 5 ml of toluene. 30 mg of paraformaldehyde and 100 mg of acetic acid were added, and the resulting mixture was kept at 100°C for 3 hours. The mixture was evaporated and separated by thin layer chromatography, obtaining 145 mg of product.

ESI-MS m/z 366.2 (M+H) ⁺ .

Obtaining connection 1j. The reaction of compound 1h (140 mg, 0.38 mmol) and compound 1i (114 mg, 0.5 mmol) was carried out in a solution of T3P in ethyl acetate at 100°C for 3 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 170 mg of product.

ESI-MS m/z 576.2 (M+H) ⁺ .

Preparation of compound I-1. In 5 ml of DMA, the reaction of compound 1j (170 mg, 0.29 mmol) and lithium chloride (50 mg, 1.18 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2 N was added. hydrochloric acid solution, bringing the pH to 5-6. The resulting mixture was filtered and the solid was dried in vacuo to give 120 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.46-7.53 (m, 2H), 7.36 (s, 2H), 7.13-7.17 (m, ZH), 6.89 (s, 1H), 6.76 (s, 1H) , 5.76-5.88 (m, 2H), 5.14 (s, 1H), 4.88-4.91 (m, 1H), 4.77-4.80 (m, 1H), 4.48-4.51 (m, 1H), 3.66-3.69 (m, 1H), 2.30 (s, 2H), 2.16 (s, 2H), 1.78-1.90 (m, 6H);

ESI-MS m/z 486.2 (M+H) ⁺ .

Embodiment 2: Preparation of Compound I-5.

Preparation of compound 2b. Compound 1h (180 mg, 0.49 mmol) and Compound 2a (264 mg, 1.0 mmol) were reacted in a solution of T3P in ethyl acetate at 100°C for 3 h in a sealed reactor. The resulting mixture was cooled, diluted with saturated aqueous NaHCO3 and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 190 mg of product.

ESI-MS m/z 612.2 (M+H) ⁺ .

Preparation of compound I-5. In 5 ml of DMA, the reaction of compound 2b (190 mg, 0.31 mmol) and lithium chloride (50 mg, 1.18 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the resulting mixture was diluted with 10 ml of water and 2 N was added. hydrochloric acid solution, bringing the pH to 5-6. The mixture was filtered and the solid was dried in vacuo to give 136 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.04-7.12 (m, 3H), 7.00-7.02 (d, 1H, J=7.6 Hz), 6.90-6.93 (m, 1H), 6.79-6.83 (m, 1H), 6.63-6.64 (d, 1H, J=7.2 Hz), 5.74-5.76 (d, 1H, J=7.6 Hz), 5.42-5.46 (m, 1H), 5.06 (s, 1H), 4.82-4.86 (m, 1H), 4.69-4.77 (m, 1H), 4.37-4.40 (m, 1H), 4.04-4.07 (m, 1H), 2.18-2.28 (m, 2H), 2.06-2.09 (m, 2H) , 1.74-1.85

- 20 045400 (m, 6N);

ESI-MS m/z (M+H)+ 522.2.

Embodiment 3: Preparation of Compound I-7.

Preparation of compound 3b. Compound 3a (5.0 g, 27.8 mmol) was added to n-butyl vinyl ether (10 ml), then palladium trifluoroacetate (100 mg, 0.3 mmol), triethylamine (3.03 g, 30 mmol) and DPPP (124 mg, 0.3 mmol) were added ), and stirred at 75°C overnight in a sealed reactor. TLC monitoring showed that the reaction was complete. The resulting mixture was added with 50 ml of water and extracted with ethyl acetate twice, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated and separated by column chromatography to obtain 4.8 g of product, which was directly used in the next step.

Getting connection 3c. Compound 3b (4.8 g, 23.3 mmol) was dissolved in 50 ml of anhydrous toluene and 1N was added. diethylzinc solution (70 ml, 70 mmol) at -40°C in an inert nitrogen atmosphere. After addition, the mixture was stirred for 1 hour and then methane chloride (8.22 g, 46.6 mmol) was added. After addition, the resulting mixture was stirred for 2 hours, slowly warmed to room temperature and stirred overnight. TLC monitoring showed that the reaction was complete, then the reaction mixture was poured into ammonium chloride solution and extracted with ethyl acetate (100 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to give 4.9 g of crude product.

Getting a 3d connection. Intermediate 3c (4.9 g, 22.2 mmol) was dissolved in 50 ml of methanol, an aqueous solution of sodium hydroxide was added and stirred at room temperature for 5 hours. TLC monitoring showed the absence of the starting compound. HCl was added to adjust the pH to 2-3 and the resulting mixture was extracted with ethyl acetate (100 ml x 3). The organic phases were evaporated to obtain 2.3 g of crude product.

Preparation of compound 3e. Compound 3d (2.3 g, 17.7 mmol) was dissolved in 15 ml of toluene, DPPA (5.84 g, 21.2 mmol) and TEA (3.58 g, 35.4 mmol) were added, stirred at room temperature for 2 h, then benzyl alcohol (5.73 g, 53.1 mmol) was added mmol) and carried out the reaction at 90°C for 2 hours. TLC monitoring showed that the reaction was complete. The resulting mixture was cooled to room temperature and 100 ml of water was added to quench the reaction, extracted with ethyl acetate (80 ml x 3) and the organic phases were combined, dried and evaporated to give the crude product, which was purified by column chromatography to give 1.5 g of a mixture of product and benzyl alcohol, which was directly used in the next stage.

Obtaining compound 3f. 1.5 g of crude compound 3e was dissolved in 10 ml of methanol and 150 mg of Pd/C and 0.2 ml of concentrated hydrochloric acid were added. The atmosphere above the resulting mixture was replaced with hydrogen three times and the reaction was carried out for 5 hours. TLC monitoring showed that the reaction was complete. The resulting mixture was filtered through diatomaceous earth, HCl was added to the filtrate, bringing the pH to 1-2 and evaporated to dryness, obtaining 0.6 g of product, which was directly used in the next stage.

Obtaining connection 3h. In 15 ml of dichloromethane, compound 3f (0.6 g, 4.36 mmol), compound 3g (1.12 g, 4.0 mmol), HATU (1.82 g, 4.8 mmol) and TEA (1.21 g, 12.0 mmol) were stirred at room temperature overnight. TLC monitoring showed that the reaction was complete, 20 ml of water was added to the resulting mixture and extracted with dichloromethane (30 mlx2), the organic phases were combined, dried and evaporated to obtain the crude product, which was separated by column chromatography to obtain 0.85 g of product.

Receiving connection 3i. Compound 3h (0.85 g, 2.6 mmol), potassium carbonate (718 mg, 5.2 mmol) and 2,4-dinitrophenylhydroxylamine (0.78 g, 3.9 mmol) were stirred in 5 ml of DMF at room temperature for 5 h. TLC monitoring showed that that the reaction was complete, they added to the resulting mixture

- 21045400 ml of water and extracted with dichloromethane (20 ml x 3) and the organic phases were combined, dried and evaporated to give the crude product, which was separated by column chromatography to give 0.73 g of product.

Preparation of compound 3j. Compound 3i (0.73 g, 2.1 mmol), acetic acid (120 mg, 2.1 mmol) and paraformaldehyde (0.23 g, 2.52 mmol) were refluxed in toluene for 2 h.

TLC monitoring showed that the reaction was complete. The resulting mixture was evaporated, 10 ml of water was added to the residue and extracted with dichloromethane (20 mlx3), the organic phases were combined, dried and evaporated, obtaining a crude product, which was separated by column chromatography, obtaining 0.45 g of product.

Getting a 3k connection. In 3 ml of a solution of T3P in ethyl acetate, compound 3j (450 mg, 1.27 mmol) and compound 2a (660 mg, 2.54 mmol) were reacted at 100°C for 3 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated NaHCO ₃ solution and then extracted with ethyl acetate. The organic phases were combined, dried, evaporated and separated by column chromatography to obtain 290 mg of product.

ESI-MS m/z 602.2 (M+H)+.

Preparation of compound I-7. In 5 ml of DMA, the reaction of compound 3k (290 mg, 0.48 mmol) and lithium chloride (50 mg, 1.18 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2 N was added. hydrochloric acid solution, bringing the pH to 5-6. The resulting mixture was filtered and the solid was dried in vacuo to give 187 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.05-7.15 (m, 3H), 7.00-7.02 (d, 1H, J=8.0 Hz), 6.94-6.98 (m, 1H), 6.81-6.85 (m, 1H), 6.65-6.67 (d, 1H, J=8.0 Hz), 5.80-5.82 (d, 1H, J=8.0 Hz), 5.38-5.42 (m, 1H), 5.13 (s, 1H), 4.96-5.00 (m, 1H), 4.21-4.27 (m, 2H), 4.02-4.06 (m, 1H), 3.61-3.67 (m, 2H), 3.22-3.25 (m, 1H), 2.84-2.91 (m, 1H) , 0.44-0.47 (m, 4H);

ESI-MS m/z (M+H)+512.2.

