CN114341137A

CN114341137A - Dihydropyrimidine derivatives and use thereof

Info

Publication number: CN114341137A
Application number: CN202080057115.8A
Authority: CN
Inventors: 沙薇; 刘洋; 孔晓博; 李建永
Original assignee: Tibet Tiansheng Taifeng Pharmaceutical Co ltd
Current assignee: Tibet Tiansheng Taifeng Pharmaceutical Co ltd
Priority date: 2019-08-16
Filing date: 2020-08-14
Publication date: 2022-04-12
Anticipated expiration: 2040-08-14
Also published as: CN114341137B; WO2021031997A1; TW202115079A

Abstract

Dihydropyrimidine derivatives of the general formula (I) which are useful in the treatment and prevention of hepatitis B virus infections. Also relates to a pharmaceutical composition containing the compound of the general formula (I) and the application thereof in treating and preventing hepatitis B virus infection.

Description

Dihydropyrimidine derivatives and use thereof

Technical Field

The invention belongs to the field of virus prevention and control. In particular, the present invention relates to a series of dihydropyrimidine derivatives, pharmaceutical compositions containing said derivatives and their uses, particularly for the treatment or prevention of viral diseases such as hepatitis b. More particularly, the present invention relates to dihydropyrimidine derivatives which can inhibit the function of Hepatitis B Virus (HBV) capsid protein, and thus can treat or prevent hepatitis b, pharmaceutical compositions containing the same and use thereof for treating or preventing hepatitis b.

Background

Hepatitis b virus infection is a major public health problem affecting approximately 20 million people worldwide. About 3.5 million of these people develop chronic infections that can lead to chronic persistent hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Every year, 50 to 100 million people die from end-stage liver disease caused by hepatitis b virus infection.

Hepatitis b virus is a small virus whose genome has only four open reading frames. HBV core protein (Cp) is a small protein block (consisting of 183 residues) that self-assembles to form the viral capsid, which regulates almost every step of the viral life cycle in infected cells, so Cp is an important target for antiviral drugs.

At present, hepatitis B cannot be cured, only contains two types of medicaments, namely interferon and nucleoside analogue, and has the defects of high drug resistance, low efficiency, poor tolerance and the like. Therefore, there is still a need in the art to develop drugs for the treatment and prevention of hepatitis b.

Disclosure of Invention

In view of the importance of Cp protein in the HBV life cycle, the present inventors have designed a series of dihydropyrimidine derivatives for their structural features to interfere with the formation of viral capsid by altering Cp conformation or Cp assembly rate, thereby producing antiviral effects.

In one aspect, the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein:

ring A is selected from 3-11 membered heterocyclyl or 5-10 membered heteroaryl;

R ₁selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、C _1-6Alkyl or C_1-6A haloalkyl group;

L ₁selected from the group consisting of a chemical bond, -CR' ═ CR "-or-C ≡ C-; wherein R 'and R' are independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

R ₂selected from H, halogen, -CN, -NO₂、-C(O)R _a、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R ₃is selected from C_6-10Aryl or5-10 membered heteroaryl;

R ₄selected from hydrogen, halogen, -CN, C_1-6Alkyl or C_1-6A haloalkyl group;

L ₂is selected from- (C)_0-6Alkylene) -, - (C)_0-6Alkylene) -O-, - (C_0-6Alkylene) -NR_b-、-(C _0-6Alkylene) - (C) (O) -, - (C)_0-6Alkylene) -C (O) O-, - (C)_0-6Alkylene) -C (O) NR_b-、-(C _0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -S (O)_p-、-(C _0-6Alkylene) -S (O)_pO-、-(C _0-6Alkylene) -S (O)_pNR _b-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c)-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-O-、-C _2-8Alkenylene radical-, -C_2-8Alkynylene-, -C_3-7Cycloalkylene-, 4-8 membered heterocyclylene, C_6-10Arylene or 5-10 membered heteroarylene;

R ₅is selected from- (C)_0-6Alkylene) -OR_a、-(C _0-6Alkylene) -NR_bR _c、-(C _0-6Alkylene) -C (O) R_a、-(C _0-6Alkylene) -C (O) OR_aOr- (C)_0-6Alkylene) -C (O) NR_bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-11Cycloalkyl, 3-15 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

and R is₂、R ₃And R₅Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R _a、R _b、R _cindependently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, - (C)_0-6Alkylene) -OR, - (C)_0-6Alkylene) -NR R, - (C)_0-6Alkylene) -C (O) R, - (C)_0-6Alkylene) -C (O) OR OR- (C)_0-6Alkylene) -c (o) NR R; or R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

r, R and R are independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; or R, R and the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2;

with the proviso that when L₁When it is a chemical bond, R₂Selected from H, halogen, -CN, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.

In another aspect, the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein:

ring A is selected from 3-11 membered heterocyclyl or 5-10 membered heteroaryl;

L ₁selected from the group consisting of a chemical bond, -CR' ═ CR "-or-C ≡ C-; wherein R 'and R' are independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl;

R ₂selected from H, halogen, -CN, -NO₂、-C(O)R _a、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R ₃is selected from C_6-10Aryl or 5-10 membered heteroaryl;

L ₂is selected from- (C)_0-6Alkylene) -, - (C)_0-6Alkylene) -O-, - (C_0-6Alkylene) -NR_b-、-(C _0-6Alkylene) - (C) (O) -, - (C)_0-6Alkylene) -C (O) O-, - (C)_0-6Alkylene) -C (O) NR_b-、-(C _0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -S (O)_p-、-(C _0-6Alkylene) -S (O)_pO-、-(C _0-6Alkylene) -S (O)_pNR _b-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-、-C _2-8Alkenylene radical-, -C_2-8Alkynylene-, -C_3-7Cycloalkylene-, 3-7 membered heterocyclylene, C_6-10Arylene or 5-10 membered heteroarylene;

R ₅is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

and R is₂、R ₃And R₅Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R _a、R _b、R _cindependently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2.

In another aspect, the invention provides compounds of the above general formula (I) with the proviso that when L₁When it is a chemical bond, R₂Selected from H, halogen, -CN, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contain an additional therapeutic agent.

In another aspect, the invention provides kits comprising a compound of the invention, and optionally other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

In another aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of viral infections, in particular hepatitis b viral infections.

In another aspect, the present invention provides a method of treating and/or preventing a viral infection, in particular a hepatitis b virus infection, in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.

In another aspect, the present invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of a viral infection, in particular a hepatitis b viral infection.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

Definition of

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below.

When a range of values is recited, it is intended that each value included in the range is encompassed within the rangeSub-ranges within. E.g. "C_1-6Alkyl "includes C₁、C ₂、C ₃、C ₄、C ₅、C ₆、C _1-6、C _1-5、C _1-4、C _1-3、C _1-2、C _2-6、C _2-5、C _2-4、C _2-3、C _3-6、C _3-5、C _3-4、C _4-6、C _4-5And C_5-6An alkyl group.

“C _1-6Alkyl "refers to a straight or branched chain saturated monovalent hydrocarbon group containing 1 to 6 carbon atoms. In some embodiments, C_1-4Alkyl groups are preferred. Typical C_1-6Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl and the like. The alkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _2-8Alkenyl "represents a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, and the like. In some embodiments, C_2-6Alkenyl groups are preferred. In some embodiments, C_2-4Alkenyl groups are particularly preferred. The term "C_2-8Alkenyl "includes cycloalkenyl and heteroalkenyl, wherein from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for a carbon atom. The alkenyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _2-8Alkynyl "refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms with at least one carbon-carbon triple bond, optionally with one or more unsaturated carbon-carbon double bonds. In some embodiments, C_2-6Alkynyl groups are preferred. In some embodiments, C_2-4Alkynyl groups are particularly preferred. Typical alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, and hexynyl. The alkynyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _1-6Alkylene "means the removal of C as defined above_1-6A hydrogen of an alkyl group, and may be substituted or unsubstituted. In some embodiments, C_1-4Alkylene groups are particularly preferred. Unsubstituted said alkylene groups include, but are not limited to: methylene (-CH)₂-) ethylene (-CH₂CH ₂-) propylene (-CH)₂CH ₂CH ₂-) butylene (-CH)₂CH ₂CH ₂CH ₂-) pentylene (-CH)₂CH ₂CH ₂CH ₂CH ₂-) and hexylene (-CH₂CH ₂CH ₂CH ₂CH ₂CH ₂-) and the like. Exemplary substituted said alkylene groups, for example, said alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH (CH)₃)-、-C(CH ₃) ₂-) substituted ethylene (-CH (CH)₃)CH ₂-、-CH ₂CH(CH ₃)-、-C(CH ₃) ₂CH ₂-、-CH ₂C(CH ₃) _2-) Substituted propylene (-CH (CH)₃)CH ₂CH ₂-、-CH ₂CH(CH ₃)CH ₂-、-CH ₂CH ₂CH(CH ₃)-、-C(CH ₃) ₂CH ₂CH ₂-、-CH ₂C(CH ₃) ₂CH ₂-、-CH ₂CH ₂C(CH ₃) ₂-) and the like.

“C _0-6Alkylene "represents C as defined above_1-6Alkylene and chemical bond (C)₀Alkylene).

“C _2-8Alkenylene "means the removal of C as defined above_2-8One hydrogen of an alkenyl group forms a divalent group, and may be substituted or unsubstituted.

“C _2-8By "alkynylene" is meant the removal of C as defined above_2-8A hydrogen of an alkynyl group and may be substituted or unsubstituted.

"halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

“C _1-6Haloalkyl "represents the above-mentioned" C_1-6Alkyl "substituted with one or more halo groups. Examples include monohalogen substituted, dihalogen substituted and polyhaloalkyl including perhalo. A monohalogen substituent may have an iodine, bromine, chlorine or fluorine atom in the group; two halogen substituents and multiple halogen substituents may have two or more of the same halogen atom or a combination of different halogens. Examples of preferred haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _3-11Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 11 ring carbon atoms and zero heteroatoms, optionally with double or triple bonds. "C_3-11Cycloalkyl "includes" C_3-7Cycloalkyl radicals "and" C_5-11Bicycloalkyl, the former being a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms, optionally with double or triple bonds; the latter being non-aromatic cyclic hydrocarbon radicals having 5 to 11 ring carbon atoms and zero heteroatomsAnd having two rings joined together in a fused, fused or tandem arrangement, optionally with double or triple bonds. In some embodiments, C_3-6Cycloalkyl is preferred, more preferably C_5-6A cycloalkyl group. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C)₃) Cyclopropenyl group (C)₃) Cyclobutyl (C)₄) Cyclobutenyl radical (C)₄) Cyclopentyl (C)₅) Cyclopentenyl group (C)₅) Cyclopentadienyl (C)₅) Cyclohexyl (C)₆) Cyclohexenyl (C)₆) Cyclohexyldienyl (C)₆) Cycloheptyl (C)₇) Cycloheptenyl (C)₇) Cycloheptadienyl (C)₇) Cycloheptatrienyl (C)₇) And so on. The cycloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"cycloalkylene" refers to a divalent group formed by removing one hydrogen from a cycloalkyl group as described above, and may be substituted or unsubstituted.

"3-15 membered heterocyclyl" refers to a radical of a 3 to 15 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. "3-15 membered heterocyclyl" includes "3-11 membered heterocyclyl", "5-11 membered biheterocyclyl", and "11-15 membered polycyclyl", wherein "3-11 membered heterocyclyl" refers to a group having a ring carbon atom and 1 to 4 ring heteroatoms in a 3 to 11 membered non-aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon; "5-11 membered biheterocyclyl" refers to a radical having a ring carbon atom and 1 to 4 ring heteroatoms in a 5 to 11 membered non-aromatic ring system, and having two rings bound together in a fused, or tandem fashion, wherein each heteroatom is independently selected fromNitrogen, oxygen, sulfur, boron, phosphorus, and silicon; "11-15 membered polycyclyl" refers to a radical of an 11 to 15 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and having three or more rings bound together in a fused, or concatenated manner. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be carbon or a nitrogen atom, as valency permits. In some embodiments, a 3-7 membered heterocyclic group is preferred which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 4-8 membered heterocyclic group which is a 4 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4-6 membered heterocyclic group which is a 4 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferred are 5-6 membered heterocyclic groups which are 5 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems wherein the aforementioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxacyclopropaneyl, thienylyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphuryl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxa-Diazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiinyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepane, oxepanyl and thiepane. Exemplary with C₆Aryl ring fused 5-membered heterocyclyl (also referred to herein as 5, 6-bicyclic heterocyclyl) includes, but is not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary with C₆Aryl ring fused 6-membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) includes, but is not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"Heterocyclylene" means a divalent group formed by removing one hydrogen of the above-mentioned heterocyclic group, and may be substituted or unsubstituted.

“C _6-10Aryl "refers to a group having a monocyclic or polycyclic (e.g., bicyclic) 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) of 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C)₆Aryl "; for example, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C)₁₀Aryl "; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be substituted at any available point of attachmentFor example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"arylene" refers to a divalent group formed by removing one hydrogen from an aryl group as described above, and may be substituted or unsubstituted.

"5-10 membered heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n +2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: a tetrazolyl group. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxacycloheptyl, and thiacycloheptyl trienyl groups. Exemplary 5, 6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisothiafuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indezinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.

