CN112469716B - Dihydropyrimidine derivatives and uses thereof - Google Patents

Abstract

The present invention relates to dihydropyrimidine derivatives of general formula (I) which are useful for the treatment and prevention of hepatitis B virus infection. The invention also relates to pharmaceutical compositions containing compounds of formula (I) and their use for the treatment and prevention of hepatitis B virus infection.

Description

Dihydropyrimidine derivatives and uses thereof

Field of the Invention

The present invention belongs to the field of virus prevention and treatment. Specifically, the present invention relates to a series of dihydropyrimidine derivatives, pharmaceutical compositions containing the derivatives and their uses, especially for treating or preventing viral diseases, such as hepatitis B. More specifically, the present invention relates to dihydropyrimidine derivatives that can inhibit the function of hepatitis B virus (HBV) capsid protein and thus treat or prevent hepatitis B, pharmaceutical compositions containing the derivatives and their uses for treating or preventing hepatitis B.

Background technique

Hepatitis B virus infection is a major public health problem, affecting approximately 2 billion people worldwide. Of these, approximately 350 million people develop chronic infection, which can lead to chronic persistent hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Between 500,000 and 1 million people die each year from end-stage liver disease caused by hepatitis B virus infection.

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

Currently, hepatitis B cannot be cured, and there are only two types of drugs, interferon and nucleoside analogs, which have disadvantages such as drug resistance, low efficiency and poor tolerance. Therefore, there is still a need to develop drugs for treating and preventing hepatitis B in this field.

Summary of the invention

In view of the importance of Cp protein in the life cycle of HBV, the inventors have designed a series of dihydropyrimidine derivatives based on its structural characteristics, which are used to interfere with the formation of the viral capsid by changing the Cp conformation or the Cp assembly rate, thereby producing an antiviral effect.

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

in:

L is selected from a chemical bond, -CR'=CR"- or -C≡C-; wherein R' and R" are independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl or 3-7 membered heterocyclyl;

X is selected from a chemical bond, CR _b R _c , NR _a , O or S(O) _q ;

R ₁ is selected from H, halogen, -CN, -NO ₂ , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl; and R ₁ is optionally substituted with 1 , 2, or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ₂ and R ₂ 'are independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or, R ₂ and R ₂ 'may form oxo or thio;

R ₃ and R ₃ 'are independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or, R ₃ and R ₃ 'may form oxo or thio;

_R4 and _R4 ' are independently selected from H, halogen, -CN, _-NO2 , -( _C0-6 alkylene) _-ORd , -( _C0-6 alkylene) _{-NReRf ,} -( _C0-6 alkylene)-C(O) _Rd , -( _C0-6 alkylene)-C(O) _ORd , -( _C0-6 alkylene)-C(O) _{NReRf ,} -( _C0-6 alkylene)-OC(O) _Rd , -( _C0-6 alkylene)-N( _Re )-C(O) _Rd , -( _C0-6 alkylene)-S(O) _pRd , -( _C0-6 alkylene) _-S (O) _{pORd ,} -( _C0-6 alkylene)-S(O) _{pNReRf ,} -(C0-6 alkylene ₎ - _{R4 and R4 ' may} form _{an oxo or thio group ;}

Alternatively, R ₂ and R ₃ combine to form a double bond, a C _3-7 carbocyclic group, a 3-7 membered heterocyclic group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group;

Alternatively, when X is CR _b R _c or NR _a , R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a double bond, a C _3-7 carbocyclic group, a 3-7 membered heterocyclic group, a C _6-10 aryl group or a 5-10 membered heteroaryl group;

_R5 is selected from H, halogen, -CN, _-NO2 , -(Co _-6 alkylene) _-ORd , -(Co _-6 alkylene) _-NReRf , -(Co _-6 alkylene)-C(O) _{Rd ,} -(Co _-6 alkylene)-C(O) _ORd , -(Co _-6 alkylene) _-C (O) _NReRf , -(Co _-6 alkylene)-OC(O) _Rd , -(Co _-6 alkylene)-N( _Re )-C(O) _Rd , -(Co _-6 alkylene)-S(O) _{pRd ,} -(Co _-6 alkylene) _-S (O) _{pORd ,} -(Co- ₆ alkylene) _-S (O) _{pNReRf ,} -(Co _-6 alkylene)-OS(O) _pRd , -(C _0-6 alkylene)-N(R _e )-S(O) _p R _d , C _1-6 alkyl or C _1-6 haloalkyl;

_R6 and _R7 are independently selected from H, halogen, -CN, _C1-6 alkyl or _C1-6 haloalkyl;

_Ra , _Rb , _Rc , _Rd , _Re and _Rf are independently selected from H, _C1-6 alkyl or _C1-6 haloalkyl;

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

n = 0, 1 or 2;

p = 1 or 2;

q=0, 1 or 2.