Embodiment 4: Preparation of Compound I-8.

Preparation of compound 4b. In 30 ml of dimethyl sulfoxide, compound 4a (2.24 g, 28.7 mmol), bromocyclopropane (3.47 g, 28.7 mmol) and potassium t-butoxide (3.22 g, 28.7 mmol) was reacted at 80°C overnight. The resulting mixture was cooled to room temperature and a saturated NaHCO ₃ solution was added to quench the reaction, then extracted with ethyl acetate (50 mlx3). The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to obtain 2.8 g of a yellow liquid. It was used directly in the next stage.

Getting connection 4c. In 20 ml of tetrahydrofuran, compound 4b (1.60 g, 13.6 mmol), phthalimide (2.39 g, 16.2 mmol), triphenylphosphine (5.34 g, 20.4 mmol) and isopropyl azodicarboxylate (4.12 g, 20.4 mmol) were reacted at room temperature overnight. Water was added to the resulting mixture to quench the reaction and extracted with ethyl acetate (20 mlx3). The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to give a crude product, which was separated by column chromatography to give 2.4 g of an oily product. It was used directly in the next stage.

Obtaining a 4d connection. Compound 4c (2.40 g, 10 mmol) was dissolved in 30 ml of methanol, 2 g of hydrazine hydrate was added, and the resulting mixture was kept at 75°C for 2 hours. TLC monitoring showed that the reaction was complete. The mixture was cooled and filtered. The filtrate was evaporated and the residue was triturated in diethyl ether. The resulting mixture was filtered and the filtrate was dried to obtain 1.04 g of crude product. It was used directly in the next stage.

Preparation of compound 4e. Compound 4d (420 mg, 3.6 mmol), Compound 3g (864 mg, 2.4 mmol), HATU (1.37 g, 3.6 mmol) and TEA (720 mg, 7.2 mmol) were stirred in 10 ml of dichloromethane at room temperature overnight. TLC monitoring showed that the reaction was complete. The resulting mixture was added with 30 ml of water and extracted with dichloromethane (30 ml x 2), the organic phases were combined, dried and evaporated to obtain the crude product, which was separated on a silica gel plate to obtain 900 mg of product.

ESI-MS m/z (M+H)+ 344.1.

- 22 045400

Obtaining connection 4f. In 5 ml of DMF, compound 4e (900 mg, 2.4 mmol), potassium carbonate (1.08 g, 7.8 mmol) and 2,4-dinitrophenylhydroxylamine (780 mg, 3.9 mmol) were stirred at 60°C for

h. 20 ml of water was added to the resulting mixture and extracted with dichloromethane (20 ml x 3), the organic phases were combined, dried and evaporated to obtain the crude product, which was separated on a silica gel plate to obtain 120 mg of product.

Getting a 4g connection. Compound 4f (120 mg, 0.33 mmol), acetic acid (36 mg, 0.06 mmol) and paraformaldehyde (100 mg, 1.1 mmol) were boiled in toluene for 6 hours. The resulting mixture was evaporated, 10 ml of water was added to the residue and extracted with dichloromethane (20 mlx3 ), the organic phases were combined, dried and evaporated to give the crude product, which was separated on a silica gel plate to give 85 mg of product.

Getting connection 4h. In 2 ml of a solution of T3P in ethyl acetate, compound 4g (85 mg, 0.23 mmol) and compound 2a (90 mg, 0.34 mmol) were reacted at 100°C for 3 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated by column chromatography to obtain 20 mg of product.

Preparation of compound I-8. In 1 ml of DMA, the reaction of compound 4h (20 mg, 0.03 mmol) and lithium chloride (50 mg, 1.18 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2N was added. hydrochloric acid solution, bringing the pH to 3-4. The resulting mixture was filtered and the solid was dried in vacuo to give 5 mg of product.

¹ H-NMR (400 MHz, CDCl3) δ 7.02-7.12 (m, 5H), 6.85 (m, 1H), 6.77 (m, 1H), 5.81 (d, 1H, J=7.6 Hz), 5.43 (m, 1H), 5.20 (s, 1H), 5.10 (d, 1H, J=12.8 Hz), 4.25 (d, 1H, J=12.8 Hz), 4.06 (d, 2H, J=14 Hz), 3.31 (m, 1H), 2.73 (t, 2H, J=6.8 Hz), 1.95 (m, 1H), 0.89 (m, 2H), 0.56 (m, 2H);

ESI-MS m/z (M+H)+528.1.

Embodiment 5: Preparation of Compound I-14.

Preparation of compound 5b. Compound 1d (360 mg, 1 mmol), compound 5a (116 mg, 1.2 mmol), TEA (303 mg, 3.0 mmol) and HATU (570 mg, 1.5 mmol) were stirred in DCM at room temperature overnight, then diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated, then the residue was separated by column chromatography to obtain 320 mg of a white solid.

Receiving connection 5c. Compound 5b (320 mg, 0.73 mmol) was dissolved in 4 ml of DCM, 1 ml of TFA was added and the reaction was carried out at 0°C for 6 hours. The resulting mixture was dried, 1 N was added. NaOH solution, bringing the reaction of the medium to alkaline, and extracted with a mixture of dichloromethane/iPrOH. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to obtain 195 mg of an oily product, which was directly used in the next step.

Obtaining connection 5d. Compound 5c (195 mg, 0.57 mmol) was dissolved in 5 ml of toluene, 30 mg of paraformaldehyde and 100 mg of acetic acid were added, then the reaction was carried out at 100°C for 3 hours. The resulting mixture was evaporated and separated by thin layer chromatography, obtaining 130 mg of product .

Preparation of compound 5e. In a solution of T3P in ethyl acetate, compound 5d (130 mg, 0.37 mmol) and compound 2a (114 mg, 0.5 mmol) were reacted at 100°C for 3 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 130 mg of product.

Preparation of compound I-14. In 1 ml of DMA, the reaction of compound 5e (130 mg, 0.23 mmol) and lithium chloride (50 mg, 1.18 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2 N was added. hydrochloric acid solution, bringing the pH to 3-4. The resulting mixture was filtered and the solid was dried in vacuo to give 35 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.03-7.11 (m, 4H), 6.94 (m, 1H), 6.82 (m, 1H), 6.67 (m, 1H), 5.78 (d, 1H, J= 7.6 Hz), 5.43 (d, 1H, J=12.8 Hz), 5.19 (t, 1H, J=7.6 Hz), 5.12 (s, 1H), 4.93 (d, 1H, J=13.2 Hz), 4.56 (d , 1H,

- 23 045400

J=13.6 Hz), 4.08 (d, 1H, J=14 Hz), 2.24 (m, 1H), 2.13 (m, 3H), 0.54 (t, 2H, J=8.0 Hz), 0.34 (m, 2H) ; ESI-MS m/z (M+H)+ 508.2.

The following compounds were synthesized using similar methods.__________

Compound Structure LCMS ([M+H] ⁺ ) Purity 1-9 It сОо ^-s 472.2 96% 1-10 O Oh oh 488.2 93% 1-21 IT Vy Before 504.2 95%

Embodiment 6: Preparation of compound I-65.

Preparation of compound 6b. Compound 6a (600 mg, 2.13 mmol), compound 3g (280 mg, 2.34 mmol), HATU (1.21 g, 3.20 mmol) and TEA (850 mg, 8.5 mmol) were stirred in 5 ml of dichloromethane at room temperature overnight. TLC monitoring showed that the reaction was complete; 20 ml of water was added to the resulting mixture and extracted with dichloromethane (30 ml x 3). The organic phases were combined, dried and evaporated to give the crude product, which was separated by column chromatography to give 455 mg of product.

Getting connection 6c. Compound 6b (455 mg, 1.46 mmol), potassium carbonate (543 mg, 4.38 mmol) and 2,4-dinitrophenylhydroxylamine (392 mg, 2.19 mmol) were stirred in 15 ml of DMF at room temperature for 16 h. TLC monitoring showed that the reaction ended, 20 ml of water was added to the resulting mixture and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated on a silica gel plate to give 200 mg of product.

ESI-MS m/z (M+H) ⁺ 326.1

Preparation of compound 6d. Compound 6c (200 mg, 0.62 mmol), acetic acid (200 mg, 3.3 mmol) and paraformaldehyde (18 mg, 0.62 mmol) were boiled in 10 ml of toluene for 2 hours. TLC monitoring showed that the reaction was complete. The resulting mixture was evaporated, 10 ml of water was added to the residue and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated by column chromatography to give 190 mg of product.