"heteroarylene" refers to a divalent group formed by removing one hydrogen from the above-mentioned heteroaryl group, and may be substituted or unsubstituted.

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like, as defined herein, are optionally substituted groups, whether preceded by the term "optionally substituted," which denotes that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is substituted with a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position is the same or different. The term "substituted" includes substitution with all permissible substituents of organic compounds (any of the substituents described herein that result in the formation of stable compounds). For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO₂、-N ₃、-SO ₂H、-SO ₃H、-OH、-OR ^aa、-ON(R ^bb) ₂、-N(R ^bb) ₂、-N(R ^bb) ₃ ⁺X ^-、-N(OR ^cc)R ^bb、-SH、-SR ^aa、-SSR ^cc、-C(＝O)R ^aa、-CO ₂H、-CHO、-C(OR ^cc) ₂、-CO ₂R ^aa、-OC(＝O)R ^aa、-OCO ₂R ^aa、-C(＝O)N(R ^bb) ₂、-OC(＝O)N(R ^bb) ₂、-NR ^bbC(＝O)R ^aa、-NR ^bbCO ₂R ^aa、-NR ^bbC(＝O)N(R ^bb) ₂、-C(＝NR ^bb)R ^aa、-C(＝NR ^bb)OR ^aa、-OC(＝NR ^bb)R ^aa、-OC(＝NR ^bb)OR ^aa、-C(＝NR ^bb)N(R ^bb) ₂、-OC(＝NR ^bb)N(R ^bb) ₂、-NR ^bbC(＝NR ^bb)N(R ^bb) ₂、-C(＝O)NR ^bbSO ₂R ^aa、-NR ^bbSO ₂R ^aa、-SO ₂N(R ^bb) ₂、-SO ₂R ^aa、-SO ₂OR ^aa、-OSO ₂R ^aa、-S(＝O)R ^aa、-OS(＝O)R ^aa、-Si(R ^aa) ₃、-OSi(R ^aa) ₃、-C(＝S)N(R ^bb) ₂、-C(＝O)SR ^aa、-C(＝S)SR ^aa、-SC(＝S)SR ^aa、-SC(＝O)SR ^aa、-OC(＝O)SR ^aa、-SC(＝O)OR ^aa、-SC(＝O)R ^aa、-P(＝O) ₂R ^aa、-OP(＝O) ₂R ^aa、-P(＝O)(R ^aa) ₂、-OP(＝O)(R ^aa) ₂、-OP(＝O)(OR ^cc) ₂、-P(＝O) ₂N(R ^bb) ₂、-OP(＝O) ₂N(R ^bb) ₂、-P(＝O)(NR ^bb) ₂、-OP(＝O)(NR ^bb) ₂、-NR ^bbP(＝O)(OR ^cc) ₂、-NR ^bbP(＝O)(NR ^bb) ₂、-P(R ^cc) ₂、-P(R ^cc) ₃、-OP(R ^cc) ₂、-OP(R ^cc) ₃、-B(R ^aa) ₂、-B(OR ^cc) ₂、-BR ^aa(OR ^cc) Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

or two geminal hydrogens on a carbon atom are replaced by groups ═ O, ═ S, ═ NN (R)^bb) ₂、＝NNR ^bbC(＝O)R ^aa、＝NNR ^bbC(＝O)OR ^aa、＝NNR ^bbS(＝O) ₂R ^aa、＝NR ^bbOr as NOR^ccSubstitution;

R ^aaeach is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R^aaThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^ddSubstituted by groups;

R ^bbeach independently selected from: hydrogen, -OH, -OR^aa、-N(R ^cc) ₂、-CN、-C(＝O)R ^aa、-C(＝O)N(R ^cc) ₂、-CO ₂R ^aa、-SO ₂R ^aa、-C(＝NR ^cc)OR ^aa、-C(＝NR ^cc)N(R ^cc) ₂、-SO ₂N(R ^cc) ₂、-SO ₂R ^cc、-SO ₂OR ^cc、-SOR ^aa、-C(＝S)N(R ^cc) ₂、-C(＝O)SR ^cc、-C(＝S)SR ^cc、-P(＝O) ₂R ^aa、-P(＝O)(R ^aa) ₂、-P(＝O) ₂N(R ^cc) ₂、-P(＝O)(NR ^cc) ₂Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R^bbThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^ddSubstituted by groups;

R ^cceach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R^ccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

R ^ddeach independently selected from: halogen, -CN, -NO₂、-N ₃、-SO ₂H、-SO ₃H、-OH、-OR ^ee、-ON(R ^ff) ₂、-N(R ^ff) ₂,、-N(R ^ff) ₃ ⁺X ^-、-N(OR ^ee)R ^ff、-SH、-SR ^ee、-SSR ^ee、-C(＝O)R ^ee、-CO ₂H、-CO ₂R ^ee、-OC(＝O)R ^ee、-OCO ₂R ^ee、-C(＝O)N(R ^ff) ₂、-OC(＝O)N(R ^ff) ₂、-NR ^ffC(＝O)R ^ee、-NR ^ffCO ₂R ^ee、-NR ^ffC(＝O)N(R ^ff) ₂、-C(＝NR ^ff)OR ^ee、-OC(＝NR ^ff)R ^ee、-OC(＝NR ^ff)OR ^ee、-C(＝NR ^ff)N(R ^ff) ₂、-OC(＝NR ^ff)N(R ^ff) ₂、-NR ^ffC(＝NR ^ff)N(R ^ff) ₂、-NR ^ffSO ₂R ^ee、-SO ₂N(R ^ff) ₂、-SO ₂R ^ee、-SO ₂OR ^ee、-OSO ₂R ^ee、-S(＝O)R ^ee、-Si(R ^ee) ₃、-OSi(R ^ee) ₃、-C(＝S)N(R ^ff) ₂、-C(＝O)SR ^ee、-C(＝S)SR ^ee、-SC(＝S)SR ^ee、-P(＝O) ₂R ^ee、-P(＝O)(R ^ee) ₂、-OP(＝O)(R ^ee) ₂、-OP(＝O)(OR ^ee) ₂Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by radicals, or two geminal R^ddSubstituents may combine to form ═ O or ═ S;

R ^eeeach independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkane is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and wherein each alkane is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroarylIndependently, the group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups;

R ^ffeach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R^ffThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^ggSubstituted by groups;

R ^ggis independently from each other: halogen, -CN, -NO₂、-N ₃、-SO ₂H、-SO ₃H、-OH、-OC _1-6Alkyl, -ON (C)_1-6Alkyl radical)₂、-N(C _1-6Alkyl radical)₂、-N(C _1-6Alkyl radical)₃ ⁺X ^-、-NH(C _1-6Alkyl radical)₂ ⁺X ^-、-NH ₂(C _1-6Alkyl radical)⁺X ^-、-NH ₃ ⁺X ^-、-N(OC _1-6Alkyl) (C_1-6Alkyl), -N (OH) (C)_1-6Alkyl), -NH (OH), -SH, -SC_1-6Alkyl, -SS (C)_1-6Alkyl), -C (═ O) (C)_1-6Alkyl), -CO₂H、-CO ₂(C _1-6Alkyl), -OC (═ O) (C)_1-6Alkyl), -OCO₂(C _1-6Alkyl), -C (═ O) NH₂、-C(＝O)N(C _1-6Alkyl radical)₂、-OC(＝O)NH(C _1-6Alkyl), -NHC (═ O) (C)_1-6Alkyl), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl), -NHCO₂(C _1-6Alkyl), -NHC (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)NH(C _1-6Alkyl), -NHC (═ O) NH₂、-C(＝NH)O(C _1-6Alkyl), -OC (═ NH) (C)_1-6Alkyl), -OC (═ NH) OC_1-6Alkyl, -C (═ NH) N (C)_1-6Alkyl radical)₂、-C(＝NH)NH(C _1-6Alkyl), -C (═ NH) NH₂、-OC(＝NH)N(C _1-6Alkyl radical)₂、-OC(NH)NH(C _1-6Alkyl), -OC (NH) NH₂、-NHC(NH)N(C _1-6Alkyl radical)₂、-NHC(＝NH)NH ₂、-NHSO ₂(C _1-6Alkyl), -SO₂N(C _1-6Alkyl radical)₂、-SO ₂NH(C _1-6Alkyl), -SO₂NH ₂、-SO ₂C _1-6Alkyl, -SO₂OC _1-6Alkyl, -OSO₂C _1-6Alkyl, -SOC_1-6Alkyl, -Si (C)_1-6Alkyl radical)₃、-OSi(C _1-6Alkyl radical)₃、-C(＝S)N(C _1-6Alkyl radical)₂、C(＝S)NH(C _1-6Alkyl), C (═ S) NH₂、-C(＝O)S(C _1-6Alkyl), -C (═ S) SC_1-6Alkyl, -SC (═ S) SC_1-6Alkyl, -P (═ O)₂(C _1-6Alkyl), -P (═ O) (C)_1-6Alkyl radical)₂、-OP(＝O)(C _1-6Alkyl radical)₂、-OP(＝O)(OC _1-6Alkyl radical)₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C₂-C ₆Alkenyl radical, C₂-C ₆Alkynyl, C₃-C ₇Cycloalkyl radical, C₆-C ₁₀Aryl radical, C₃-C ₇Heterocyclic group, C₅-C ₁₀A heteroaryl group; or two geminal R^ggSubstituents may combine to form ═ O or ═ S; wherein, X^-Are counter ions.

Exemplary substituents on the nitrogen atom include, but are not limited toIn the following steps: hydrogen, -OH, -OR^aa、-N(R ^cc) ₂、-CN、-C(＝O)R ^aa、-C(＝O)N(R ^cc) ₂、-CO ₂R ^aa、-SO ₂R ^aa、-C(＝NR ^bb)R ^aa、-C(＝NR ^cc)OR ^aa、-C(＝NR ^cc)N(R ^cc) ₂、-SO ₂N(R ^cc) ₂、-SO ₂R ^cc、-SO ₂OR ^cc、-SOR ^aa、-C(＝S)N(R ^cc) ₂、-C(＝O)SR ^cc、-C(＝S)SR ^cc、-P(＝O) ₂R ^aa、-P(＝O)(R ^aa) ₂、-P(＝O) ₂N(R ^cc) ₂、-P(＝O)(NR ^cc) ₂Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom^ccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^ddIs substituted by radicals, and wherein R^aa、R ^bb、R ^ccAnd R^ddAs described above.

Other definitions

The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the act of verb treatment, the latter being as just defined.

The term "pharmaceutically acceptable salts" as used herein refers to those carboxylic acid salts, amino acid addition salts, of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including, where possible, the zwitterionic forms of the compounds of the present invention.

The term "salts" denotes the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. The salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, isethionate and the like. Salts may also be prepared from organic acids such as aliphatic mono-and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoic acid basin, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are Salts of amino acids such as arginate, gluconate, galacturonate, and the like (see, e.g., "Pharmaceutical Salts," J.pharm.Sci., 1977; 66:1-19, incorporated herein by reference).

The term "prodrug" means a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. For a thorough discussion see T.Higuchi and V.Ste11a, "Pro-drugs as Novel Delivery Systems," Vol.14 of the A.C.S.Symphosis Series and Bioreversible Carriers in Drug Delivery, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated by reference.

The "subject" to which the drug is administered includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise specified, the term "treatment" includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes the effect that occurs before the subject begins to have the particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound is an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on the following factors: for example, biological goals, pharmacokinetics of the compound, the disease being treated, mode of administration, and the age, health, and condition of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.

As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.

"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the present invention may be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or simultaneously with the other therapeutic agent in a single unit dosage form.

Detailed description of the preferred embodiments

Herein, "compound of the present invention" refers to a compound of formula (I) -formula (IV) below (including, for example, (I), (I-1), (I-2), (I-3), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (IV-1), (IV-2), (IV-3), or (IV-4)), a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and a mixture thereof.

Compounds are generally described herein using standard nomenclature. Compounds having asymmetric centers, it is understood (unless otherwise indicated) that all optical isomers and mixtures thereof are included. Furthermore, all isomeric compounds and carbon-carbon double bonds encompassed by the present invention may occur as Z and E unless otherwise specified. Compounds that exist in different tautomeric forms, one such compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

In one embodiment, the present invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein:

ring A is selected from 3-11 membered heterocyclyl or 5-10 membered heteroaryl;

R ₃is selected from C_6-10Aryl or 5-10 membered heteroaryl;

R ₅is selected from- (C)_0-6Alkylene) -OR_a、-(C _0-6Alkylene) -NR_bR _c、-(C _0-6Alkylene) -C (O) R_a、-(C _0-6Alkylene) -C (O) OR_aOr- (C)_0-6Alkylene group) -C (O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-11Cycloalkyl, 3-15 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2;

In another embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein:

ring A is selected from 3-11 membered heterocyclyl or 5-10 membered heteroaryl;

R ₃is selected from C_6-10Aryl or 5-10 membered heteroaryl;

L ₂is selected from- (C)_0-6Alkylene) -, - (C)_0-6Alkylene) -O-, - (C_0-6Alkylene) -NR_b-、-(C _0-6Alkylene) - (C) (O) -, - (C) _0-6Alkylene) -C (O) O-, - (C)_0-6Alkylene) -C (O) NR_b-、-(C _0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -S (O)_p-、-(C _0-6Alkylene) -S (O)_pO-、-(C _0-6Alkylene) -S (O)_pNR _b-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-、-C _2-8Alkenylene radical-, -C_2-8Alkynylene-, -C_3-7Cycloalkylene-, 3-7 membered heterocyclylene, C_6-10Arylene or 5-10 membered heteroarylene;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2;

with the proviso that when L₁When it is a chemical bond, R₂Selected from H, halogen, -CN, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl.