In another aspect, the present invention provides compounds of the above general formula (I), wherein the proviso is that when L is a chemical bond, R ₁ is selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl.

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

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, which may also contain another therapeutic agent.

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

In another aspect, the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating and/or preventing viral infection, especially hepatitis B virus infection.

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

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

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

Chemical Definition

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

When a numerical range is listed, each value and subrange within the stated range is intended to be included. For example, "C _1-6 alkyl" includes C ₁ , 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 _4-5 , and C _5-6 alkyl.

"C _1-6 alkyl" refers to a linear or branched saturated monovalent alkane (hydrocarbon) group containing 1 to 6 carbon atoms. In some embodiments, C _1-4 alkyl is preferred. Typical C _1-6 alkyls include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, etc. The alkyl group can be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

" _C2-8 alkenyl" means a straight or branched hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-butene-1-yl, 2-vinylbutyl, 3-hexene-1-yl, etc. In some embodiments, _C2-6 alkenyl is preferred. In some embodiments, _C2-4 alkenyl is particularly preferred. The term " _C2-8 alkenyl" includes cycloalkenyl and heteroalkenyl, wherein 1 to 3 nitrogen atoms selected from O, S, N or substitution can replace carbon atoms. The alkenyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

" _C2-8 alkynyl" refers to a straight or branched hydrocarbon group having 2 to 8 carbon atoms, wherein there are one or more unsaturated carbon-carbon double bonds, wherein there is at least one carbon-carbon triple bond. In some embodiments, _C2-6 alkynyl is preferred. In some embodiments, _C2-4 alkynyl is particularly preferred. Typical alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl and hexynyl. The alkynyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

"C _1-6 alkylene" refers to a divalent alkylene group formed by removing one hydrogen of a C _1-6 alkyl group, and may be substituted or unsubstituted alkylene. In some embodiments, C _1-4 alkylene is particularly preferred. The unsubstituted alkylene group includes, but is not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH _{2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 - ) ,} hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH _{2 CH 2} -), and the like. Exemplary substituted alkylene groups, for example, substituted alkylene groups with one or more alkyl(methyl) groups, include, but are not limited to, substituted methylene groups (—CH(CH ₃ )—, —C(CH ₃ ) ₂ —), substituted ethylene groups (—CH(CH ₃ )CH ₂ —, —CH ₂ CH(CH ₃ )—, —C(CH ₃ ) ₂ CH ₂ —, —CH ₂ C(CH ₃ ) _{2 —} ), substituted propylene groups (—CH(CH ₃ )CH ₂ CH ₂ —, —CH ₂ CH(CH ₃ )CH ₂ —, —CH ₂ CH ₂ CH(CH ₃ )—, —C(CH ₃ ) ₂ CH ₂ CH ₂ —, —CH ₂ C(CH ₃ ) ₂ CH ₂ —, —CH ₂ CH ₂ C(CH ₃ ) ₂ —), and the like.

The “C _0-6 alkylene group” means the C _1-6 alkylene group described above and a chemical bond (C ₀ alkylene group).

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

"Oxo" means =0.

"Thio" means =S.

"C _1-6 haloalkyl" means the above-mentioned "C _1-6 alkyl" which is substituted by one or more halogen groups. Examples include monohalogen substitution, dihalogen substitution and polyhalogen substitution including perhalogenation. A monohalogen substituent may have one 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 atoms or a combination of different halogens. Preferred examples of haloalkyl include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The haloalkyl group may be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

" _C3-7 carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, _C3-6 carbocyclyl is preferred, more preferably _C5-6 carbocyclyl. Carbocyclyl also includes ring systems in which the above carbocyclyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the carbocyclyl system. Exemplary carbocyclyls include, but are not limited to, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclopentadienyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), etc. The carbocyclyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"3-7 membered heterocyclyl" refers to a group of a 3-7 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. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. In some embodiments, a 3-6 membered heterocyclyl is preferably a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; and a 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more carbocyclyls, wherein the point of attachment is on the carbocyclyl ring, or a ring system in which the above-mentioned 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 a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to: aziridine, oxirane, thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to: azetidine, oxirane and thiorenyl. Exemplary 5-membered heterocyclyls 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, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thianyl. Exemplary 5-membered heterocyclyls fused to a _C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyls fused to a _C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are 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.