ESI-MS m/z (M+H) ⁺ 338.1

Preparation of compound 6e. In 3 ml of a solution of T3P in ethyl acetate, compound 6d (190 mg, 0.56 mmol) and compound 2a (223 mg, 0.84 mmol) were reacted at 100°C for 1.5 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 227 mg of product.

Preparation of compound I-65. In 5 ml of DMA, the reaction of compound 6e (227 mg, 0.4 mmol) and lithium chloride (86 mg, 2.0 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2N was added. hydrochloric acid solution, bringing the pH to 5-6. The resulting mixture was filtered and the solid was dried in vacuo to give 100 mg of product.

¹ H-NMR (400 MHz, CDCls) δ 7.10 (m, 3H), 6.99 (m, 2H), 6.84 (m, 1H), 6.70 (m, 1H), 5.75 (d, 1H,

- 24 045400

J=7.6 Hz), 5.40 (d, 1H, J=15.2), 5.14 (s, 1H), 4.82 (d, 1H, J=12.8 Hz), 4.25 (d, 1H, J=12.8 Hz), 4.04 ( d, 1H,

J=14.0 Hz), 3.76 (m, 3H), 2.98 (m, 2H), 2.54 (s, 1H), 2.05-2.15 (m, 6H);

ESI-MS m/z (M+H)+ 494.1.

Embodiment 7: Preparation of Compound I-66.

Preparation of compound 7b. Compound 7a (250 mg, 1.82 mmol), compound 3g (465 mg, 1.65 mmol), HATU (941 mg, 2.48 mmol) and TEA (660 mg, 6.6 mmol) were stirred in 10 ml of dichloromethane at room temperature overnight. TLC monitoring showed that the reaction was complete; 20 ml of water was added to the resulting mixture and extracted with dichloromethane (30 ml x 3). The organic phases were combined, dried and evaporated to give the crude product, which was separated by column chromatography to give 430 mg of product.

Getting connection 7c. Compound 7b (430 mg, 1.30 mmol), potassium carbonate (538 mg, 3.9 mmol) and 2,4-dinitrophenylhydroxylamine (391 mg, 1.96 mmol) were stirred in 15 ml of DMF at room temperature for 16 h. TLC monitoring showed that the reaction ended, 20 ml of water was added to the resulting mixture and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated on a silica gel plate to give 220 mg of product.

ESI-MS m/z (M+H)+ 344.1

Preparation of compound 7d. Compound 7c (220 mg, 0.64 mmol), acetic acid (200 mg, 3.3 mmol) and paraformaldehyde (20 mg, 0.64 mmol) were boiled in 10 ml of toluene for 2 h. TLC monitoring showed that the reaction was complete. The resulting mixture was evaporated, 10 ml of water was added to the residue and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated on a silica gel plate to give 165 mg of product.

ESI-MS m/z (M+H)+ 356.1

Preparation of compound 7e. In 3 ml of a solution of T3P in ethyl acetate, compound 7d (165 mg, 0.46 mmol) and compound 2a (184 mg, 0.70 mmol) were reacted at 100°C for 1.5 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 100 mg of product.

Preparation of compound I-66. In 3 ml of DMA, the reaction of compound 7e (100 mg, 0.17 mmol) and lithium chloride (35 mg, 0.83 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2N was added. hydrochloric acid solution, bringing the pH to 5-6. The resulting mixture was filtered and the solid was dried in vacuo to give 45 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.11 (m, 3H), 6.96 (m, 1H), 6.82 (m, 1H), 6.63 (m, 1H), 5.98 (d, 1H, J=9.2 Hz ), 5.39 (m, 1H), 5.02-5.12 (m, 2H), 4.23 (d, 1H, J=12.8 Hz), 4.06 (d, 1H, J=14.0 Hz), 2.39-2.49 (m, 5H) ;

ESI-MS m/z (M+H)+ 512.1.

Embodiment 8: Preparation of Compound I-77.

- 25 045400

Preparation of compound 8b. Compound 8a (250 mg, 2.5 mmol), compound 3g (705 mg, 2.5 mmol), HATU (1.19 g, 3.1 mmol) and TEA (1.01 g, 10.5 mmol) were stirred in 10 ml of dichloromethane at room temperature overnight. TLC monitoring showed that the reaction was complete; 20 ml of water was added to the resulting mixture and extracted with dichloromethane (30 ml x 3). The organic phases were combined, dried and evaporated to give the crude product, which was separated by column chromatography to give 780 mg of product.

Getting connection 8c. Compound 8b (780 mg, 2.5 mmol), potassium carbonate (1.04 g, 7.5 mmol) and 2,4-dinitrophenylhydroxylamine (752 mg, 3.8 mmol) were stirred in 10 ml of DMF at room temperature for 16 h. TLC monitoring showed that the reaction ended, 20 ml of water was added to the resulting mixture and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated on a silica gel plate to give 390 mg of product.

ESI-MS m/z (M+H)+ 326.1.

Obtaining connection 8d. Compound 8c (390 mg, 1.2 mmol), acetic acid (500 mg, 8.3 mmol) and paraformaldehyde (36 mg, 1.2 mmol) were boiled in 10 ml of toluene for 2 hours. TLC monitoring showed that the reaction was complete. The resulting mixture was evaporated, 10 ml of water was added to the residue and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated on a silica gel plate to give 280 mg of product.

ESI-MS m/z (M+H) ⁺ 338.1

Preparation of compound 8e. In 1.5 ml of a solution of T3P in ethyl acetate, the reaction of compound 8d (99 mg, 0.30 mmol) and compound 2a (117 mg, 0.45 mmol) was carried out at 100°C for 1.5 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 150 mg of product.

Preparation of compound I-77. In 3 ml of DMA, the reaction of compound 8e (150 mg, 0.26 mmol) and lithium chloride (70 mg, 1.66 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2 N was added. hydrochloric acid solution, bringing the pH to 5-6. The resulting mixture was filtered and the solid was dried in vacuo to give 75 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.13-7.14 (m, 3H), 7.1-7.03 (d, 2H, J=8.0), 6.84-6.88 (m, 1H), 6.70-6.72 (d, 1H , J=8.0), 5.81-5.83 (d, 1H, J=8.0), 5.42-5.44 (m, 1H), 5.15 (s, 1H), 4.84-4.87 (m, 1H), 4.29-4.32 (m, 1H), 4.06-4.09 (m, 1H), 2.09-2.19 (m, 7H);

ESI-MS m/z (M+H) ⁺ 494.1.

The following compounds were synthesized using a similar procedure. ____________

Compound Structure LCMS ([M+H] ⁺ ) Purity 1-69 O 458.2 95% 1-81 W to F 476.1 94% 1-83 yeah ^{^ n'nJ} 476.2 97% 1-85 O SU O 476.2 97% 1-89 /OU* 492.1 96%

- 26 045400

Embodiment 9: Preparation of Compound II-5.

Preparation of compound 9b. In a mixture of DMF (7.5 ml) and toluene (7.5 ml), the reaction of compound 9a (250 mg, 2.02 mmol), phthalic anhydride (300 mg, 2.02 mmol), triethylamine (408 mg, 4.04 mmol) was carried out at 130°C for 5 h. TLC monitoring showed that the reaction was complete, water was added to the resulting mixture, stirred for 1 h and filtered to obtain 332 mg of a white solid, which was used directly in the next step.

Getting connection 9c. Compound 9b (332 mg, 1.53 mmol) and bromoacetaldehyde dimethyl acetal (517 mg, 3.06 mmol) were dissolved in 15 ml of DMA, heated to 40°C, then potassium tert-butoxide (294 mg, 3.06 mmol) was added, and the resulting mixture was stirred at 40°C for 5 hours. The mixture was cooled to room temperature, 10 ml of water was added to quench the reaction, glacial acetic acid was added to adjust the pH to 3-4, extracted with ethyl acetate, dried, evaporated, and separated by column chromatography, obtaining 265 mg of product .

Obtaining connection 9d. Compound 9c (265 mg, 0.87 mmol) was dissolved in 30 ml of methanol, 2 g of hydrazine hydrate was added, and the resulting mixture was kept at 75°C for 2 hours. TLC monitoring showed that the reaction was complete. The resulting mixture was cooled and filtered. The filtrate was evaporated and triturated in diethyl ether. The resulting mixture was filtered and the filtrate was dried to obtain 96 mg of crude product. It was used directly in the next stage.

Preparation of compound 9e. Compound 1d (137 mg, 0.38 mmol), compound 9d (96 mg, 0.55 mmol), TEA (115 mg, 1.14 mmol) and HATU (289 mg, 0.76 mmol) were stirred in DCM at room temperature overnight, then diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated, then the residue was separated by column chromatography to obtain 155 mg of product.