Ring A

In one embodiment, ring a is a 3-11 membered heterocyclyl; in another embodiment, ring A is a 5-10 membered heteroaryl.

In one embodiment, ring A is

Wherein X, Y, Z, which may be the same or different, are each independently selected from C, N, O or S atoms, and their oxidized forms (e.g., C (O), SO, and SO)₂) (ii) a Wherein two ortho-positions X, Y or Z may together form an optionally substituted-C ═ C-double bond, -C ═ N-double bond, or fused ring; or X, Y and the two substituents on Z may be linked to form a bridged ring structure; or X, Y or Z is a carbon atom, two substituents on the same carbon atom may be linked to form a ring structure;

n is 0, 1, 2 or 3.

In a specific embodiment, X, Y or Z is a C atom; in another specific embodiment, X, Y or Z is an N atom; in another specific embodiment, X, Y or Z is an O atom; in another specific embodiment, X, Y or Z is an S atom.

In a particular embodiment, the two ortho positions X, Y or Z may together form an optionally substituted-C ═ C-double bond; in another specific embodiment, two ortho positions X, Y or Z may together form an optionally substituted-C ═ N-double bond; in another embodiment, two ortho X, Y or Z positions may together form an optionally substituted fused ring.

In a toolIn a particular embodiment, X, Y and two substituents on Z may be joined to form C_3-7A cycloalkyl group; in one embodiment, X, Y and two substituents on Z may be joined to form a 3-7 membered heterocyclyl; in one embodiment, X, Y and two substituents on Z may be joined to form a 4-8 membered heterocyclyl; in one embodiment, X, Y and two substituents on Z may be joined to form C_6-10An aryl group; in one embodiment, X, Y and two substituents on Z may be joined to form a 5-10 membered heteroaryl.

In the specific embodiment when X, Y or Z is a carbon atom, two substituents on the same carbon atom may be linked to form C_3-7A cycloalkyl group; in one embodiment, two substituents on the same carbon atom may be linked to form a 3-7 membered heterocyclyl; in one embodiment, two substituents on the same carbon atom may be linked to form a 4-8 membered heterocyclyl.

In one particular embodiment of the process of the present invention,

the structural unit is selected from the following structures:

R ₁、R ₁' or R₁”

In one embodiment, R₁、R ₁' or R₁"is H; in another embodiment, R₁、R ₁' or R₁"is F; in another embodiment, R₁、R ₁' or R₁"is Cl; in another embodiment, R₁、R ₁' or R₁"is Br; in another embodimentIn the embodiment, R₁、R ₁' or R₁"is methyl; in another embodiment, R₁、R ₁' or R₁is-CHF₂(ii) a In another embodiment, R₁、R ₁' or R₁Is "CF₃。

L ₁

In a particular embodiment, L₁Is a chemical bond; in another specific embodiment, L₁is-CR' ═ CR "-; in another specific embodiment, L₁is-C.ident.C-.

In one embodiment, R' is H; in another embodiment, R' is halogen; in another embodiment, R' is C_1-6An alkyl group; in another embodiment, R' is C_1-6A haloalkyl group; in another embodiment, R' is C_3-7A cycloalkyl group; in another embodiment, R' is a 3-7 membered heterocyclyl; in another embodiment, R' is a 4-8 membered heterocyclyl.

In one embodiment, R "is H; in another embodiment, R "is halogen; in another embodiment, R' is C_1-6An alkyl group; in another embodiment, R' is C_1-6A haloalkyl group; in another embodiment, R' is C_3-7A cycloalkyl group; in another embodiment, R' is a 3-7 membered heterocyclyl; in another embodiment, R' is a 4-8 membered heterocyclyl.

R ₂

In one embodiment, R₂Is H; in another embodiment, R₂Is halogen; in another embodiment, R₂is-CN; in another embodiment, R₂is-NO₂(ii) a In another particular embodiment of the process of the present invention,R ₂is-C (O) R_a(ii) a In another embodiment, R₂is-C (O) OR_a(ii) a In another embodiment, R₂is-C (O) NR_bR _c(ii) a In another embodiment, R₂Is C_1-6An alkyl group; in another embodiment, R₂Is C_1-6A haloalkyl group; in another embodiment, R₂Is C_2-8An alkenyl group; in another embodiment, R₂Is C_2-8An alkynyl group; in another embodiment, R₂Is C_3-7A cycloalkyl group; in another embodiment, R₂Is a 3-7 membered heterocyclic group; in another embodiment, R₂Is a 4-8 membered heterocyclic group; in another embodiment, R₂Is C_6-10An aryl group; in another embodiment, R₂Is a 5-10 membered heteroaryl.

In one embodiment, R₂Optionally substituted with 1R group; in another embodiment, R₂Optionally substituted with 2R groups; in another embodiment, R₂Optionally substituted with 3R groups.

In a specific embodiment, R is independently H; in another embodiment, R is independently halogen; in another specific embodiment, R is independently-CN; in another embodiment, R is independently-NO₂(ii) a In another embodiment, R is independently-OR_a(ii) a In another embodiment, R is independently-NR_bR _c(ii) a In another embodiment, R is independently-C (O) OR_a(ii) a In another embodiment, R is independently-C (O) NR_bR _c(ii) a In another embodiment, R is independently C_1-6An alkyl group; in another embodiment, R is independently C _1-6A haloalkyl group; in another embodiment, R is independently C_3-7A cycloalkyl group; in another embodiment, R is independently a 3-7 membered heterocyclyl; in another embodiment, R is independently a 4-8 membered heterocyclyl; in another embodiment, R is independently C_6-10An aryl group; in another embodiment, R is independently 5-10 membered heteroaryl.

In a specific embodiment, -L₁-R ₂Is H; in another specific embodiment, -L₁-R ₂Is halogen; in another specific embodiment, -L₁-R ₂is-CN; in another specific embodiment, -L₁-R ₂is-NO₂(ii) a In another specific embodiment, -L₁-R ₂is-C (O) R_a(ii) a In another specific embodiment, -L₁-R ₂is-C (O) OR_a(ii) a In another specific embodiment, -L₁-R ₂is-C (O) NR_bR _c(ii) a In another specific embodiment, -L₁-R ₂Is C_1-6An alkyl group; in another specific embodiment, -L₁-R ₂Is C_1-6A haloalkyl group; in another specific embodiment, -L₁-R ₂Is C_3-7A cycloalkyl group; in another specific embodiment, -L₁-R ₂is-CH ═ CH-halogen; in another specific embodiment, -L₁-R ₂is-CH ═ CH-C (O) OR_a(ii) a In another specific embodiment, -L₁-R ₂is-CH ═ CH-C (O) NR_bR _c(ii) a In another specific embodiment, -L₁-R ₂is-C ≡ C-H; in another specific embodiment, -L₁-R ₂is-C ≡ C-CN; in another specific embodiment, -L₁-R ₂is-C ≡ C-C_1-6An alkyl group; in another specific embodiment, -L₁-R ₂is-C ≡ C-C_1-6A haloalkyl group; in another specific embodiment, -L₁-R ₂is-C ≡ C-C_2-8An alkenyl group; in another specific embodiment, -L₁-R ₂is-C ≡ C-C (O) NR_bR _c(ii) a In another embodiment, -L₁-R ₂is-C ≡ C-C (O) OR_a(ii) a In another specific embodiment, -L₁-R ₂is-C ≡ C-C_3-7A cycloalkyl group; in another specific embodiment, -L₁-R ₂is-C ≡ C-C_6-10And (4) an aryl group.

R ₃

In one embodiment, R₃Is C_6-10An aryl group; in another embodiment, R₃Is a 5-10 membered heteroaryl; in another embodiment, R₃Is a 5-6 membered heteroaryl; in another embodiment, R₃Is a 5-6 membered heteroaryl group containing a N atom; in another embodiment, R₃Is an oxazolyl group (e.g., pyrrolyl, thiazolyl, imidazolyl, oxazolyl), oxadiazolyl (e.g., thiadiazole, oxadiazole), triazolyl, or pyridyl group; in another embodiment, R₃Is a pyrrolyl group; in another embodiment, R₃Is thiazolyl; in another embodiment, R₃Is imidazolyl; in another embodiment, R₃Is oxazolyl; in another embodiment, R₃Is thiadiazole; in another embodiment, R₃Is oxadiazole; in another embodiment, R₃Is triazolyl; in another embodiment, R₃Is a pyridyl group.

R ₄

In one embodiment, R₄Is hydrogen; in another embodiment, R₄Is halogen; in another embodiment, R₄is-CN; in another embodiment, R₄Is C_1-6An alkyl group; in another embodiment, R₄Is C_1-6A haloalkyl group.

L ₂

In a particular embodiment, L₂Is- (C)_0-6Alkylene) -; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -O-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -NR_b-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -c (o) -; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -C (O) O-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -C (O) NR_b-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -O-C (O) -; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -O-C (O) O-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -O-C (O) NR_b-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -N (R)_b) -c (o) -; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -N (R)_b) -C (O) O-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -N (R)_b)-C(O)NR _c-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -S (O)_p-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -S (O)_pO-; in thatIn another embodiment, L₂Is- (C)_0-6Alkylene) -S (O)_pNR _b-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -O-S (O)_p-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c) -; in another specific embodiment, L₂Is- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-O-; in another specific embodiment, L₂is-C_2-8Alkenylene-; in another specific embodiment, L₂is-C_2-8Alkynylene-; in another specific embodiment, L₂is-C_3-7Cycloalkylene-; in another specific embodiment, L₂Is a 3-7 membered heterocyclylene group; in another specific embodiment, L₂Is a 4-8 membered heterocyclylene group; in another specific embodiment, L₂Is C_6-10An arylene group; in another specific embodiment, L₂Is a 5-10 membered heteroarylene.

R ₅

In one embodiment, R₅Is- (C)_0-6Alkylene) -OR_a(ii) a In another embodiment, R₅Is- (C)_0-6Alkylene) -NR_bR _c(ii) a In another embodiment, R₅Is- (C)_0-6Alkylene) -C (O) R_a(ii) a In another embodiment, R₅Is- (C)_0-6Alkylene) -C (O) OR_a(ii) a In another embodiment, R₅Is- (C)_0-6Alkylene) -C (O) NR_bR _c(ii) a In another toolIn a particular embodiment, R₅Is C_1-6An alkyl group; in another embodiment, R₅Is C_1-6A haloalkyl group; in another embodiment, R₅Is C_2-8An alkenyl group; in another embodiment, R₅Is C_2-8An alkynyl group; in another embodiment, R₅Is C_3-11A cycloalkyl group; in another embodiment, R₅Is a 3-15 membered heterocyclyl; in another embodiment, R₅Is C_6-10An aryl group; in another embodiment, R₅Is a 5-10 membered heteroaryl.

R _a、R _bAnd R_c

In one embodiment, R_a、R _bAnd R_cIndependently is H; in another embodiment, R_a、R _bAnd R_cIndependently is C_1-6An alkyl group; in another embodiment, R_a、R _bAnd R_cIndependently is C_1-6A haloalkyl group; in another embodiment, R_a、R _bAnd R_cIndependently is- (C)_0-6Alkylene) -OR; in another embodiment, R_a、R _bAnd R_cIndependently is- (C)_0-6Alkylene) -NR × (R) ×; in another embodiment, R_a、R _bAnd R_cIndependently is- (C)_0-6Alkylene) -c (o) R; in another embodiment, R_a、R _bAnd R_cIndependently is- (C)_0-6Alkylene) -c (o) OR; in another embodiment, R_a、R _bAnd R_cIndependently is- (C)_0-6Alkylene) -c (o) NR R; in another embodiment, R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclic group; in another embodiment, R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heteroaryl group.

m

In a specific embodiment, m ═ 0; in another specific embodiment, m ═ 1; in another specific embodiment, m is 2; in another specific embodiment, m is 3; in another specific embodiment, m is 4; in another specific embodiment, m is 5.

n

In a specific embodiment, n ═ 0; in another specific embodiment, n ═ 1; in another specific embodiment, n ═ 2; in another specific embodiment, n is 3.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein,

ring A is

n is 0, 1, 2 or 3;

preferably, the first and second electrodes are formed of a metal,

the structural unit is selected from the following structures:

in a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein R is a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, wherein R is a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, hydrate, polymorph, or isotopic variation thereof, or a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, or isotopic variation thereof, or a mixture thereof₁Selected from H, halogen, -CN, methyl, trifluoromethyl or difluoromethyl; preferably, R₁Selected from H, F, Cl, Br, -CN or CH₃(ii) a Preferably, R₁Selected from H, F, Cl or Br.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein L is a compound of formula (I) wherein L is a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, or a mixture thereof₁Is selected from-CR' ═ CR ≡ C —; wherein R 'and R' are independently selected from H, halogen, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, L₁Is selected from-CR' ═ CR ≡ C —; wherein R 'and R' are independently selected from H or halogen.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein R is a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, wherein R is a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, hydrate, polymorph, or isotopic variation thereof, or a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, or isotopic variation thereof, or a mixture thereof₂Selected from H, halogen, -CN, -C (O) OR_a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10An aryl group; preferably, R₂Selected from H, halogen, -C (O) OR_a、C _1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10And (4) an aryl group.