"C _6-10 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl has six ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more carbocyclic or heterocyclic 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 can be substituted at any available point of attachment, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more carbocyclic or heterocyclic 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 is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system 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, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. 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, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Specific examples of preferred heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furanyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl). The heteroaryl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, etc., as defined herein, are optionally substituted groups, whether or not preceded by the term "optionally substituted", which means that at least one hydrogen present on the group (e.g., carbon or nitrogen atom) is replaced by a permissible substituent, for example, a substituent that produces a stable compound upon substitution, for example, a compound that does not spontaneously undergo a transformation (e.g., by rearrangement, cyclization, elimination or other reactions). 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 an organic compound (any substituent described herein that results in the formation of a stable compound). For the present invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituents described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety.

Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, _-NO2 , _-N3 , _-SO2H , _-SO3H , -OH, ^-ORaa , -ON( ^Rbb ) ₂ , -N( ^Rbb ) ₂ , -N( ^Rbb ) ₃ ^{+ X-} , -N( ^ORcc ) ^Rbb , -SH, ^-SRaa , ^-SSRcc , -C(=O ₎ ^Raa , _-CO2H , -CHO, -C( ^ORcc ) ₂ , ^-CO2Raa , -OC(=O)Raa ^{, -OCO2Raa} , _{-C(=O)N(Rbb)2, -OC(=O)N(Rbb)2} ^, _-NRbbC ⁽ ₌ ^{O ) Raa} _, ^-NRbbCO2Raa , ^-NRbb -C(＝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 ^bb C(＝NR ^bb )N(R ^bb ) ₂ , -C(＝O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(＝O)R ^aa , -OS(＝O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R -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) ₂ R ^aa , -OP(＝O) ₂ R ^aa , -P(＝O)(R ^aa ) ₂ , -OP(＝O)(R ^aa ) ₂ , -OP(＝O)(OR ^cc ) ₂ , -P(＝O) ₂ N(R ^bb ) ₂ , -OP(＝O) ₂ N(R ^bb ) ₂ , -P(＝O)(NR ^bb ) ₂ , -OP(＝O)(NR ^bb ) ₂ , -NR ^bb P(＝O)( ^ORcc ) ₂ , -NRbbP(＝O)(NRbb) ₂ , -P( ^Rcc ) ₂ , -P( ^{Rcc )} ₃ , -OP _{(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2} ^{, -BRaa (} _ORcc ⁾ _, ^alkyl _, ^{haloalkyl ,} alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 ^Rdd groups;

or two geminal hydrogens on a carbon atom are replaced by groups =0, =S, =NN( ^Rbb ) ₂ , = ^NNRbbC (=O) ^Raa , =NNRbbC(=O) ^{ORaa ,} = ^NNRbbS (=O) _2Raa , = ^NRbb or ^{= NORcc} ;

each of ^Raa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Ra groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 ^Rdd groups;

Each of R ^bb is independently selected from the group consisting of hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(═O)R ^aa , -C(═O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(═NR ^cc )OR ^aa , -C(═NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(═S)N(R ^cc ) ₂ , -C(═O)SR ^cc , -C(═S)SR ^cc , -P(═O) ₂ R ^aa , -P(═O)(R ^aa ) ₂ , -P(═O) ₂ N(R ^cc ) ₂ , -P(=O)( ^NRcc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two ^Rbb groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 ^Rdd groups;

each of R ^cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^cc groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each of R ^dd is independently selected from the group consisting of halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -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 ₂ H , -CO ₂ R ^ee , -OC(＝O)R ^ee , -OCO ₂ R ^ee , -C(＝O)N(R ^ff ) ₂ , -OC(＝O)N(R ^ff ) ₂ , -NR ^ff C(＝O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(＝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 ^ff C(＝NR ^ff )N(R ^ff ) ₂ 、-NR ^ff SO ₂ R ^ee 、-SO ₂ N(R ^ff ) ₂ 、-SO ₂ R ^ee 、-SO ₂ OR ^ee 、-OSO ₂ R ^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) ₂ R ^ee , -P(＝O)(R ^ee ) ₂ , -OP(＝O)(R ^ee ) ₂ , -OP(＝O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal R ^dd substituents may combine to form ＝O or ＝S;

Each of R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

each of ^Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two ^Rff groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 ^Rgg groups;