Obtaining compound 9f. 18 ml of acetonitrile and 3 ml of water were added to compound 9e (155 mg, 0.3 mmol), the resulting mixture was heated to 60°C, methanesulfonic acid (8 mg, 0.9 mmol) was added dropwise and stirred for 6 hours. TLC monitoring showed that that the reaction is over. An aqueous solution of sodium bicarbonate was added to the resulting mixture until it became slightly alkaline, it was evaporated and extracted with dichloromethane. The organic phases were combined, dried, evaporated and separated on a silica gel plate to give 60 mg of a white solid.

Preparation of compound 9g. In a solution of T3P in ethyl acetate, compound 9f (60 mg, 0.17 mmol) and compound 2a (69 mg, 0.26 mmol) were reacted at 100°C for 3 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a chiral column to obtain 15 mg of product.

Preparation of compound II-5. In 1 ml of DMA, the reaction of compound 9g (15 mg, 0.025 mmol) and lithium chloride (10 mg, 0.24 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2N was added. hydrochloric acid solution, bringing the pH to 3-4. The resulting mixture was filtered and the solid was dried in vacuo to give 5 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.28-7.34 (m, 1H), 7.09-7.16 (m, 2H), 6.83-7.01 (m, 2H), 6.66-6.68 (d, 1H, J=8.0 ); 6.56-6.59 (m, 1H), 5.77-5.90 (m, 1H), 5.28-5.37 (m, 1H), 5.02-5.18 (m, 1H), 4.61-4.71 (m, 1H), 3.91-4.17 (m , 3H), 3.59-3.68 (m, 1H), 2.95-3.07 (m, 1H), 0.23-0.89 (m, 4H);

ESI-MS m/z (M+H)+ 510.1.

- 27 045400

The following compounds were synthesized using a similar procedure.

Compound Structure LCMS ([M+H] ⁺ ) Purity II-1 -O 474.2 95% P-8 OH O _G ° ^CH z g\- _a 528.1 94% P-9 IT 0¾ g 492.1 94% II-13 UZh ° \ ^ζι ' \ J (D У 492.1 95% II-17 IT 492.1 96%

Embodiment 10: Preparation of Compound II-6.

Preparation of compound 10a. Compound 1c (388 mg, 1 mmol) was dissolved in 3 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the resulting mixture was stirred at room temperature for 3 hours. TLC monitoring showed that the reaction was complete, 3 N was added to the resulting mixture. sodium hydroxide solution, bringing the pH to 9-10. The resulting mixture was extracted with dichloromethane, the organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to obtain 270 mg of solid, which was used directly in the next step.

Receiving connection 10s. Compound 10b (1.0 g, 7.8 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, then the atmosphere in the flask was replaced with nitrogen three times. The resulting mixture was cooled to -78°C and a 2.5 M solution of n-butyllithium (3.1 ml, 7.8 mmol) was slowly added under an inert nitrogen atmosphere. After addition, the resulting mixture was stirred at the same temperature for 2 hours. Allyl chloroformate (0.94 g, 7.8 mmol) was then added dropwise. After addition, the mixture was stirred at the same temperature for 2 hours, and TLC monitoring showed complete disappearance of the starting compound. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (15 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to

- 28 045400 tea 1.65 g oily product.

Obtaining connection 10d. Compound 10c (1.65 g, 7.8 mmol) was dissolved in 15 ml of anhydrous tetrahydrofuran and a 1 M solution of diisobutylaluminum hydride (11.7 ml, 11.7 mmol) was slowly added at -78°C under an inert nitrogen atmosphere. After addition, the resulting mixture was stirred at the same temperature for 2 hours. TLC monitoring showed complete disappearance of the starting compound. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (20 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to give 1.57 g of an oily product.

Receiving connection 10e. Compound 10d (1.57 g, 7.4 mmol) was dissolved in 15 ml of methanol and p-toluenesulfonic acid monohydrate (140 mg, 0.74 mmol) was added. The resulting mixture was stirred at room temperature overnight. TLC monitoring showed complete disappearance of the starting compound. A saturated solution of sodium bicarbonate was added to the resulting mixture until the pH value was neutral, then it was evaporated. The residue was separated by column chromatography to give 0.86 g of a yellow oily product.

Receiving connection 10f. Compound 10a (270 mg, 0.94 mmol) and compound 10e (255 mg, 1.13 mmol) were dissolved in 5 ml of acetonitrile. Under an inert atmosphere of nitrogen and at -20°C, a 1 M solution of tin tetrachloride in dichloromethane (1.4 ml, 1.41 mmol) was added dropwise. After addition, the mixture was stirred at the same temperature for 3 hours. A saturated sodium bicarbonate solution was added to the resulting mixture, stirred for 30 minutes and separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to give 428 mg of crude product.

Getting connection 10g. Compound 10f (428 mg, 0.89 mmol) was dissolved in 5 ml of tetrahydrofuran, tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol) and morpholine (774 mg, 8.9 mmol) were added and the reaction was carried out at room temperature for 2 hours. TLC- monitoring showed that the reaction was over. The resulting mixture was evaporated and the residue was separated by column chromatography to obtain 216 mg of product.

Receiving connection 10h. In a 3 ml solution of T3P in ethyl acetate, compound 10g (216 mg, 0.61 mmol) and compound 2a (242 mg, 0.92 mmol) were reacted at 100°C for 3 hours in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated NaHCO ₃ solution and then extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated by column chromatography to give 200 mg of crude product, which was separated on a chiral column to give 40 mg of product.

Preparation of compound II-6. In 1 ml of DMA, the reaction of compound 10h (40 mg, 0.067 mmol) and lithium chloride (20 mg, 0.48 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the resulting mixture was diluted with 10 ml of water and 2N was added. hydrochloric acid solution, bringing the pH to 3-4. The resulting mixture was filtered and the solid was dried in vacuo to give 25 mg of product.

¹ H-NMR (400 MHz, CDCl3) δ 7.05-7.15 (m, 5H), 6.85 (m, 1H), 6.70 (d, 1H, J=7.6 Hz), 5.78 (d, 1H, J=7.6 Hz) , 5.3 (m, 2H), 4.69 (d, 1H, J=6.8 Hz), 4.17 (d, 1H, J=14 Hz), 4.09 (d, 1H, J=14 Hz), 3.90 (m, 1H) , 3.69 (m, 1H), 3.44 (d, 1H, J=15.2 Hz), 0.95 (m, 1H), 0.74 (m, 3H);

ESI-MS m/z (M+H)+ 510.1.

The following compounds were synthesized using a similar procedure.

- 29 045400

II-10 IT 492.1 95% II-14 IT 492.1 96% II-18 OH O θγγ _Ν ^ OgR 492.1 95% P-22 A 7° \ , ^ZI ' \ J o/ />/O Λ— ^/ O o 508.1 96% P-29 it fAHO 528.1 96%

Embodiment 11. Preparation of compound P-66.

11a 11b 11c 11d c _e 11f

Getting connection 11c. In 100 ml of dichloromethane, compound PA (5.00 g, 58 mmol), compound 11b (5.98 g, 64 mmol), HATU (33.0 g, 87 mmol) and DIPEA (30 ml, 174 mmol) were stirred at room temperature overnight. TLC monitoring showed that the reaction was complete; 100 ml of water was added to the resulting mixture and extracted with dichloromethane (30 mlx3). The organic phases were combined, dried and evaporated to give the crude product, which was separated by column chromatography to give 6.0 g of product.

Obtaining lid connection. Compound 11c (1.00 g, 8.0 mmol) was dissolved in 240 ml of dichloromethane, then Grubbs catalyst II (260 mg, 0.32 mmol) was added and boiled for 12 h in an inert nitrogen atmosphere. TLC monitoring indicated that the reaction was complete and the resulting mixture was evaporated to give the crude product, which was separated by column chromatography to give 150 mg of product.

Receiving connection Not. Compound lid (150 mg, 1.54 mmol) was dissolved in 4 ml of anhydrous tetrahydrofuran and the atmosphere was replaced with nitrogen by pumping three times. The resulting mixture was cooled to 78°C and a 2.5 M solution of n-butyllithium (0.62 ml, 1.54 mmol) was slowly added under a nitrogen atmosphere. After addition, the mixture was stirred at the same temperature for 2 hours. Allyl chloroformate (186 mg, 1.54 mmol) was then added dropwise. After addition, the resulting mixture was stirred for 2 hours and TLC indicated completion of the reaction. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (15 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to give 235 mg of an oily product.