-L ₁-R ₂selected from H, halogen, -CN, -NO₂、-C(O)R _a、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, -CH ═ CH-halogen, -CH ═ CH-c (o) OR_a、-CH＝CH-C(O)NR _bR _c、-C≡C-H、-C≡C-CN、-C≡C-C _1-6Alkyl, -C ≡ C-C_1-6Haloalkyl, -C ≡ C-C_2-8Alkenyl, -C ≡ C (O) NR_bR _c、-C≡C-C(O)OR _a、-C≡C-C _3-7Cycloalkyl or-C ≡ C-C_6-10An aryl group;

preferably, -L₁-R ₂Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, -CH ═ CH-halogen, -CH ═ CH-c (o) OR_a、-CH＝CH-C(O)NR _bR _c、-C≡C-H、-C≡C-C _3-7Cycloalkyl or-C ≡ C-C_6-10And (4) an aryl group.

R ₃is a 5-6 membered heteroaryl; preferably, R₃Is a 5-6 membered heteroaryl group containing a N atom; preferably, R₃Is oxazolyl (such as pyrrolyl, thiazolyl, imidazolyl, oxazolyl), oxadiazolyl (such as thiadiazolyl)Oxazole, oxadiazole), triazolyl or pyridyl; preferably, R₃Is thiazol-2-yl.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein R is a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, wherein R is a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, hydrate, polymorph, or isotopic variation thereof, or a pharmaceutically acceptable salt of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, or isotopic variation thereof, or a mixture thereof₄Is H or methyl; preferably, R₄Is H and R₄The carbon atom is in R configuration.

L ₂is selected from- (C)_0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-or- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c)-；

Preferably, the first and second electrodes are formed of a metal,

L ₂selected from the group consisting of-O-C (O) -, -O-C (O) O-, -O-C (O) NR_b-、-N(R _b)-C(O)-、-N(R _b)-C(O)O-、-N(R _b)-C(O)NR _c-、-O-S(O) _p-、-N(R _b)-S(O) _p-or-N (R)_b)-S(O) _p-N(R _c)-；

Preferably, the first and second electrodes are formed of a metal,

L ₂is selected from-N (R)_b)-C(O)-、-N(R _b)-C(O)O-、-N(R _b)-S(O) ₂-or-N (R)_b)-S(O) _p-N(R _c)-。

R ₅is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

preferably, the first and second electrodes are formed of a metal,

R ₅is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, having the structure of formula (I-1), (I-2), (I-3), or (I-4):

wherein,

R ₁' and R₁"is halogen or methyl;

L ₁is selected from-CH ═ CH-or-C ≡ C-;

R ₂selected from H, halogen, -CN,-C(O)OR _a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10An aryl group;

L ₂is selected from- (C)_0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c) -or- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-；

R ₅Is selected from-NR_bR _c、-(C _0-6Alkylene) -OR_a、-(C _0-6Alkylene) -NR_bR _c、-(C _0-6Alkylene) -C (O) R_a、-(C _0-6Alkylene) -C (O) OR_a、-(C _0-6Alkylene) -C (O) NR_bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group;

R _a、R _b、R _cindependently selected from H, - (C)_0-6Alkylene) -OH, - (C)_0-6Alkylene) -NH₂、-(C _0-6Alkylene) -C (O) H, - (C)_0-6Alkylene) -C (O) OH, - (C)_0-6Alkylene) -C (O) NH₂、C _1-6Alkyl or C_1-6A haloalkyl group; or R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

p is 0, 1 or 2.

In a more specific embodiment, the present invention provides a compound of formula (I-1), (I-2), (I-3), or (I-4) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein:

R ₁' is F, and R₁"is Cl or Br;

L ₁is selected from-CH ═ CH-or-C ≡ C-;

R ₂selected from H, halogen, -CN, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10An aryl group;

L ₂is selected from-N (R)_b)-C(O)-、-N(R _b)-C(O)O-、-N(R _b)-C(O)NR _c-、-O-S(O) ₂-、-N(R _b)-S(O) ₂-or- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c)-；

R ₅Is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group;

R _a、R _b、R _cindependently selected from H, - (C)_0-6Alkylene) -C (O) OH, C_1-6Alkyl or C_1-6A haloalkyl group;

p is 0, 1 or 2.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, having the structure of formula (II-1), (II-2), or (II-3):

wherein,

R ₁、R ₁' and R₁"is H, halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂、R ₃、R ₅、L ₂x, Y, Z, m and n are as defined herein.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, having the general formula (II-4):

wherein,

R ₁' and R₁"is halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂selected from H, halogen, -CN, -NO₂、C _1-6Alkyl or C_1-6A haloalkyl group; preferably, R₂Selected from H, halogen or C_1-6A haloalkyl group; preferably, R₂Selected from CHF₂Or CF₃；

R ₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heteroA cyclic group.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having the general formula (III-1), (III-2), (III-3), (III-4), (III-5) or (III-6):

wherein,

R ₂、R ₃、R ₅、L ₂x, Y, Z, R', R ", m and n are as defined herein.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having the general formula (III-7), (III-8), (III-9), (III-10), (III-11) or (III-12):

wherein,

R ₂selected from H, halogen, -CN, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl group、C _3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₂Selected from halogen, -C (O) OR_a、C _1-6Alkyl or C_1-6A haloalkyl group;

R ₅is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₅Is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

R _a、R _b、R _cindependently selected from H, - (C)_0-6Alkylene) -OH, - (C)_0-6Alkylene) -NH₂、-(C _0-6Alkylene) -C (O) H, - (C)_0-6Alkylene) -C (O) OH, - (C)_0-6Alkylene) -C (O) NH₂、C _1-6Alkyl or C_1-6A haloalkyl group; or R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl.

In a more specific embodiment, the present invention provides a compound of formula (III-7), (III-8), (III-9), (III-10), (III-11), or (III-12) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein:

R ₂selected from H, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heteroCyclic group OR-C (O) OR_a(ii) a Preferably, R₂Selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl OR-C (O) OR_a；

R ₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

R _aindependently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having the general formula (IV-1), (IV-2) or (IV-3):

wherein,

R ₂、R ₅、L ₂x, Y, Z, m and n are as defined herein.

In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having the general formula (IV-4), (IV-5) or (IV-6):

wherein,

R ₂selected from H, -C (O) OR_a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl; and R is₂Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _aor-NR_bR _c；

Preferably, R₂Selected from H, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl or C_6-10An aryl group; and R is₂Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _aor-NR_bR _c；

Preferably, R₂Selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-8 membered heterocyclyl or C_6-10An aryl group; and R is₂Optionally substituted with 1, 2 OR 3R groups, wherein R is independently selected from halogen, -OR_aor-NR_bR _c；

R _a、R _bAnd R_cIndependently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

R ₅is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl; preferably, R₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.

Any of the above embodiments, or any combination thereof, may be combined with any of the other embodiments, or any combination thereof. For example, any of the embodiments of A, or any combination thereof, can be combined with L₁、L ₂、R ₁-R ₅And m, or any combination thereof. The present invention is intended to include all combinations of these solutions, limited to space, not listed one by one.

In a more specific embodiment, the compounds of the present invention are selected from, but not limited to, the following compounds:

the compounds of the invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

One skilled in the art will appreciate that the organic compound may form a complex with a solvent in which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

The term "solvate" refers to a form of a compound or salt thereof that is combined with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term "hydrate" refers to a compound that is associated with an aqueous phase. In general, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, hydrates of the compounds can be used, for example, of the formula R. x H₂O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), e.g., hemihydrate (R0.5H)₂O)) and polyhydrates (x is a number greater than 1, e.g. dihydrate (R.2H)₂O) and hexahydrate (R.6H)₂O))。

The compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystalline form to dominate. Various polymorphs of a compound may be prepared by crystallization under different conditions.

The invention also includes isotopically-labeled compounds (isotopic variations) which are identical to those recited in formulas I-VIII, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、 ³H、 ¹³C、 ¹¹C、 ¹⁴C、 ¹⁵N、 ¹⁸O、 ¹⁷O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes (e.g. by introducing³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Tritium, i.e.³H and carbon-14, i.e.¹⁴The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e.²H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labelled compounds of formulae I-VIII of the present invention and prodrugs thereof can generally be prepared by carrying out the following schemes and/or proceduresIn the processes disclosed in examples and preparations, a readily available isotopically labeled reagent is used in place of a non-isotopically labeled reagent.

A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner such that the modification is effected by routine manipulation or in vivo cleavage to produce the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, cleaves to form a hydroxy, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of hydroxy, mercapto, and amino functional groups of the compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like may be used. The ester itself may be active and/or may hydrolyze under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which readily break down in the human body to release the parent acid or salt thereof.

The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formulae I-VIII, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the present invention.

Pharmaceutical composition and kit

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The invention also includes kits (e.g., pharmaceutical packages). The provided kits can include a compound of the invention, an additional therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispensable packages or other suitable containers) containing the compound of the invention, the additional therapeutic agent. In some embodiments, provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, the compound of the present invention and the additional therapeutic agent provided in the first container and the second container are combined to form one unit dosage form.

Administration of drugs

The pharmaceutical compositions provided by the present invention may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implant or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by a physician, as the case may be, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

When used to prevent a condition according to the invention, a subject at risk of developing the condition is administered a compound provided herein, typically based on physician's advice and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a particular disorder, typically include subjects with a family history of the disorder, or those determined to be particularly susceptible to developing the disorder by genetic testing or screening.

The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). By long-term administration is meant administration of the compound or pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue for an indefinite period of time, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within the therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the targeted systemic level of the active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses result in slow release of the active ingredient, while a bolus delivered directly to the vein (e.g., by IV intravenous drip) can be delivered more rapidly, resulting in a rapid rise in the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV intravenous drip, to provide a steady state concentration of the active ingredient in the body of the subject. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are provided in unit dosage form for convenient administration of the precise dosage. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for the purpose of producing the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful in forming the desired form of administration.

For oral dosages, a representative regimen is one to five oral dosages, particularly two to four oral dosages, typically three oral dosages per day. Using these dosing modes, each dose provides about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10mg/kg, especially about 1 to about 5 mg/kg.

In order to provide a blood level similar to, or lower than, the use of the injected dose, a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To obtain sufficient steady state levels, a preload bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, as well as buffers, suspending and dispersing agents, coloring and flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds with similar properties: a binder, for example, microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example, starch or lactose, disintegrants, for example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, e.g., colloidal silicon dioxide; sweetening agents, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with a cream base, for example of the oil-in-water type. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.

The compounds of the present invention may also be administered by transdermal means. Thus, transdermal administration can be achieved using a reservoir (reservoir) or porous membrane type, or a patch of various solid matrices.

The above components of the compositions for oral, injectable or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences,17th edition,1985, Mack Publishing Company, Easton, Pennsylvania, section 8, which is incorporated herein by reference.

The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, e.g., U.S.5,376,645. In some embodiments, the formulation includes hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Combination therapy

The compounds or compositions of the present invention may be administered concurrently with, before, or after one or more additional agents, for use as a combination therapy. The medicament includes a therapeutically active agent. The medicament also includes a prophylactically active agent. Agents include small organic molecules, such as pharmaceutical compounds (e.g., human or veterinary compounds approved by the U.S. food and drug administration as provided in the federal regulations Compilation (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In some embodiments, the additional agent is an agent for treating and/or preventing a disease described herein. Each additional agent may be administered at a dose and/or on a schedule determined by the agent. The additional agents may also be administered together with each other and/or with the compounds or compositions described herein, in a single dose or separately in different doses. The particular combination employed in this regimen will take into account the compatibility of the compounds of the present invention with additional agents and/or the desired therapeutic and/or prophylactic effect that will be achieved. Typically, the additional agents are used in combination at a level that is no greater than the level at which they are used individually. In some embodiments, the levels used in combination will be lower than they are used individually.

In particular embodiments, the additional agent is an antiviral agent selected from the group consisting of HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, capsid assembly modulators, reverse transcriptase inhibitors, TLR-agonists, and drugs of different or unknown mechanisms, and combinations thereof.

In another embodiment, the pegylated interferon is pegylated interferon alpha (IFN-alpha), pegylated interferon lambda (IFN-lambda), or pegylated interferon gamma (IFN-gamma).

In another embodiment, the reverse transcriptase inhibitor is at least one of: zidovudine (Zidovudine), Didanosine (Didanosine), Zalcitabine (Zalcitabine), ddA (2',3' -dideoxyadenosine) (ddA (2',3' -dideoxyyadenosine)), Stavudine (Stavudine), Lamivudine (Lamivudine), Abacavir (Abacavir), Emtricitabine (Emtricitabine), Entecavir (Entecavir), aricitabine (Apricitabine), Atevirapine, ribavirin (ribivirin), acyclovir (acyclovir), famciclovir (famciclovir), valacyclovir (ganciclovir), ganciclovir (ganciclovir), valganciclovir (valganciclovir), Tenofovir (Tenofovir), Adefovir (Adefavir), nevirazine (Advidorivir), Nevirapine (Efavirenz), Nevirapine (efavirine), etavirenz (etavirenz), valganciclovir (efavir), valvirenz (valvirine (valvirucine), valvirucine (valvirginine), valvirginine (ribavirin).

In another embodiment, the additional agent is, for example, a T cell response activator, AIC 649; interferons-based biological agents such as interferon and pegylated interferon; TLR modulators such as TLR-7 agonists or TLR-9 agonists such as SM360320 (9-benzyl-8-hydroxy-2- (2-methoxy-ethoxy) adenine), AZD8848([ methyl 3- ({ [3- (6-amino-2-butoxy-8-oxo-7, 8-dihydro-9H-purin-9-yl) propyl ] [3- (4-morpholinyl) propyl ] amino } methyl) phenyl ] acetate), GS-9620 and RO 6864018; a therapeutic vaccine that stimulates an HBV-specific immune response; immune activators such as SB-9200; RNA interference agents (RNAi) or small RNA interference agents (siRNA) such as ARC-520, ARC-521; or reverse transcriptase inhibitors such as lamivudine, telbivudine, emtricitabine, entecavir, tenofovir disoproxil, adefovir disoproxil.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, prepared, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what is claimed herein.

In general, the following conditions are used in the following examples. All water sensitive reactions were performed under dry conditions. Benzene or tetrahydrofuran is used after refluxing, drying and distillation in the presence of metal sodium; the dichloromethane was refluxed, dried and distilled in the presence of phosphorus pentoxide and used. All intermediates were purified by silica gel chromatography. All final compounds were purified by preparative HPLC using a C18 reverse phase chromatography column with either acidic (A: 0.1% trifluoroacetic acid in water; B: acetonitrile) or basic conditions (A: 0.1% aqueous ammonia; B: acetonitrile) mobile phase. Based on HPLC, LC-MS and¹h NMR analysis showed that all final compounds were greater than 95% pure.

Example 1

Compound 2

Compound 1 (prepared according to CN 2019093578) (1.5g, 4.27mmol,1 equiv.) is added into dichloromethane 30mL, the temperature is increased to reflux, NBS (0.69g,3.87mmol,0.9 equiv.) is added in batches, NBS (0.77g,4.27mmol,1 equiv.) is added in batches after stirring for reaction for 1h, after TLC detection reaction is finished, water (40mL) is added for quenching reaction, DCM (30mLx3) is extracted, then drying and concentrating are carried out, and crude product 2 is directly used for next reaction.

Compound 4

Compound 3(1.59g, 12mmol) was dissolved in anhydrous DMF (30mL), sodium hydride (0.21g, 8.9mmol) was added portionwise at room temperature, and after stirring at room temperature for 2 hours, compound 2(3.0g, 6mmol) was added to the reaction mixture, after which the addition was complete, and the mixture was stirred at room temperature under nitrogen atmosphere overnight.The reaction solution was extracted with ethyl acetate (40mL × 3), the organic phases were combined, washed successively with water (100mL × 2) and saturated sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to obtain compound 4 in 52% total yield in two steps. LCMS (ESI) M/z 517,519[ M + H ]] ⁺。

Compound 5

10% Palladium on carbon (0.25g), (Boc)₂O (3.06g,14mmol) and Compound 4(2.41g,4.65mmol) were dissolved in THF (100mL), air was removed in vacuo and replaced three times with a hydrogen balloon and the reaction was stirred overnight at room temperature. The reaction mixture was filtered to remove the palladium/carbon catalyst, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to give product 5. LCMS (ESI) M/z 587,589[ M + H ]] ⁺。

Compound 6

Compound 5(1.0g, 1.7mmol) was dissolved in anhydrous THF (100mL) and NaBH added portionwise at room temperature₄(65mg,1.7mmol), followed by addition of methanol (0.1mL), gentle reflux with nitrogen, and stirring at reflux for 6 h. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was stirred in ice water (150mL) for 30 min. Ethyl acetate (40mL × 3) was added for extraction, the combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain 0.7g of compound 6 in 75% yield. LCMS (ESI) M/z 545,547[ M + H ]] ⁺。

Compound 7

Compound 6(600mg, 1.1mmol) was dissolved in anhydrous dichloromethane (50mL), triethylamine (0.22mL,1.54mmol) and methanesulfonyl chloride (0.3g,1.54mmol) were added dropwise at room temperature, the temperature was raised to 45 ℃ after the addition, and stirred overnight under nitrogen. The reaction was cooled and concentrated under reduced pressure, the residue was partitioned between water (30mL) and ethyl acetate (30mL × 3), the organic phases were combined and washed successively with water (20mL) and saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1)) 0.3g of compound 7 is obtained in 52% yield. LCMS (ESI) M/z 528,530[ M + H ]] ⁺。

Compound 8

Compound 7(4.45g, 8.4mmol, 1.00 equiv.), tert-butyl acrylate (3.24g, 25.24mmol, 3.00 equiv.), Pd₂(dba) ₃(0.77g, 0.84mmol, 0.10 equiv.), dicyclohexylmethylamine (1.97g, 10.08mmol, 1.20 equiv.), and P (^tBu) ₃.HBF ₄(0.49g, 1.68mmol, 0.20 equiv.) of dioxane (86mL) was stirred under nitrogen at 120 ℃ overnight. The mixture was cooled to room temperature, quenched by addition of water (50mL), and extracted with EA (3X 80 mL). The organic layers were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 30% EA/PE) to give product 8(3.2g, 76%) as a yellow solid. LCMS (ESI) M/z 503[ M + H ]] ⁺。

Compound 9

Compound 8(2.67g, 5.3mmol) was dissolved in 1, 4-dioxane (40mL), HCl in dioxane (4M,5mL) was added dropwise under nitrogen at room temperature, and after the addition was complete, the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to obtain 2.1g of compound 9, which was directly subjected to the next reaction without purification. LCMS (ESI) M/z:420[ M + H ]] ⁺。

Compound 10a

Compound 9(84mg, 0.2mmol) was dissolved in anhydrous pyridine (3mL), isobutyryl chloride (24 μ L,0.24mmol) was added at 0 deg.C, the temperature was raised to room temperature after the addition was complete, and the mixture was stirred overnight under nitrogen. When TLC (petroleum ether: ethyl acetate ═ 2:1) showed disappearance of the starting material, the reaction solution was poured into saturated sodium bicarbonate solution (10mL) and extracted with dichloromethane (20mL x3), the organic phases were combined, washed successively with water (10mL x2), saturated sodium chloride solution (10mL x2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give 80mg of 10a in 82% yield. LCMS (ESI) M/z 490[ M + H ]] ⁺。

Compound 11a

Compound 10a (80mg, 0.16mmol, 1.00 equiv.) is dissolved in MeOH (5mL) and ACN (5mL)Mixing the solvents, and slowly adding Na dropwise at room temperature₂CO ₃(34mg, 0.32mmol, 2.00 equiv.) and NaBr (83mg, 0.8mmol, 5.00 equiv.) in water (5mL), then Oxone (14mg, 0.08mmol, 0.50 equiv.) in water (2mL) was added dropwise to the mixture over 20 minutes, the reaction was stirred for half an hour, quenched with brine and sodium sulfite, and the reaction was extracted with EA (3X 15 mL). The organic layers were combined, dried, filtered and concentrated, and the residue was purified by silica gel column chromatography (0% to 40% EA/PE) to give product 11a (43mg, 51%) as a yellow solid.¹H NMR(300MHz,CD ₃OD-d ₄)δ8.31(s,2H),7.66-7.78(m,1H),7.35-7.41(m,1H),7.18-7.31(m,1H),6.97-7.05(m,1H),6.41-6.57(m,1H),6.31(s,1H),4.39-4.69(m,3H),3.28(s,2H),2.62-2.68(m,1H),1.11(d,3Hx2)；LCMS(ESI)m/z:524,526[M+H] ⁺。

Using the above synthetic route, compounds 11b and 11c were similarly prepared:

¹HNMR(400MHz,CDC1 ₃)δ:7.95-7.97(m,1H),7.78-7.80(m,1H),7.39-7.43(m,1H),7.31-7.36(m,1H),7.27-7.31(m,1H),7.22-7.25(m,1H),6.96-7.01(m,1H),6.17(s,1H),5.84-5.71(m,1H),4.65-4.77(m,1H),4.04-4.07(m,1H),3.64-3.56(m,4H),3.23-3.32(m,1H)；LCMS(ESI)m/z:512,514[M+H] ⁺。

¹HNMR(300MHz,CD ₃OD-d ₄)δ8.31(s,2H),7.66-7.78(m,1H),7.35-7.41(m,1H),7.18-7.31(m,1H),6.97-7.05(m,1H),6.41-6.57(m,1H),6.31(s,1H),4.39-4.69(m,3H),3.28(s,2H),2.62-2.78(m,1H),1.10-1.22(m,4H)；LCMS(ESI)m/z:558,560[M+H] ⁺。

example 2

Compound 13

Compound 12 (prepared by the method of CN 2019093578) (1.69g, 4.27mmol,1 eq) was added to dichloromethane 30mL, the mixture was heated to reflux, NBS (0.69g,3.84mmol,0.9 eq) was added in portions, the mixture was stirred for reaction for 1 hour, NBS (0.77g,4.27mmol,1 eq) was added in portions, after TLC detection, water (40mL) was added to quench the reaction, DCM (30mLx3) was extracted, dried and concentrated, and the product 13 was used directly in the next reaction.

Compound 14

Compound 3(1.12g, 8.4mmol) was dissolved in anhydrous DMF (30mL), sodium hydride (0.15g, 6.3mmol) was added portionwise at room temperature, and after stirring at room temperature for 2 hours, crude compound 13 (1.93g, 4.2mmol) was added to the reaction solution, the addition was complete, and the mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction solution was extracted with ethyl acetate (40mL × 3), the organic phases were combined, washed successively with water (100mL × 2) and a saturated sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to obtain 1.18g of compound 14 with a yield of 49% in two steps. LCMS (ESI) M/z 561,563,565[ M + H ]] ⁺。

Compound 15

10% Palladium on carbon (0.25g), (Boc)₂O (3.06g,14mmol) and compound 14(2.63g,4.68mmol) were dissolved in THF (100mL), air was removed in vacuo and replaced three times with a hydrogen balloon, and the reaction was stirred overnight at room temperature. The reaction mixture was filtered to remove the palladium/carbon catalyst, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give product 15. LCMS (ESI) M/z 631,633,635[ M + H ]] ⁺。

Compound 16

Compound 15(1.0g, 1.6mmol) was dissolved in anhydrous THF (100mL) and NaBH added portionwise at room temperature₄(61mg,1.6mmol), followed by addition of methanol (0.1mL), gentle reflux with nitrogen, and stirring at refluxFor 6 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was stirred in ice water (150mL) for 30 min. Ethyl acetate (40mL x3) was added for extraction, the combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give 708mg of compound 16 in 75% yield. LCMS (ESI) M/z 589,591,593[ M + H ]] ⁺。

Compound 17

Compound 16(600mg, 1.03mmol) was dissolved in anhydrous dichloromethane (50mL), triethylamine (0.22mL,1.54mmol) and methanesulfonyl chloride (0.3g,1.54mmol) were added dropwise at room temperature, the temperature was raised to 45 ℃ after the addition, and stirred overnight under nitrogen. The reaction was cooled and concentrated under reduced pressure, the residue was partitioned between water (30mL) and ethyl acetate (30mL × 3), the organic phases were combined and washed successively with water (20mL) and saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the crude product was isolated by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give 0.3g of compound 17 in 52% yield. LCMS (ESI) M/z 572,574,576[ M + H ]] ⁺。

Compound 18

Compound 17(2.67g, 5.3mmol) was dissolved in 1, 4-dioxane (40mL), HCl in dioxane (4M,5mL) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was concentrated under reduced pressure to obtain 2.4g of Compound 18, which was then allowed to proceed to the next reaction without further purification. LCMS (ESI) M/z 472,474,476[ M + H ]] ⁺。

Compound 19

Compound 18(102mg, 0.2mmol) was dissolved in anhydrous pyridine (3mL), cyclopropylsulfonyl chloride (24. mu.L, 0.24mmol) was added at 0 ℃ and after addition the temperature was raised to room temperature and stirred under nitrogen overnight. When TLC (petroleum ether: ethyl acetate ═ 2:1) showed disappearance of the starting material, the reaction solution was poured into saturated sodium bicarbonate solution (10mL) and extracted with dichloromethane (20mL x3), the organic phases were combined, washed successively with water (10mL x2) and saturated sodium chloride solution (10mL x2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1)Ester 3:1) to yield 94mg of 19 in 82% yield. LCMS (ESI) M/z 576,578,580[ M + H ]] ⁺。

Compound 20

Compound 19(4.85g, 8.41mmol, 1.00 equiv.), tert-butyl acrylate (3.24g, 25.24mmol, 3.00 equiv.), Pd₂(dba) ₃(0.77g, 0.84mmol, 0.10 equiv.), P: (^tBu) ₃.HBF ₄(0.49g, 1.68mmol, 0.20 equiv.) and Cy₂A solution of NMe (3.65mL,17mmol,2.0 equiv.) in dioxane (86mL) was stirred under nitrogen at 120 ℃ overnight. The mixture was cooled to room temperature, quenched by addition of water (50mL), and extracted with EA (3X 80 mL). The organic layers were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 30% EA/PE) to give the product 20 as a yellow solid (3.99g, 76%). LCMS (ESI) M/z 523,525[ M + H ]] ⁺。