Receiving Ilf connection. The He compound (235 mg, 1.3 mmol) was dissolved in 3 ml of anhydrous tetrahydrofuran and a 1 M solution of diisobutylaluminum hydride (1.7 ml, 1.7 mmol) was slowly added at -78°C under an inert nitrogen atmosphere. After addition, the mixture was stirred at the same temperature for 2 hours. TLC showed completion of the reaction. The reaction mixture was poured into a saturated solution of tar-30045400 sodium potassium waste and extracted with ethyl acetate (20 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to give 200 mg of an oily product.

Obtaining connection 11g. Compound 11f (200 mg, 1.1 mmol) was dissolved in 3 ml of methanol, p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol) was added, and the resulting mixture was stirred at room temperature for 5 h. TLC indicated completion of the reaction. Saturated sodium bicarbonate solution was added to the resulting mixture until the pH was neutral and extracted with dichloromethane (20 mlx3). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to give a crude product, which was separated by column chromatography to give 180 mg of an oily product.

Receiving connection 11h. Compound 11g (180 mg, 0.65 mmol) and compound 10a (150 mg, 0.75 mmol) were dissolved in 15 ml of acetonitrile. Under an inert nitrogen atmosphere and at -20°C, a 1 M solution of tin tetrachloride in dichloromethane (0.95 ml, 0.95 mmol) was added dropwise. After addition, the mixture was stirred at the same temperature for 3 hours.

A saturated solution of sodium bicarbonate was added to the resulting mixture, stirred for 30 minutes and separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried and evaporated to give 300 mg of solid. The resulting solid was dissolved in 5 ml of tetrahydrofuran, tetrakis(triphenylphosphine) palladium (55 mg, 0.065 mmol) and morpholine (5 g, 55 mmol) were added and the reaction was carried out at room temperature for 2 hours. TLC monitoring showed that the reaction was complete . The resulting mixture was evaporated and the residue was separated by column chromatography to obtain 150 mg of product.

Getting an 11i connection. In 3 ml of a solution of T3P in ethyl acetate, compound 11h (70 mg, 0.22 mmol) and compound 2a (86 mg, 0.32 mmol) were reacted at 100°C for 1.5 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated by column chromatography to obtain 100 mg of crude product.

Preparation of compound II-66. In 3 ml of DMA, the reaction of compound 11i (100 mg, 0.18 mmol) and lithium chloride (37 mg, 0.88 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2 N was added. hydrochloric acid solution, bringing the pH to 3-4. The resulting mixture was filtered and the solid was dried in vacuo to give 30 mg of product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.28 (d, 2H, J=8.0 Hz), 7.21 (m, 1H), 7.05-7.15 (m, 5H), 6.98-7.01 (m, 1H), 6.91 (kv, 1H, J=8.4 Hz), 6.85 (m, 1H), 6.69 (m, 1H), 6.63 (m, 1H), 5.88 (d, 1H, J=7.6 Hz), 5.78 (d, 1H, J=7.6 Hz), 5.69 (m, 4H), 5.46 (m, 1H), 5.32 (m, 1H), 5.28 (s, 1H), 5.15 (s, 1H), 5.03 (m, 2H), 4.62 ( dd, 1H, J=3.6, 11.2 Hz), 4.49 (dd, 1H, J=4.0, 10.8 Hz), 4.07 (t, 2H, J=14.4 Hz), 3.44 (d, 1H, J=18.8 Hz), 3.27 (m, 1H), 2.57 (m, 2H), 2.30 (m, 2H);

ESI-MS m/z (M+H)+ 480.1.

The following compounds were synthesized using a similar procedure.

Compound Structure LCMS ([M+H]+) Purity P-34 it With 538.2 96% P-65 it Sh f 494.1 94% P-67 OH 0 Wn 512.2 93%

- 31 045400

Embodiment 12: Preparation of Compound II-101.

Preparation of compound 12b. In 10 ml of tetrahydrofuran, compound 12a (520 mg, 2.6 mmol), compound 10a (570 mg, 2.0 mmol) and DBU (490 mg, 3.3 mmol) were stirred at 55°C overnight. The resulting mixture was evaporated, 30 ml of water was added and extracted with ethyl acetate (30 mlx3). The organic phases were combined, dried and evaporated to give a crude product, which was separated by column chromatography to give 720 mg of product.

Receiving connection 12c. Compound 12b (720 mg, 1.6 mmol), ethyl glyoxalate (50% solution in toluene, 1.66 g, 8.3 mmol) and acetic acid (20 mg, 0.3 mmol) were boiled in 10 ml of toluene for 6 h. After completion of the reaction, the resulting mixture diluted with 30 ml of ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phases were dried and evaporated to obtain a crude product, which was separated by column chromatography to obtain 450 mg of product.

Obtaining connection 12d. Compound 12c (400 mg, 0.76 mmol) was dissolved in 15 ml of dichloromethane, 5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was dried and added with 10 ml of water, cooled in an ice bath, and a saturated bicarbonate solution was added sodium to pH 9-10 and stirred at room temperature overnight. The reaction solution was extracted with dichloromethane, the organic phases were dried and separated on a silica gel plate to obtain 150 mg of product.

Getting connection 12e. In 6 ml of a solution of T3P in ethyl acetate, compound 12d (150 mg, 0.39 mmol) and compound 2a (156 mg, 059 mmol) were reacted at 100°C for 1.5 h in a hermetically sealed reactor. The resulting mixture was cooled, diluted with water and extracted with ethyl acetate. The organic phases were combined, dried and evaporated, then the residue was separated on a silica gel plate to obtain 100 mg of product.

Preparation of compound I-101. In 1 ml of DMA, the reaction of compound 12e (100 mg, 0.16 mmol) and lithium chloride (35 mg, 0.83 mmol) was carried out at 100°C for 3 hours. After the end of the reaction, the mixture was diluted with 10 ml of water and 2N was added. hydrochloric acid solution, bringing the pH to 5-6. The resulting mixture was filtered and the solid was dried in vacuo to give 27 mg of product.

¹ H-NMR (400 MHz, CDCl3) δ 7.72 (d, 1H, J=6.0 Hz), 7.30 (m, 1H), 7.10-7.17 (m, 2H), 6.85-7.02 (m, 2H), 6.66- 6.78 (m, 1H), 6.38-6.51 (m, 1H), 6.19 (d, 1H, J=6.0 Hz), 5.09 (m, 1H), 4.74 (m, 1H), 4.55 (m, 1H), 4.42 (m, 1H), 3.84-4.00 (m, 2H), 3.73 (m, 2H), 3.60 (m, 2H), 3.40 (m, 2H), 2.88 (m, 1H), 1.84 (m, 1H), 1.52 (m, 2H);

ESI-MS m/z (M+H)+ 537.2.

Embodiment 13: Preparation of Compound III-1.

Preparation of compound III-1. In 1 ml of N,N-dimethylacetamide, the reaction of compound II-5 (50 mg, 0.1 mmol), chloromethyl methyl carbonate (25 mg, 0.2 mmol), potassium carbonate (28 mg, 0.2 mmol) and potassium iodide (3 mg, 0.02 mmol) was carried out ) at 60°C for 5 hours. TLC monitoring showed that the reaction was complete; the mixture was quenched by adding water. Added 1N. hydrochloric acid, bringing the pH to 3-4. The solid precipitate was filtered off, dried and separated by column chromatography, obtaining 48 mg of product.

1H-NMR (400 MHz, DMSOSH ₆ ) δ 7.37-7.44 (m, 2H), 7.13-7.18 (m, 2H), 7.10 (m, 1H), 6.93 (m, 1H), 6.85 (t, 1H, J =7.6 Hz ), 5.75 (m, 1H), 5.70 (m, 1H), 5.66 (m, 2H), 5.43 (d, 1H, J=14.8 Hz), 4.43 (dd, 1H, J=2.4, 9.6 Hz ), 4.10 (dd, 1H, J=2.8, 10.8 Hz), 4.07 (d, 1H, J=14.4 Hz), 3.75 (d, 1H, J=12.0 Hz), 3.72 (s, 3H), 3.44 (m , 1H), 3.02 (d, 1H, J=11.2 Hz), 1.76 (m, 1H), 1.13 (m, 1H), 0.48 (m, 1H), 0.24 (m, 1H);

ESI-MS m/z (M+H)+ 598.1.

Embodiment 14: Preparation of Compound III-2.

Preparation of compound Ш-2. In 1 ml of N,N-dimethylacetamide, the reaction of compound II-6 (40 mg, 0.08 mmol), chloromethyl methyl carbonate (25 mg, 0.2 mmol), potassium carbonate (28 mg, 0.2 mmol) and potassium iodide (3 mg, 0.02 mmol) was carried out ) at 60°C for 5 hours. TLC monitoring showed that the reaction was complete; the mixture was quenched by adding water. Added 1N. hydrochloric acid, bringing the pH to 3-4. The solid was filtered off, dried and separated by column chromatography to obtain 35 mg of product.