Compound 21

Compound 20(3.3g, 5.3mmol) was dissolved in 1, 4-dioxane (40mL), HCl in dioxane (4M,5mL) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature under nitrogen. The reaction solution was concentrated under reduced pressure to obtain 2.82g of compound 21, which was directly subjected to the next reaction without purification. LCMS (ESI) M/z 568,570[ M + H ]] ⁺。

Compound 22

Compound 21(91mg, 0.16mmol, 1.00 equiv.) is dissolved in a mixed solvent of MeOH (5mL) and ACN (5mL), and Na is slowly dropped at room temperature₂CO ₃(34mg, 0.32mmol, 2.00 equiv.) and NaBr (83mg, 0.8mmol, 5.00 equiv.) in water (5mL), then Oxone (14mg, 0.08mmol, 0.50 equiv.) in water (2mL) was added dropwise to the mixture over 20 minutes, the reaction was stirred for half an hour, quenched with brine and sodium sulfite, and the reaction was extracted with EA (3X 15 mL). The organic layers were combined, dried, filtered and concentrated, and the residue was purified by silica gel column chromatography (0% to 40% EA/PE) to give product 22(43mg, 51%) as a yellow solid.¹HNMR(400MHz,CDC1 ₃)δ:7.94-7.97(m,1H),7.78-7.80(m,1H),7.45-7.66(m,1H),7.33-7.40(m,2H),7.34(m,1H),7.20-7.26(m,1H),6.99-7.04(m,1H),6.17(s,1H),5.94-5.96(m,1H),4.63-4.7(m,1H),4.01-4.05(m,1H),3.53-3.56(m,1H),3.16-3.20(m,1H),2.45-2.57(m,1H),1.22-1.27(m,2H),1.06-1.08(m,2H)；LCMS(ESI)m/z:602,604[M+H] ⁺。

Example 3

Compound 23a

Compound 19(850mg,1.48mmol,1 equiv.) and DMF (15ml) were added to a reaction flask, stirred to dissolve, and then Pd (PPh) was added₃) ₂Cl ₂(103.7mg, 148. mu. mol,0.1 equiv.), CuI (28mg, 148. mu. mol,0.1 equiv.), triethylamine (300mg, 2.95mmol,2 equiv.), and trimethylsilylacetylene (230mg, 2.95mmol,2 equiv.), reacted at room temperature for 12h under a liquid nitrogen atmosphere. After completion of the TLC detection reaction, it was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.2), the combined organic phases were washed with saturated sodium chloride (100 mL. times. 3), dried over anhydrous sodium sulfate, filtered and the resulting residue was concentrated and chromatographed on a silica gel column (PE: EA 1:1) to give product 23a as a yellow solid (400mg, 61% yield).¹H NMR(300MHz,CD ₃OD-d ₄)δ8.29(s,1H),8.25(s,1H),7.74-7.83(m,1H),7.42(d,J＝6.9Hz,1H),7.29(t,J＝7.8Hz,1H),6.26(d,J＝10.5Hz,1H),4.69-4.79(m,1H),4.51-4.60(m,1H),4.43(s,1H),3.21-3.29(m,1H),2.95-3.05(m,1H),2.83(s,1H),2.60-2.67(m,1H),1.01-1.13(m,4H)；MS-ESI m/z：522,524[M+H] ⁺。

Using the same synthetic method, compounds 23b and 23c were prepared:

¹H NMR(300MHz,CD ₃OD-d ₄)δ8.29(s,1H),8.24(s,1H),7.74-7.83(m,1H),7.42(d,J＝6.9Hz,1H),7.29(t,J＝7.8Hz,1H),6.26(d,J＝10.5Hz,1H),4.69-4.79(m,1H),4.51-4.60(m,1H),4.43(s,1H),3.21-3.29(m,1H),2.95-3.05(m,1H),2.83(s,1H),2.63-2.69(m,1H),0.97-1.09(m,9H)；MS-ESI m/z：562,564[M+H] ⁺。

¹H NMR(300MHz,CD ₃OD-d ₄)δ8.30(s,1H),8.23(s,1H),7.30-7.83(m,8H),6.26(d,J＝10.5Hz,1H),4.69-4.79(m,1H),4.51-4.60(m,1H),4.43(s,1H),3.21-3.29(m,1H),2.95-3.05(m,1H),2.83(s,1H),2.63-2.69(m,1H),1.09(d,J＝7.8Hz,4H)；MS-ESI m/z：598,600[M+H] ⁺。

example 4

Mixing compound 19(120mg, 0.2mmol), CuI (70mg, 0.4mmol), KF (35mg, 0.6mmol) and TMSCF₃(170mg, 1.2mmol) was dispersed in NMP-THF (1: 4, 5mL) mixed solvent, placed in a microwave reactor and stirred at 80 ℃ for reaction for 3h, 10mL of water was added to quench the reaction, the resulting solution was extracted with 3X 20mL of ethyl acetate, dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE/EA, 1: 10) to give 80mg of product 24 as a yellow solid in 71% yield.¹H NMR(300MHz,CD ₃OD-d ₄)δ8.30(s,2H),7.74-7.83(m,1H),7.42(d,J＝6.9Hz,1H),7.29(t,J＝7.8Hz,1H),6.26(d,J＝10.5Hz,1H),4.69-4.79(m,1H),4.51-4.60(m,1H),4.43(s,1H),3.21-3.29(m,1H),2.95-3.05(m,1H),2.63-2.69(m,1H),1.09(d,J＝7.8Hz,4H)；LCMS(ESI)m/z:522，524[M+H] ⁺。

Example 5

Compound 27

Compound 25(20g, 61.85mmol, 1 eq) was added to 200mL tetrahydrofuran, followed by the addition of N, N' -carbonyldiimidazole (CDI, 11.03g, 68.04mmol, 1.1 eq) and the reaction stirred at room temperature for 2 hours. Monotert-butyl malonate 26(14.86g, 92.78mmol, 1.5 equiv.) was added to 100mL tetrahydrofuran, isopropyl magnesium bromide (2N, 102mL, 204.12mmol, 3.3 equiv.) was slowly added dropwise under ice-bath, and after addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. This reaction solution was slowly added dropwise to the reaction solution of 25 above under ice bath, and after the addition was completed, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with 2N HCl, extracted with ethyl acetate, concentrated in the organic phase, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain 27(20g, 47.45mmol, 76.71%) as a white solid. MS-ESI (ESI, pos.ion) m/z: 444.29[ M + Na ]] ⁺。

Compound 28

A reaction flask was charged with thiazole-2-carboxamidine (10g, 63.07mmol, 1 eq.), compound 27(31.9g, 75.68mmol, 1.2 eq.), 2-chloro-4-fluorobenzaldehyde (11.35g, 69.38mmol, 1.1 eq.) and potassium acetate (12.38g, 126.14mmol, 2 eq.), added with 200mL of methanol, and allowed to warm to 80 ℃ for overnight reaction. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 200mL of dichloromethane, triethylamine (19.15g, 189.21mmol, 3 equiv.) was added, isobutyl chloroformate (17.23g, 126.14mmol, 2 equiv.) was added dropwise over an ice bath, and the mixture was allowed to warm to room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with 100mL of water, extracted with dichloromethane, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to obtain a yellow solid product 28(23.8g, 42.3mmol, 67%). MS-ESI (ESI, pos.ion) m/z: 563.21[ M + H] ⁺。

Compound 29

Compound 28(11.9g, 21.14mmol, 1 eq.) is dissolved in 180mL tetrahydrofuran and cooled to-5 ℃. Reacting NaBH₄(1.6g, 42.27mmol, 2 equiv.) was dissolved in 9mL of water, added to the above 28 solution in tetrahydrofuran and stirred at 0 ℃ overnight. After completion of the reaction, 100mL of water was added to quench the reaction, the pH was adjusted to 7 with 1N HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentratedCompound 29(11.99g, 21.14mmol, 100%) was obtained as a tan oil. MS-ESI (ESI, pos.ion) m/z: 567.25[ M ]] ⁺。

Compound 30

Compound 29(11.99g, 21.14mmol, 1 equiv.) is dissolved in 120mL of dichloromethane, triethylamine (21.40g, 211.44mmol, 10 equiv.) is added, MsCl (4.84g, 42.29mmol, 2 equiv.) is added under ice bath, and after addition, the reaction is allowed to proceed overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1-4:1) to obtain a yellow solid product 30(11.4g, 20.76mmol, 98.20%). MS-ESI (ESI, pos.ion) m/z: 549.21[ M ]] ⁺。

Compound 31

Compound 30(11.4g, 20.76mmol, 1 eq.) is added to a mixed solvent of 450mL acetonitrile and 22mL water, cooled to-5 deg.C and BiCl is added portionwise₃(32.74g, 103.81mmol, 5 equivalents), after the addition, the reaction was warmed to 50 ℃ for 1 hour. After completion of the reaction, the reaction mixture was quenched by addition of 200mL of a saturated sodium bicarbonate solution, filtered, the filtrate was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give product 31(9.32g, 20.76mmol, 99.99%) as a yellow solid. MS-ESI (ESI, pos.ion) m/z: 449.20[ M ]] ⁺。

Compound 32

Compound 31(3.6g, 8.019mmol, 1.00 eq) was dissolved in 50mL of dichloromethane, triethylamine (2.43g, 24.057mmol, 3 eq) and DMAP (1.96g, 16.044mmol, 0.10 eq) were added, cyclopropylsulfonyl chloride (2.25g, 16.038mmol, 2.0 eq) was added dropwise under ice bath and allowed to warm to room temperature for 2 hours after addition was complete. After completion of the reaction, the reaction mixture was quenched with 50mL of water, extracted with dichloromethane, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain product 32(3.7g, 6.7mmol, 83.43%) as a yellow oily substance. MS-ESI (ESI, pos.ion) m/z: 553.15[ M ]] ⁺。

Compound 33

To a reaction flask was added compound 32(3.7g, 6.690mmol, 1.00 eq.), dioxyhexa-HCl (N-hydroxyhexa-HCl)The ring solution (30mL, 4N) was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give 33(3.2g, 96.25%) as a yellow solid. MS-ESI (ESI, pos.ion) m/z: 497.15[ M ]] ⁺。

Compound 34

Compound 33(3.0g, 6.037mmol, 1.00 equiv.) was added to 180mL of a mixed solution of methanol/acetonitrile/water (1/1/1), sodium carbonate (1279.64mg, 12.073mmol, 2.00 equiv.) and sodium iodide (4524.34mg, 30.184mmol, 5.0 equiv.) were added, and oxone (1855.34mg, 3.018mmol, 0.50 equiv.) was added in portions and reacted at room temperature for 5 hours after the addition was completed. After completion of the reaction, 100mL of 10% sodium bisulfite solution was added and quenched, extracted with ethyl acetate, the organic phase was concentrated and purified by preparative chromatography to afford product 34(1.07g, 30.5%) as a yellow solid.¹H NMR (300MHz,CD3OD-d ₄)δ8.30(s,2H),7.74-7.83(m,1H),7.42(d,J＝6.9Hz,1H),7.29(t,J＝7.8Hz,1H),6.26(d,J＝10.5Hz,1H),4.69-4.79(m,1H),4.51-4.60(m,1H),4.43(s,1H),3.21-3.29(m,1H),2.95-3.05(m,1H),2.63-2.69(m,1H),1.09(d,J＝7.8Hz,4H)；MS-ESI:(ESI，pos.ion)m/z：579.10[M] ⁺。

Compound 35

Compound 34(400mg, 0.691mmol, 1.00 eq) was dissolved in 10mL dioxane, tert-butyl acrylate (310mg, 2.419mmol, 3.50 eq), Pd was added₂(dba) ₃(63.28mg 0.069mmol 0.1 equiv.), dicyclohexylmethylamine (161.17mg, 0.829mmol, 1.20 equiv.), tri-tert-butylphosphine tetrafluoroborate (40.1mg, 0.138mmol, 0.20 equiv.), and under nitrogen atmosphere, the temperature is raised to 100 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was quenched with 20mL of water, extracted with ethyl acetate, concentrated in the organic phase, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to obtain 35(400mg, 99%) as a yellow oily product.

Compound 36

Compound 35(400mg, 0.691mmol, 1.00 equiv) and 15mL of 4N HCl dioxane solution were added to a reaction flask, reacted at room temperature for 2 hours, and after the reaction was completed, the solvent was evaporated under reduced pressure to obtain crude compound 36 as yellow oil, which was directly subjected to the next reaction. MS-ESI (ESI, pos.ion) m/z:523.15[M] ⁺。

Compound 37

Compound 36(400mg, 0.765mmol, 1.00 equiv.) is added to 60mL of a mixed solution of methanol/acetonitrile/water (1/1/1), sodium carbonate (162.13mg, 1.53mmol, 2.00 equiv.) and sodium bromide (393.48mg, 3.824mmol, 5.0 equiv.) are added, and oxone (234.8mg, 0.382mmol, 0.50 equiv.) is added in portions and reacted at room temperature for 1.5 hours after the addition is completed. After completion of the reaction, it was quenched by the addition of 50mL of 10% sodium bisulfite solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by preparative chromatography to afford product 37(40mg, 10%) as a yellow solid.¹H NMR(300MHz,CD3OD-d ₄)δ8.31(s,2H),7.66-7.78(m,1H),7.35-7.41(m,1H),7.18-7.31(m,1H),6.97-7.05(m,1H),6.41-6.57(m,1H),6.31(s,1H),4.39-4.69(m,3H),3.28(s,2H),2.62-2.78(m,1H),1.10-1.22(m,4H)；MS-ESI:(ESI，pos.ion)m/z：558，560[M] ⁺。

Example 6

Compound 28a

Ethyl acetate/tetrahydrofuran (50mL/50mL) was added to compound 28 per 10g of solid, heated to 50 deg.C, and 100mL n-heptane was added, stirred for 1 hour, slowly cooled to room temperature, stirred overnight, and the solid filtered to give compound 28a (De >95, 27%).