¹ H-NMR (400 MHz, DMSO-66) δ 7.40-7.42 (m, 2H), 7.25 (d, 1H, J=7.6 Hz), 7.15 (m, 1H), 7.10 (m, 1H), 7.00 ( d, 1H, J=7.2 Hz), 6.84 (t, 1H, J=7.6 Hz), 5.75 (m, 4H), 5.43 (d, 1H, J=16.4 Hz), 4.57 (dd, 1H, J=3.2 , 9.6 Hz), 3.96-4.03 (m, 3H), 3.73 (s, 3H), 3.51 (t, 1H, J=10.0 Hz), 3.41 (s, 1H), 0.75 (t, 2H, J=8.4 Hz ), 0.50 (m, 2H);

ESI-MS m/z (M+H)+ 598.1.

Embodiment 15: Preparation of Compound III-57.

Preparation of compound III-57. In 1 ml of N,N-dimethylacetamide, the reaction of compound I-77 (49 mg, 0.1 mmol), chloromethyl methyl carbonate (25 mg, 0.2 mmol), potassium carbonate (28 mg, 0.2 mmol) and potassium iodide (3 mg, 0.02 mmol) was carried out ) at 60°C for 5 hours. TLC monitoring showed that the reaction was complete; the mixture was quenched by adding water. Added 1N. hydrochloric acid, bringing the pH to 3-4. The solid was filtered off, dried and separated by column chromatography to obtain 43 mg of product.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.40 (m, 2H), 7.16 (m, 3H), 6.91 (m, 2H), 5.83 (d, 1H, J=7.2 Hz), 5.74 (m , 1H), 5.57 (m, 1H), 5.44 (m, 1H), 5.29 (s, 1H), 4.94 (d, 1H, J=13.6Hz), 4.21 (d, 1H, J=14.4Hz), 3.74 (s, 3H), 2.45 (s, 1H), 2.05 (m, 4H), 1.93 (m, 2H);

ESI-MS m/z (M+H)+ 582.1.

- 33 045400

The following compounds were synthesized using a similar procedure.

Compound Structure LCMS ([M+H]+) Purity Sh-3 M --OSO 614.2 93% Ш-4 X o* l L=O m o I ω 616.2 97% Ш-5 M O am OOO 580.2 95% Ш-6 ° O 0 OOO F ^S 580.2 95% Ш-9 "O . o V ΐ 580.2 94% III-10 ^N!% 4 0 _F OCp 580.2 95% III-17 °< ° s/ X 580.2 95%

- 34 045400

III-18 ° 0 0 ^ ⁿ ' _N A^o s 580.2 97% Sh-21 J-δ ysr 596.2 96% Sh-22 ^Nz %h _o ^ ^s ^z 596.2 95% Sh-33 ^Нз % Ж ° О 0 ЖуЧ'-^оСНз ^n. _n ^o ,-ό F 616.2 94% Ш-50 o C ₂ H ₅ oD OO _F ^XO _F ' 612.2 96% Sh-51 O (Η ₃ Ο) ₂ ΗΟθΆ ^υ O O --Zho f' 626.2 97% Sh-52 O s ^%^0 F ^S 640.2 97% Sh-54 O s ₂ n ₅ oL _o ^ θ °уЦАм-^ Μ' _Ν ^0 r^ _s 612.2 96%

- 35 045400

Sh-56 ^0 F ^S 640.2 95% Sh-59 X "o" And 564.2 95% Sh-61 _l R o LL °% r T 564.2 96% Sh-66 ₀ yes F 596.2 95% Ш-67 0 (H ₃ C) ₂ NSOD kv 610.2 94% IV-1 0 but-p; "give jCOO F γ 604.2 93% IV-3 jCOO 780.2 95% IV-9 HO~|J to F 620.5 93% IV-10 0 H0 ^S °to 0 fOYO F 620.5 92% IV-11 ^Η =θ°Λ- ₀ _γ ' ^Ύ ~ “ύΐδ yes 796.2 96% IV-12 n ₃ with Ο^ό °' _{0 o} °Axt yes 796.2 95%

- 36 045400

Embodiment 16: In vitro bioactivity and cytotoxicity study.

Tested connections. Compounds of the present invention: Compound I-1, Compound I-5, Compound I-7, Compound I-8, Compound I-9, Compound I-10, Compound I-14, Compound I-21, Compound I-65, connection I-66, connection I-69, connection I-77, connection I-81, connection I-83, connection I-85, connection I-89, connection II-1, connection II-2, connection II-5, connection II-6, connection II-7, connection II-8, connection II-9, connection II-10, connection II-13, connection II-14, connection II-17, connection II-18, connection II-22, compound II-29, compound II-34, compound II-65, compound II-66, compound II-67, compound II-101; control compounds: VX-787, baloxavir acid.

Testing method for in vitro bioactivity analysis. MDCK cells were seeded in a 384-well cell culture plate at a density of 2000 cells per well and then incubated at 37°C overnight in a 5% CO2 incubator. The next day, the compounds were diluted and added to the wells (3-fold dilutions, 8 test concentrations), then the influenza virus strain A/PR/8/34 (H1N1) was added to the cells with cell cultures in an amount of 2*TCID90 per well, at In this case, the final concentration of DMSO in the medium was 0.5%. The cell culture plate was incubated at 37°C for 5 days in a 5% CO2 incubator. After 5 days of incubation, cell viability was measured using a kit to determine the proportion of viable cells CC8. The obtained data were processed by nonlinear analysis methods in terms of the inhibition coefficient and cytotoxicity of compounds using the GraphPad Prism program, calculating EC50 values (see results in Table 1).

Methodology for studying cytotoxicity: Cytotoxicity analysis and testing of antiviral activity of compounds were carried out in parallel, with the exception of the absence of virus, all other experimental conditions coincided with testing of antiviral activity. After 5 days of incubation, cell viability was measured using a CCK8 cell viable cell kit. The data obtained were used to calculate the cytotoxicity of the compound (CC ₅₀ ) (see results in Table 1).

Table 1

Cytotoxicity and inhibitory activity of compounds against influenza virus A/PR/8/34 (H1N1)

Results (nM) Conn. ECso CC50 Conn. EU ₅ o CC50 Conn. EU ₅ o CC50 1-1 0.50 >1000 1-81 0.19 >1000 II-13 0.38 >1000 1-5 0.44 >1000 1-83 0.21 >1000 II-14 0.31 >1000 1-7 0.83 >1000 1-85 0.18 >1000 II-17 0.26 >1000 1-8 0.75 >1000 1-89 0.17 >1000 II-18 0.28 >1000 1-9 0.40 >1000 II-1 0.45 >1000 P-22 0.36 >1000 1-10 0.70 >1000 P-2 0.51 >1000 P-29 0.57 >1000 1-14 0.32 >1000 P-5 0.22 >1000 P-34 0.39 >1000 1-21 0.60 >1000 P-6 0.26 >1000 P-65 0.45 >1000 1-65 0.37 >1000 P-7 0.93 >1000 P-66 0.18 >1000 1-66 0.58 >1000 P-8 0.47 >1000 P-67 0.48 >1000 1-69 0.35 >1000 P-9 0.28 >1000 P-101 0.94 >1000 1-77 0.16 >1000 II-10 0.24 >1000 VX-78 7 1.4 >100 Baloxavir acid 1.4 >1000

The results obtained indicate that the compounds of the present invention have higher activity against H1N1 and have lower cytotoxicity compared to control compounds.

Embodiment 17: Pharmacokinetic Study in Rat Intravenous injection: About 2 mg of Compound II-5, Compound II-6, and Compound I-77 were carefully weighed out and the required amount of DMA was added, then vortexed until a clear solution was obtained. Add the required volume of a 30% aqueous solution of Solutol HS-15 and a saturated solution of sodium chloride, mix on a vortex mixer, and the ratio of DMA 30% Solutol HS-15: NaCl solution should be 20:20:60 (v/v/v ). The resulting solution was filtered to obtain a pharmaceutical preparation with a concentration of 0.05 mg-ml ^-1 . SD rats received a single intravenous injection of 0.25 mg-kg ^-1 compounds II-5, II-6 and I-77. 0.20 ml of blood was taken from the jugular vein before administration and then 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours after administration, and placed in a test tube with the addition of the anticoagulant EDTA-K ₂ . Immediately, 150 μl of whole blood was carefully pipetted and placed in a test tube, to which 450 μl of acetonitrile was added to precipitate proteins, the test tube was mixed on a vortex mixer and placed in ice. Stored in a freezer at -90–60°C until analysis of this biological sample. Concentration of the corresponding compound in the blood plasma of rats

- 37 045400 SD lines were determined by LC-MS/MS analysis. The corresponding pharmacokinetic parameters were calculated using a non-compartmental model using Pharsight Phoenix 7.0 software. The results obtained are presented in table. 2a.