The compounds 29a to 31a were synthesized by the same synthesis method as that for the compounds 29 to 31.

Compound 38

Compound 31a (10.3g, 22.94mmol, 1 eq) was dissolved in 100mL of dichloromethane, triethylamine (2.79g, 27.53mmol, 1.2 eq) was added, the temperature was reduced to 0 deg.C, Cbz-Cl (4.31g, 25.24mmol, 1.1 eq) was added dropwise and the mixture was stirred at 0 deg.C overnight. After completion of the reaction, the reaction mixture was quenched with 100mL of water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1-4:1) to obtain product 38(10.7g, 18.35mmol, 79.99%) as a yellow solid. MS-ESI:(ESI，pos.ion)m/z：583.21[M] ⁺。

Compound 39

Compound 38(10.7g, 18.35mmol, 1 eq) was dissolved in 100mL DCM, and 50mL trifluoroacetic acid was added with stirring and reacted at room temperature for 4 hours. After the reaction is finished, the solvent is evaporated under reduced pressure to obtain a brown oily compound 39 crude product, and the next reaction is directly carried out without purification. MS-ESI (ESI, pos.ion) m/z: 527.14[ M ]] ⁺。

Compound 40

Compound 39(9.67g, 18.35mmol, 1 equiv.) is added to a mixed solvent of 100mL methanol and 100mL acetonitrile, sodium carbonate (3.89g, 36.70mmol, 2 equiv.) and sodium iodide (13.75g, 91.75mmol, 5 eq.) and 100mL water are added, the temperature is reduced to-5 deg.C, potassium bisulfate (13.30g, 42%, 36.70mmol, 2 equiv.) is added in portions, after the addition, the temperature is raised to 40 deg.C, and the mixture is stirred overnight. After completion of the reaction, the reaction mixture was quenched with 100mL of a saturated aqueous solution of sodium hydrogensulfite, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1-4:1) to obtain product 40(8.6g, 14.12mmol, 76.97%) as a yellow solid. MS-ESI (ESI, pos.ion) m/z: 609.03[ M ]] ⁺。

Compound 41

Compound 40(8.6g, 14.12mmol, 1 eq) was dissolved in 100mL dioxane, tert-butyl acrylate (6.34g, 49.44mmol, 3.5 eq), Pd, was added₂(dba) ₃(1.29g, 1.41mmol, 0.1 eq.), P (t-Bu)₃.HBF ₄(0.82g, 2.82mmol, 0.2 equiv.) and Cy₂NMe (3.31g, 16.94mmol, 1.2 eq.) was reacted overnight at 100 ℃ under nitrogen after addition. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1-4:1) to obtain product 41(8.6g, 14.12mmol, 100%) as a yellow solid. MS-ESI (ESI, pos.ion) m/z: 609.11[ M ]]+。

Compound 42

Compound 41(8.6g, 14.12mmol, 1 eq) was dissolved in 80mL of dichloromethane, and 25mL of trifluoroacetic acid was added with stirring and reacted at room temperature for 4 hours. After the reaction is finished, the solvent is evaporated under reduced pressure to obtain a crude compound 42, and the next reaction is directly carried out without purification. MS-ESI (ESI, pos.ion) m/z: 553.16[ M ] +.

Compound 43

Compound 42(7.1g, 12.84mmol, 1 equiv.) is dissolved in 100mL of dichloromethane, triethylamine (3.9g, 38.52mmol, 3 equiv.) is added, the temperature is raised to 30 ℃, NBS (3.43g, 19.26mol, 1.5 equiv.) is added in portions, and the reaction is continued for 2 hours after the addition is completed. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain product 43(3.45g, 5.87mmol, 43.27%) as a yellow solid. MS-ESI (ESI, pos.ion) m/z: 587.13, 589.13[ M ]] ⁺。

Compound 44

Compound 43(3.45g, 5.87mmol, 1 eq) was dissolved in 70mL of dichloromethane, cooled to 0 deg.C, boron tribromide (2.94g, 11.74mmol, 2 eq) was added dropwise, and after addition was complete, the reaction was allowed to warm to room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water, separated into layers, the organic phase was extracted twice with water, the aqueous phases were combined, the pH was adjusted to 7 with a sodium hydrogencarbonate solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a brown solid product 44(2.3g, 5.87mmol, 86.37%). MS-ESI (ESI, pos.ion) m/z: 453.08, 455.08[ M ]] ⁺。

Compound 45

Compound 44(431mg, 0.95mmol) was dissolved in 5mL dioxane, and sulfuryl diamide (183mg, 1.9mmol) was added to react at 110 ℃ for 8 h. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1) to obtain compound 45(200mg, 0.37mmol, 40%) as a brown yellow solid.¹H NMR(400MHz,CDCl ₃)δ7.80(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.24–7.19(m,1H),7.19–7.13(m,1H),6.98–6.92(m,1H),6.74(d,J＝13.6Hz,1H),6.01(s,1H),5.78(d,J＝ 13.6Hz,1H),5.55(d,J＝6.9Hz,1H),5.23(s,2H),4.57–4.40(m,2H),4.36–4.22(m,1H),3.20(dd,J＝16.3,6.9Hz,1H),2.87(dd,J＝16.3,6.6Hz,1H)；MS-ESI:(ESI，pos.ion)m/z：532.0,534.0。

Example 7

Compound 46

Compound 44(200mg, 440.76umol, 1 eq) was dissolved in 4mL DCM, triethylamine (133.81mg, 1.32mmol, 3 eq) was added, the temperature was reduced to-10 deg.C and 77(85.66mg, 661.14umol, 1.5 eq) was added and stirred at this temperature for 1 h. After the reaction was completed, the reaction solution was quenched with water, adjusted to pH 6-7 with 1N HCl, extracted with dichloromethane, the organic phase was concentrated, purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1-4:1), and the resulting crude product was recrystallized from ethyl acetate/N-hexane solvent system (2mL/10mL) to give 46(100mg, 182.86umol, 41.49%) as a yellow solid.¹H NMR(400MHz,CDCl ₃)δ7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.32–7.29(m,1H),7.17(dd,J＝8.5,2.5Hz,1H),7.04–6.95(m,1H),6.77(d,J＝13.7Hz,1H),6.05(s,1H),5.80(d,J＝13.7Hz,1H),4.64–4.52(m,2H),4.47(dd,J＝12.3,5.3Hz,1H),4.24(s,1H),3.22–3.13(m,3H),2.78(d,J＝4.4Hz,3H)；MS-ESI:(ESI，pos.ion)m/z：546.0，548.0[M+1] ⁺。

Using a similar synthetic approach, compounds 47-52 were prepared:

¹H NMR(400MHz,CDCl ₃)δ7.84(d,J＝2.7Hz,1H),7.43(s,1H),7.28–7.25(m,1H),7.24–7.13(m,1H),7.02–6.87(m,1H),6.77(d,J＝13.7Hz,1H),6.07(s,1H),5.85(d,J＝13.7Hz,1H),4.58–4.47(m,2H),4.25(s,1H),3.76–3.71(m,1H),3.12–2.99(m,2H),2.87(s,6H)；MS-ESI:(ESI，pos.ion)m/z：560.1,562.1。

¹H NMR(400MHz,CDCl ₃)δ7.84(d,J＝3.1Hz,1H),7.43(d,J＝3.1Hz,1H),7.26–7.20(m,1H),7.19–7.14(m,1H),6.99–6.93(m,1H),6.76(d,J＝13.8Hz,1H),6.05(s,1H),5.83(d,J＝13.8 Hz,1H),5.12(d,J＝7.0Hz,1H),4.66–4.52(m,1H),4.47–4.38(m,1H),4.24–4.15(m,1H),3.80–3.74(m,4H),3.27–3.23(m,4H),3.21–3.17(m,1H),2.94–2.84(m,1H)；MS-ESI:(ESI，pos.ion)m/z：602.1,604.1。

¹H NMR(400MHz,CDCl ₃)δ7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.27–7.21(m,1H),7.18(dd,J＝8.5,2.6Hz,1H),7.04–6.94(m,1H),6.77(d,J＝13.8Hz,1H),6.06(s,1H),5.81(d,J＝13.7Hz,1H),4.73(d,J＝6.2Hz,1H),4.51(d,J＝3.4Hz,2H),4.29(d,J＝3.3Hz,1H),3.87(t,J＝5.4Hz,2H),3.41–3.32(m,5H),3.11–2.97(m,2H)；MS-ESI:(ESI，pos.ion)m/z：575.1,577.1。

¹H NMR(400MHz,CDCl ₃)δ7.87(s,1H),7.52(s,1H),7.41(s,1H),7.15(dd,J＝8.4,2.6Hz,1H),7.01(d,J＝6.7Hz,1H),6.74(d,J＝13.8Hz,1H),6.10(s,1H),6.00–5.88(m,1H),4.71–4.60(m,1H),4.59–4.50(m,1H),4.43(s,1H),4.15(s,2H),3.81(s,3H),3.73–3.71(m,1H),3.09(s,2H)；MS-ESI:(ESI，pos.ion)m/z：589.1,591.1。

¹H NMR(400MHz,DMSO)δ8.07(s,1H),7.94(d,J＝3.2Hz,1H),7.83(d,J＝3.2Hz,1H),7.55(dd,J＝8.7,6.3Hz,1H),7.45(dd,J＝8.8,2.6Hz,1H),7.20–7.11(m,1H),6.87(d,J＝13.7Hz,1H),5.91(s,1H),5.68(d,J＝13.7Hz,1H),4.42–4.32(m,2H),4.27–4.17(m,3H),3.18–3.06(m,2H),2.99–2.89(m,1H)；MS-ESI:(ESI，pos.ion)m/z：575.1,577.1。

¹H NMR(400MHz,DMSO)δ12.99(s,1H),7.94(d,J＝3.2Hz,1H),7.83(d,J＝3.2Hz,1H),7.46(dd,J＝8.8,2.6Hz,1H),7.38(dd,J＝8.7,6.3Hz,1H),7.17–7.05(m,1H),6.88(d,J＝13.7Hz,1H),5.91(s,1H),5.68(d,J＝13.7Hz,1H),4.71–4.63(m,1H),4.61–4.52(m,1H),4.33(dd,J＝11.8,4.6Hz,1H),4.05(d,J＝2.7Hz,2H),3.31–3.21(m,1H),3.13(s,3H),3.07–2.99(m,1H)；MS-ESI:(ESI，pos.ion)m/z：589.1,590.1。

example 8: in vitro anti-HBV Activity assay

The experimental method comprises the following steps:

HepG2.2.15 cells were seeded in 96-well microplates at a density of 3X 10 in 0.1mL of medium per well⁴Cells, multi-well plates were incubated at 37 ℃ overnight. The next day test compounds were serially diluted in DMSO to different concentrations, and then 100 μ L of decreasing compound DMSO solution was added to the wells on the plate to give a final DMSO concentration of 0.5% per well. Five days after compound exposure, culture supernatants were collected for further analysis. For extracellular HBV DNA quantitative detection by PCR, 100. mu.L of culture supernatant was collected and extracted in the Magna Pure 96 nucleic acid purification system. The extracted samples were quantified for HBV DNA by qPCR and the concentration of the compound (EC) at which 50% of HBV replication was inhibited was determined₅₀)。

The experimental results are as follows:

the compounds of the present invention were tested for their ability to inhibit HBV replication in vitro according to the above method and the results are shown in the following table:

compound (I)	EC ₅₀(μM)	Compound (I)	EC ₅₀(μM)	Compound (I)	EC ₅₀(μM)
11a	A	11b	A	11c	A
20	A	22	A	23a	A
23b	A	23c	A	24	C
37	A	45	A	46	A
47	A	48	B	49	B
50	C	51	A	52	A

A:EC ₅₀≤0.1μM；B:0.1μM<EC ₅₀≤1μM；C:1μM<EC ₅₀≤10μM；D:EC ₅₀>10μM

Conclusion of the experiment

Preliminary in vitro activity experiments confirmed that most of the compounds of the invention had EC₅₀Less than 0.1. mu.M, showing that the compound of the present invention has a strong anti-HBV replication activity. The compounds have unexpected antiviral activity and can be used for treating diseases caused by HBV infection.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims

A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:

wherein:

ring A is selected from 3-11 membered heterocyclyl or 5-10 membered heteroaryl;

R ₁selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、C _1-6Alkyl or C_1-6A haloalkyl group;

L ₁selected from the group consisting of a chemical bond, -CR' ═ CR "-or-C ≡ C-; wherein R 'and R' are independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