Intragastric administration. Approximately 4 mg of Compound III-2 was carefully weighed and the required amount of PEG400 was added, then vortexed until a clear solution was obtained. The required volume of a 30% aqueous solution of Solutol HS-15 and a saturated solution of sodium chloride was added, mixed on a vortex mixer, obtaining a pharmaceutical preparation with a concentration of 0.3 mg-ml ^-1 , with the ratio PEG400:30% Solutol HS-15:NaCl solution should be 2:2:6 (v/v/v). SD rats were administered a single oral dose of 3.0 mg-kg ^-1 of compounds III-2 and the concentration of compound II-6 in the blood plasma of SD rats was determined before administration and then after 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h after administration. The results obtained are presented in table. 2b.

Table 2a

Pharmacokinetic (PK) parameters (intravenous administration) of tested compounds

RK (intravenous) Compound P-5 P-6 1-77 T1/2 (h) 2.49 2.97 2.96 AUCo-t (ngchml' ¹ ) 187 276 307 CL (ml kg' ¹ min' ¹ ) 20.9 13.6 13.0 Vdss (l kg' ¹ ) 3.69 3.12 2.77

Table 2b

Pharmacokinetic (PK) parameters (intragastric administration) of tested compounds

RK (intragastric) Compound Sh-2 T1/2 (h) 3.32 Tmax(h) 1.67 Smack (ig-ml' ¹ ) 253 AUCo-t (ngchml' ¹ ) 1377 F (%) 47.2

The results presented above show that the compounds of the present invention have a low rate of elimination from the body and a long half-life. The compounds of the present invention are effective as prodrugs and show high absorption in vivo.

Embodiment 18: Efficacy in mice.

Female BALB/c mice were infected with influenza A virus (H1N1, A/WSN/33) by intranasal administration, creating a mouse model of influenza A virus (IAV) infection. Vehicle, compound III-2 (15 mg/kg) or oseltamivir phosphate (15 mg/kg) was administered orally twice daily. Animal weight and survival status were monitored daily during the test and on day 5, some animals were sacrificed for lung tissue collection to determine virus titer, and the remaining mice were used to monitor survival rate. Efficacy against influenza virus in vivo for the tested compounds was determined by virus titer in lung tissue, change in body weight of mice and survival rate.

Virus titer in lung tissue. On the 5th day after infection with the virus, the average titer of the virus in the lung tissue of mice from the control group (on the vehicle) reached 7.20 Log 10 (number of plaques per gram of lung tissue), while the average titer of the virus in the lung tissue of mice in the group on oseltamivir phosphate was 3.74 Log 10 (number of plates per gram of lung tissue). Compared with the vehicle group, oseltamivir phosphate significantly inhibited viral replication in mice, and the mean viral titer decreased to 3.46 Log 10 (number of plaques per gram of lung tissue), and the difference was highly statistically significant (p < 0.01) between the results. demonstrating expected effectiveness; The average titer of virus in the lung tissue of mice on day 5 after administration of test compound III-2 was 3.28 Log 10 (number of plaques per gram of lung tissue), and, compared with the vehicle group, the test compound significantly inhibited viral replication in mice, and the average virus titer decreased to 3.92 Log 10 (number of plaques per gram of lung tissue), while the difference had extremely high statistical significance (p < 0.001) between the results, which is superior

-

Claims (37)