R ₂selected from H, halogen, -CN, -NO₂、-C(O)R _a、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R ₃is selected from C_6-10Aryl or 5-10 membered heteroaryl;

R ₄selected from hydrogen, halogen, -CN, C_1-6Alkyl or C_1-6A haloalkyl group;

L ₂is selected from- (C)_0-6Alkylene) -, - (C)_0-6Alkylene) -O-, - (C_0-6Alkylene) -NR_b-、-(C _0-6Alkylene) - (C) (O) -, - (C)_0-6Alkylene) -C (O) O-, - (C)_0-6Alkylene) -C (O) NR_b-、-(C _0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -S (O)_p-、-(C _0-6Alkylene) -S (O)_pO-、-(C _0-6Alkylene) -S (O)_pNR _b-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c)-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-O-、-C _2-8Alkenylene radical-, -C_2-8Alkynylene-, -C_3-7Cycloalkylene-, 4-8 membered heterocyclylene, C_6-10Arylene or 5-10 membered heteroarylene;

R ₅is selected from- (C)_0-6Alkylene) -OR_a、-(C _0-6Alkylene) -NR_bR _c、-(C _0-6Alkylene) -C (O) R_a、-(C _0-6Alkylene) -C (O) OR_aOr- (C)_0-6Alkylene) -C (O) NR_bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-11Cycloalkyl, 3-15 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

and R is₂、R ₃And R₅Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R _a、R _b、R _cindependently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, - (C)_0-6Alkylene) -OR, - (C)_0-6Alkylene) -NR R, - (C)_0-6Alkylene) -C (O) R, - (C)_0-6Alkylene) -C (O) OR OR- (C)_0-6Alkylene) -c (o) NR R; or R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

r, R and R are independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; or R, R and the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2;

with the proviso that when L₁When it is a chemical bond, R₂Selected from H, halogen, -CN, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.
A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:

wherein:

ring A is selected from 3-11 membered heterocyclyl or 5-10 membered heteroaryl;

R ₁selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、C _1-6Alkyl or C_1-6A haloalkyl group;

L ₁selected from the group consisting of a chemical bond, -CR' ═ CR "-or-C ≡ C-; wherein R 'and R' are independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl;

R ₂selected from H, halogen, -CN, -NO₂、-C(O)R _a、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R ₃is selected from C_6-10Aryl or 5-10 membered heteroaryl;

R ₄selected from hydrogen, halogen, -CN, C_1-6Alkyl or C_1-6A haloalkyl group;

L ₂is selected from- (C)_0-6Alkylene) -, - (C)_0-6Alkylene) -O-, - (C_0-6Alkylene) -NR_b-、-(C _0-6Alkylene) - (C) (O) -, - (C)_0-6Alkylene) -C (O) O-, - (C)_0-6Alkylene) -C (O) NR_b-、-(C _0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -S (O)_p-、-(C _0-6Alkylene) -S (O)_pO-、-(C _0-6Alkylene) -S (O)_pNR _b-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-、-C _2-8Alkenylene radical-, -C_2-8Alkynylene-, -C_3-7Cycloalkylene-, 3-7 membered heterocyclylene, C_6-10Arylene or 5-10 membered heteroarylene;

R ₅is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

and R is₂、R ₃And R₅Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _a、-NR _bR _c、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R _a、R _b、R _cindependently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

m is 0, 1, 2, 3, 4 or 5;

p is 0, 1 or 2;

with the proviso that when L₁When it is a chemical bond, R₂Selected from H, halogen, -CN, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C _2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and a mixture thereof,

ring A is

Wherein X, Y, Z, which may be the same or different, are each independently selected from C, N, O or S atoms, and their oxidized forms (e.g., C (O), SO, and SO)₂) (ii) a Wherein two ortho-positions X, Y or Z may together form an optionally substituted-C ═ C-double bond, -C ═ N-double bond, or fused ring; or X, Y and the two substituents on Z may be linked to form a bridged ring structure; or X, Y or Z is a carbon atom, two substituents on the same carbon atom may be linked to form a ring structure;

n is 0, 1, 2 or 3;

preferably, the first and second electrodes are formed of a metal,
the structural unit is selected from the following structures:
a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein R is₁Selected from H, halogen, -CN, AA group, trifluoromethyl or difluoromethyl; preferably, R₁Selected from H, F, Cl, Br, -CN or CH₃(ii) a Preferably, R₁Selected from H, F, Cl or Br.
The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein L is₁Is selected from-CR' ═ CR ≡ C —; wherein R 'and R' are independently selected from H, halogen, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, L₁Is selected from-CR' ═ CR ≡ C —; wherein R 'and R' are independently selected from H or halogen.
The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein R is₂Selected from H, halogen, -CN, -C (O) OR_a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10An aryl group; preferably, R₂Selected from H, halogen, -C (O) OR_a、C _1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10And (4) an aryl group.
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and a mixture thereof,

-L ₁-R ₂selected from H, halogen, -CN, -NO₂、-C(O)R _a、-C(O)OR _a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, -CH ═ CH-halogen, -CH ═ CH-c (o) OR_a、-CH＝CH-C(O)NR _bR _c、-C≡C-H、-C≡C-CN、-C≡C-C _1-6Alkyl, -C ≡ C-C_1-6Haloalkyl, -C ≡ C-C_2-8Alkenyl, -C ≡ C (O) NR_bR _c、-C≡C-C(O)OR _a、-C≡C-C _3-7Cycloalkyl or-C ≡ C-C_6-10An aryl group;

preferably, -L₁-R ₂Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, -CH ═ CH-halogen, -CH ═ CH-c (o) OR_a、-CH＝CH-C(O)NR _bR _c、-C≡C-H、-C≡C-C _3-7Cycloalkyl or-C ≡ C-C_6-10And (4) an aryl group.
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and a mixture thereof,

R ₃is a 5-6 membered heteroaryl; preferably, R₃Is a 5-6 membered heteroaryl group containing a N atom; preferably, R₃Is an oxazolyl group (e.g., pyrrolyl, thiazolyl, imidazolyl, oxazolyl), oxadiazolyl (e.g., thiadiazole, oxadiazole), triazolyl, or pyridyl group; preferably, R₃Is thiazol-2-yl.
The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof, wherein R is₄Is H or methyl; preferably, R₄Is H and R₄The carbon atom is in R configuration.
The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof,

L ₂is selected from- (C)_0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-or- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c)-；

Preferably, the first and second electrodes are formed of a metal,

L ₂selected from the group consisting of-O-C (O) -, -O-C (O) O-, -O-C (O) NR_b-、-N(R _b)-C(O)-、-N(R _b)-C(O)O-、-N(R _b)-C(O)NR _c-、-O-S(O) _p-、-N(R _b)-S(O) _p-or-N (R)_b)-S(O) _p-N(R _c)-；

Preferably, the first and second electrodes are formed of a metal,

L ₂is selected from-N (R)_b)-C(O)-、-N(R _b)-C(O)O-、-N(R _b)-S(O) ₂-or-N (R)_b)-S(O) _p-N(R _c)-。
The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof,

R ₅is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

preferably, the first and second electrodes are formed of a metal,

R ₅is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having a structure of formula (I-1), (I-2), (I-3) or (I-4):

wherein,

R ₁' and R₁"is halogen or methyl;

L ₁is selected from-CH ═ CH-or-C ≡ C-;

R ₂selected from H, halogen, -CN, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10An aryl group;

L ₂is selected from- (C) _0-6Alkylene) -O-C (O) -, - (C)_0-6Alkylene) -O-C (O) O-, - (C)_0-6Alkylene) -O-C (O) NR_b-、-(C _0-6Alkylene) -N (R)_b)-C(O)-、-(C _0-6Alkylene) -N (R)_b)-C(O)O-、-(C _0-6Alkylene) -N (R)_b)-C(O)NR _c-、-(C _0-6Alkylene) -O-S (O)_p-、-(C _0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c) -or- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-；

R ₅Is selected from-NR_bR _c、-(C _0-6Alkylene) -OR_a、-(C _0-6Alkylene) -NR_bR _c、-(C _0-6Alkylene) -C (O) R_a、-(C _0-6Alkylene) -C (O) OR_a、-(C _0-6Alkylene) -C (O) NR_bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group;

R _a、R _b、R _cindependently selected from H, - (C)_0-6Alkylene) -OH, - (C)_0-6Alkylene) -NH₂、-(C _0-6Alkylene) -C (O) H, - (C)_0-6Alkylene) -C (O) OH, - (C)_0-6Alkylene) -C (O) NH₂、C _1-6Alkyl or C_1-6A haloalkyl group; or R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

p is 0, 1 or 2.
A compound of general formula (I-1), (I-2), (I-3) or (I-4) according to claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein:

R ₁' is F, and R₁"is Cl or Br;

L ₁is selected from-CH ═ CH-or-C ≡ C-;

R ₂selected from H, halogen, -CN, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or C_6-10An aryl group;

L ₂is selected from-N (R)_b)-C(O)-、-N(R _b)-C(O)O-、-N(R _b)-C(O)NR _c-、-O-S(O) ₂-、-N(R _b)-S(O) ₂-or- (C)_0-6Alkylene) -N (R)_b)-S(O) _p-N(R _c)-；

R ₅Is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group;

R _a、R _b、R _cindependently selected from H, - (C)_0-6Alkylene) -C (O) OH, C_1-6Alkyl or C_1-6A haloalkyl group;

p is 0, 1 or 2.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having a structure of general formula (II-1), (II-2) or (II-3):

wherein,

R ₁、R ₁' and R₁"is H, halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂、R ₃、R ₅、L ₂x, Y, Z, m and n are as defined in any one of claims 1 to 11.
The compound according to claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, having the general formula (II-4):

wherein,

R ₁' and R₁"is halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂selected from H, halogen, -CN, -NO₂、C _1-6Alkyl or C_1-6A haloalkyl group; preferably, R₂Selected from H, halogen or C_1-6A haloalkyl group; preferably, R₂Selected from CHF₂Or CF₃；

R ₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having the general formula (III-1), (III-2), (III-3), (III-4), (III-5) or (III-6):

wherein,

R ₁、R ₁' and R₁"is H, halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂、R ₃、R ₅、L ₂x, Y, Z, R', R ", m and n are as defined in any one of claims 1 to 10.
The compound according to claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, having the general formula (III-7), (III-8), (III-9), (III-10), (III-11) or (III-12):

wherein,

R ₁' and R₁"is halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂selected from H, halogen, -CN, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₂Selected from halogen, -C (O) OR_a、C _1-6Alkyl or C_1-6A haloalkyl group;

R ₅is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₅Is selected from-NR_bR _c、-(C _0-6Alkylene) -C (O) OH, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

R _a、R _b、R _cindependently selected from H, - (C)_0-6Alkylene) -OH, - (C)_0-6Alkylene) -NH₂、-(C _0-6Alkylene) -C (O) H, - (C)_0-6Alkylene) -C (O) OH, - (C)_0-6Alkylene) -C (O) NH₂、C _1-6Alkyl or C_1-6A haloalkyl group; or R_b、R _cAnd the N atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl.
A compound of general formula (III-7), (III-8), (III-9), (III-10), (III-11) or (III-12) according to claim 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, wherein:

R ₁' and R₁"is halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂selected from H, halogen, -CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl OR-C (O) OR_a(ii) a Preferably, R₂Selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl OR-C (O) OR_a；

R ₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl; preferably, R₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl;

R _aindependently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof, and mixtures thereof, having the general formula (IV-1), (IV-2) or (IV-3):

wherein,

R ₁、R ₁' and R₁"is H, halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂、R ₅、L ₂x, Y, Z, m and n are as defined in any one of claims 1 to 11.
The compound according to claim 19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, having the general formula (IV-4), (IV-5) or (IV-6):

wherein,

R ₁' and R₁"is halogen or methyl; preferably, R₁' is F, and R₁"is Cl or Br;

R ₂selected from H, -C (O) OR_a、-C(O)NR _bR _c、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl; and R is₂Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _aor-NR_bR _c；

Preferably, R₂Selected from H, -C (O) OR_a、C _1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl or C_6-10An aryl group; and R is₂Optionally substituted with 1, 2 or 3R groups, wherein R is independently selected from H, halogen, -CN, -NO₂、-OR _aor-NR_bR _c；

Preferably, R₂Selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-8 membered heterocyclyl or C_6-10An aryl group; and R is₂Optionally substituted with 1, 2 OR 3R groups, wherein R is independently selected from halogen, -OR_aor-NR_bR _c；

R _a、R _bAnd R_cIndependently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

R ₅is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl, 4-8 membered heterocyclyl; preferably, R₅Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 4-8 membered heterocyclyl.
A compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, wherein the compound is selected from the group consisting of:
a pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and a pharmaceutically acceptable excipient; preferably, the pharmaceutical composition further comprises an additional therapeutic agent.
Kit of parts comprising

A first container comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof; and optionally, a second container containing an additional therapeutic agent; and optionally, a third container containing pharmaceutically acceptable excipients for diluting or suspending the compound and/or other therapeutic agent.
Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of viral infections, in particular hepatitis b viral infections.
A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition according to claim 22, for use in the treatment and/or prophylaxis of viral infections, in particular hepatitis b viral infections.
A method of treating and/or preventing a viral infection, in particular a hepatitis b viral infection, in a subject, the method comprising administering to the subject a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of claim 22.