results of the control compound - oseltamivir phosphate (Table 3). Table 3 Virus titer in lung tissue Group Influenza virus titer Log 10 (number of plaques per gram of lung tissue) Statistical analysis (Compared to vehicle group) Mean difference Statistical difference Vehicle 7.20±0.1024 - - Oseltamivir phosphate 3.74±0.5205 3.46 **( p<0.01) Compound Sh-2 3.28±0.2813 3.92 ***(p<0.001) **p<0.01 means a very significant difference; *** p < 0.001 indicates an extremely significant difference. Changes in body weight and analysis of results. Mice in the vehicle control group showed significant body weight loss on day 3 post-infection and then continued to lose weight or even died; The weight of mice in the oseltamivir phosphate and compound III-2 group remained stable throughout the experiment, showed no noticeable decrease, and the mice showed good health. Survival rate and analysis of results. Mice in the vehicle control group began to die on day 7 post-infection, and by day 10, all mice died or were euthanized due to weight loss to the lower humane limit, with a 0% survival rate; mice in the oseltamivir phosphate group and the compound III-2 group remained healthy throughout the experiment, and all animals survived to the predefined endpoint with a survival rate of 100%, demonstrating excellent efficacy against influenza virus in vivo. The above description of embodiments is provided solely to assist in understanding the method and key concept of the present invention. It should be noted that a person skilled in the art is capable of making various modifications and improvements in the present invention without departing from the technical principle of the present invention, and these improvements and modifications are also within the scope of protection of the present invention. CLAIM 1. A pyridone derivative having formula (I), or a pharmaceutically acceptable salt thereof where (1) A is selected from N or CR ₁ , and R1 is selected from hydrogen, halogen or C _1-6 hydrocarbyl; 2. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, where R1 is selected from hydrogen, halogen or C _1-6 alkyl; and/or R2 is selected from hydrogen, hydroxy, _C1-6 alkyl or _C1-6 alkoxy; and/or R ₃ is selected from hydrogen or C _1-6 alkyl; and/or R ₄ and R ₅ are independently selected from hydrogen or C _1-6 alkyl; and/or R ₇ is selected from hydrogen, hydroxy, cyano, halogen, carboxyl, C _1-6 alkyl or C _1-6 alkoxy; and/or R8 is selected from C _1-6 alkyl or C _1-6 alkoxy. (2) M is selected from N or CR ₂ , and R2 is selected from hydrogen atom, hydroxy group, C _1-6 hydrocarbyl or C _1-6 hydrocarbyloxy; 3. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, where m is 0, 1, 2 or 3; and/or A represents CR1, R1 represents a hydrogen atom; and/or M represents CR ₂ , R2 represents a hydrogen atom; and/or Q represents N; and/or when R6 represents the fifth ring, R represents CR4R5, R4 and R5 both represent a hydrogen atom; and/or X represents S. (3) Q is selected from N or CR ₃ , and R ₃ is selected from hydrogen atom or C _1-6 hydrocarbyl; 4. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, where m is 0, 1, 2 or 3; A represents CR1, with R1 being a hydrogen atom; M represents CR2, R2 being a hydrogen atom; Q represents N; X represents S. (4) R is selected from NH or CR ₄ R ₅ , and R ₄ and R 5 are independently selected from hydrogen or C _1-6 hydrocarbyl; 5. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the case where the sixth ring is a spiro ring, the ring in the spiro ring that shares a nitrogen atom with the parent ring is a 5-, 6-, 7 - or an 8-membered ring and the other ring is a 3-, 4-, 5- or 6-membered carbocyclic, oxygen-containing heterocyclic or sulfur-containing heterocyclic ring, unsubstituted or having a substituent selected from halogen, C _1-3 hydrocarbyl, C _{1- 3} halohydrocarbyl, hydroxymethyl, methoxymethyl or methoxyethyl. (5) R6 and R are connected and form a sixth ring together with the nitrogen atom to which they are both connected, and the sixth ring is a spiro ring or a 4-, 5-, 6- or 7-membered monocyclic and optionally contains 1, 2, 3 or more groups independently selected from a heteroatom and C=O, in addition to the nitrogen atom to which R and R6 are both connected, where the heteroatom is independently selected from N, O or S; or R ₆ represents a fifth ring and the fifth ring is an unsubstituted or substituted carbocyclic ring, continuous or interrupted by 1, 2, 3 or more members independently selected from a heteroatom and C=O, and the fifth ring is a spiro or bridged ring, wherein the heteroatom is independently selected from N, O or S; when the sixth ring is a spiro ring, the common carbon atom of the spiro ring and the nitrogen atom common to the spiro ring and the mother ring are adjacent or separated by one atom; and the ring in the spiro ring that shares a nitrogen atom with the mother ring contains an oxygen atom or a nitrogen atom in a position opposite that nitrogen atom; when the sixth ring is a 4-, 5-, 6-, or 7-membered monocyclic ring, formula (I) is further subject to the following condition: the sixth ring contains an endocyclic ring - 39 045400 carbon-carbon ethylene bond or sixth ring contains an exocyclic carbon-carbon ethylene bond sharing one carbon atom with the sixth ring; 6. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein, in the case where the other ring has a substituent, this substituent is selected from methyl, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methoxyethyl or chloromethyl. (6) m is 0, 1, 2, 3, 4 or 5 and R ₇ is selected from hydrogen, hydroxy, cyano, halogen, carboxyl, C _1-6 hydrocarbyl, C _1-6 halohydrocarbyl or C _{1 -6} hydrocarbyloxy; 7. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (I) the sixth ring is selected from the following groups: - 40 045400 (7) X is selected from -CH(OCH3), -CH(SCH3) or S; 8. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridone derivative has formula IIa or formula IIb: where in formula IIa and formula IIb G represents O; Z is selected from CH2, O or S; p and q are respectively 0, 1 or 2 and cannot both be 0 at the same time, and when Z is O or S then p+q is greater than or equal to 2; the definitions of W, R7 and m are respectively the same as in paragraph 1. (8) W represents a hydrogen atom or W is selected from the following groups: (a) -C(=O)-R8; (b) -C(=O)-(CH ₂ ) _k -R8, where k is selected from 0-3; (c) -C(=o)-O-(CH ₂ ) _k -R ₈ , where k is selected from 0-3; (d) -CH2-O-R8; (e) -CH2-O-C(=O)-R8; (f) -CH2-O-C(=O)-O-R8; (g) -CH(-CH3)-O-C(=O)-R8; (h) -CH(-CH ₃ )-OC(C=O)-O-(CH ₂ ) _k -R ₈ , where k is selected from 0-3; (i) -CH ₂ -OP(=O)(OH) ₂ ; (j) -CH2-OP(=O)(OPh)(NHR8); or (k) -CH ₂ -OP(=O)(OCH ₂ OC(=O)OR ₈ ) ₂ , wherein R ₈ is selected from C _1-6 hydrocarbyl or C _1-6 hydrocarbyloxy; 9. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 8, wherein in formula IIa and formula IIb p+q=1, or 2, or 3, and Z represents CH2 or p=1 or 2, q=1 or 2 , and Z represents O or S. (9) Ar1 and Ar2 are both phenyl rings. 10. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 9, wherein formula IIa and formula IIb Z represents CH2 and p=0, q=1, or p=0, q=2, or p=1, q=0, or p=1, q=1, or p=1, q=2, or p=2, q=0, or p=2, q=1; or Z represents O and p=1, q=1, or p=1, q=2, or p=2, q=1, or p=2, q=2; or Z represents S and p=1, q=1, or p=1, q=2, or p=2, q=1, or p=2, q=2. 11. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridone derivative has formula IIc -s Hc in formula IIc a, b, c and d are equal to 0, 1, 2 or 3 respectively, and a and b are not equal to 0 or 3 at the same time, and c and d are not equal to 0 or 3 at the same time same time; E represents CH2 or O; K represents CH2 or O; the definitions of W, R ₇ and m are respectively the same as in paragraph 1. 12. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 11, where in formula IIc a+b=1, or 2, or 3 and c+d=1, or 2, or 3. 13. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the case where the fifth ring is a bridge ring, the bridge ring is bicyclic or tricyclic and a carbon atom at the head of the bridge or a carbon atom not at the head of the bridge of the bridge ring is connected to the corresponding nitrogen atom of the mother ring. 14. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the case where the fifth ring is a bridging ring, the bridging ring is selected from bicyclo[1.1.1]pentane, bicyclo[2.1.0]pentane, bicyclo[2.1 .1]hexane, bicyclo[2.2.0]hexane, bicyclo[3.1.1]heptane, bicyclo[3.2.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.0 ]octane. 15. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 14, wherein in the case where the fifth ring is a bridging ring, the bridging ring is unsubstituted or is substituted with 1, 2, 3 or more substituents selected from fluorine, chlorine, bromine, trifluoromethyl, -CH2OH or -CH2OCH3. 16. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, where the pyridone - 41 045400 derivative has formula IId or formula IIe: where in formula IId and formula IIe R ₁₂ is selected from hydrogen atom, hydroxy group, cyano group, halogen, C _1-6 hydrocarbyl, C _1-6 halohydrocarbyl, C ₁ . ₆ alkoxy _C1 . ₆ hydrocarbyl, hydroxy C ₁ . ₆ hydrocarbyl, C ₁ . ₆ hydrocarbyloxy, carboxyl; the definitions of W, R7 and m are respectively the same as in paragraph 1. 17. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 16, wherein R ₁₂ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, methoxymethyl or hydroxymethyl. 18. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, where R ₆ is selected from the following groups: 19. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the case where the sixth ring is a 4-, 5-, 6- or 7-membered monocyclic ring, the sixth ring contains a total of 1 heteroatom, which is a nitrogen atom , connected to both R and R ₆ . 20. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (I) the sixth ring is selected from the following groups: 21. A pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R ₇ is connected to a phenyl ring. 22. A pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 20, wherein R7 is selected from hydrogen atom, hydroxy group, cyano group, halogen, C _1-6 hydrocarbyl, C _1-6 halohydrocarbyl or C _1-6 hydrocarbyloxy. 23. A pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, where - 42 045400 R7 is connected to a phenyl ring; R7 is selected from fluorine, chlorine, bromine, trifluoromethyl or methyl; and m is 0, 1, 2 or 3. 24. A pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, where W represents a hydrogen atom or W is selected from the following groups: (e) -CH2-O-C(=O)-R8; (f) -CH2-O-C(=O)-O-R8; (g) -CH(-CH3)-O-C(=O)-R«; (h) -CH(-CH ₃ )-OC(C=O)-O-(CH ₂ ) _k -R ₈ , where k is selected from 0-3; (i) -CH2-O-P(=O)(OH)2; (j) -CH2-O-P(=O)(OPh)(NHR8); or (k) -CH2-O-P(=O)(OCH2OC(=O)OR8)2. 25. A pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 24, wherein R ₈ is selected from methyl, ethyl, isopropyl or butyl. 26. A pyridone derivative or a pharmaceutically acceptable salt thereof, where the pyridone derivative is selected from the following compounds: ? ⁿ 9 on o OSO COI 1-1 1-2 OH O o^1 1 ζν/χ YV^N-< X > ^Μψ y ^{x S} F ' 1-5 OI O OH 0 k*·, SSO (X 1- 9 |_· OH O he o / X θχΧΧ·'/ \Оо ^ο χ0γΑΝι,./7 ^Λ ο st οόο - V s''-' ^S -' 1-3 1-4 he o __Г> ^χΊΜι· / О LX ОСО F 1-6 у · ΌΟ ⁵ Ό 10 - 43 045400 - 44 045400 - 45 045400 - 46 045400 - 47 045400 - 48 045400 - 49 045400 - 50 045400 27. A pyridone derivative or a pharmaceutically acceptable salt thereof, where the pyridone derivative is 28. An antiviral pharmaceutical composition, where the composition contains a therapeutically effective amount of a pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier. 29. An antiviral pharmaceutical composition, where the composition contains a therapeutically effective amount of a pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 27 and a pharmaceutically acceptable carrier. 30. The antiviral pharmaceutical composition according to claim 28 or 29, where the composition further contains one or more therapeutic agents selected from the group consisting of a neuraminidase inhibitor, a nucleoside drug, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor or other anti-influenza drugs. 31. An antiviral pharmaceutical composition according to claim 28 or 29, which is a pharmaceutical preparation selected from a tablet, powder, capsule, granule, oral liquid, injectable preparation, suppository, pill, cream, paste, gel, powder (powder- - 51 045400 ry), inhalation drug, suspension, dry suspension, patch or lotion. 32. The use of a pyridone derivative, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 28 in the preparation of a medicinal product for the treatment of a viral infectious disease, where the viral infectious disease is an influenza virus type A infection and/ or influenza B virus infection. 33. The use of a pyridone derivative, or a pharmaceutically acceptable salt thereof according to claim 27, or a pharmaceutical composition according to claim 29 in the preparation of a medicinal product for the treatment of a viral infectious disease, where the viral infectious disease is an influenza A virus infection and/or an influenza virus infection type B. 34. The use of a pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 28 in the preparation of an antiviral drug, where the antiviral drug is a drug or agent that inhibits the activity of a cap-dependent endonuclease. 35. The use of a pyridone derivative or a pharmaceutically acceptable salt thereof according to claim 27 or a pharmaceutical composition according to claim 29 in the preparation of an antiviral drug, where the antiviral drug is a drug or agent that inhibits the activity of a cap-dependent endonuclease. 36. A method of treating a viral infectious disease, which includes administering to an animal or human in need of treatment an effective amount of a pyridone derivative, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 28, wherein the viral infectious disease is an infectious disease caused by influenza virus type A and/or influenza virus type B. 37. A method of treating a viral infectious disease, which includes administering to an animal or human in need of treatment an effective amount of a pyridone derivative, or a pharmaceutically acceptable salt thereof according to claim 27, or a pharmaceutical composition according to claim 29, wherein the viral infectious disease is an infectious disease, caused by influenza virus type A and/or influenza virus type B. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2