Each of R ^gg is independently: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(＝O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(＝O)(C 1-6 alkyl), -OCO ₂ (C _1-6 alkyl) -C(＝NH) ₂ , -C(＝O)NH2, -C(＝O)N(C _1-6 alkyl) ₂ , -OC(＝O)NH(C _1-6 alkyl), -NHC(＝O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(＝O)(C _1-6 alkyl), _-NHCO2 (C _1-6 alkyl), -NHC(＝O)N(C _1-6 alkyl) ₂ , -NHC(＝O)NH(C _1-6 alkyl), -NHC(＝O) _NH2 , -C(＝NH)O(C _1-6 alkyl), -OC(＝NH)(C _1-6 alkyl), -OC(＝NH)OC _1-6 alkyl, -C(＝NH)N(C _1-6 alkyl) ₂ , -C(＝NH)NH(C _1-6 alkyl), -C(＝NH) _NH2 , -OC(＝NH)N(C _1-6 alkyl) -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC ₍ NH)N(C _1-6 alkyl) ₂ , -NHC(═NH)NH ₂ , -NHSO _{2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl ) , -SO 2 NH 2} , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(═S)N(C _1-6 alkyl) ₂ , C(═S)NH(C _1-6 alkyl), C(═S)NH ₂ , -C(═O)S(C 1-6 _alkyl ) -C _1-6 alkyl), -C(＝S)SC _1-6 alkyl, -SC(＝S)SC _1-6 alkyl, -P(＝O) ₂ (C _1-6 alkyl), -P(＝O)(C _1-6 alkyl) ₂ , -OP(＝O)(C _1-6 alkyl) ₂ , -OP(＝O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two geminal R ^gg substituents may combine to form ＝O or ＝S; wherein X ^- is a counter ion.

Exemplary substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, ^-ORaa , -N( ^Rcc ) ₂ , -CN, -C(=O ₎ ^Raa , -C(=O) _N ( ^Rcc ) ₂ ^{, -CO2Raa} , -SO2Raa, -C(= ^NRbb ) ^Raa , ^-C (=NRcc) ^ORaa , -C(= ^NRcc )N( ^Rcc ) ₂ , -SO2N _{(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2} ^, _-C ⁽ ₌ ^{O ) SRcc} _{, -C} ⁽ =S) ^SRcc , -P(=O) ^2Raa , -P(=O)( ^Raa ) _{2 ,} -P(=O) ₂ N( ^Rcc ) ₂ , -P(=O)( ^NRcc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two ^Rcc groups attached to the nitrogen atom combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 ^Rdd groups, and wherein ^Raa , ^Rbb , ^Rcc and ^Rdd are as described above.

Other definitions

The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, the latter being as just defined.

The term "pharmaceutically acceptable salt" as used herein refers to those carboxylates, amino acid addition salts of the compounds of the present invention which are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

The term "salt" refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of the invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid and isolating the resulting salt. As long as the compounds of the invention are basic compounds, they are capable of forming a variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often necessary to first separate the pharmaceutically unacceptable salt of the base compound from the reaction mixture and then simply convert it to the free base compound by treatment with an alkaline agent, after which the free base is converted to a pharmaceutically acceptable acid addition salt. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form the salt. The free base can be regenerated by contacting the salt form with a base in a conventional manner and isolating the free base. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

Base addition salts of acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but for purposes of the present invention, the salts are equivalent to their respective free acids.

Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate and isethionate, etc. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as argininate, gluconate, galacturonate, and the like (see, e.g., Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include _C1 - _C6 alkyl esters, wherein the alkyl group is linear or branched. Acceptable esters also include _C5 - _C7 cycloalkyl esters and aryl alkyl esters, such as but not limited to benzyl esters. _C1 - _C4 alkyl esters are preferred. Esters of the compounds of the present invention can be prepared according to conventional methods, for example: March's Advanced Organic Chemistry, 5 Edition "MB Smith & J. March, John Wiley & Sons, 2001.

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include amides derived from ammonia, primary C ₁ -C ₆ alkylamines and secondary C ₁ -C ₆ dialkylamines, wherein the alkyl group is linear or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom. Amides derived from ammonia, C ₁ -C ₃ alkyl primary amines and C ₁ -C ₂ dialkyl secondary amines are preferred. Amides of the compounds of the present invention can be prepared according to conventional methods, for example: March's Advanced Organic Chemistry, 5 Edition", MB Smith & J. March, John Wiley & Sons, 2001.

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

"Subjects" for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. 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, and unless otherwise indicated, the terms "treatment," "treating," "treating," "treating," and "treatment" include actions that occur while a subject has a particular disease, disorder, or condition, that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), and also include actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

Generally, the "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein 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 the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an 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" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

Unless otherwise specified, a "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount 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 that provides a prophylactic benefit in the process of preventing a disease, disorder, or condition when used alone or in combination with other agents. The term "prophylactically effective amount" may include an amount that improves overall prevention, 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 other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form.

Specific implementation plan

As used herein, "compounds of the present invention" refers to compounds of formula (I) to (IV) below (including, for example, (II-1), (II-2), (II-3), (II-4), (II-5), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6)), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof.

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are included. In addition, unless otherwise specified, all isomeric compounds with carbon-carbon double bonds that may occur in both Z and E forms are included in the present invention. Compounds that exist in different tautomeric forms, a compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms. General formulas used to describe certain compounds, including variables. Unless otherwise specified, each variable in such a formula is defined independently of any other variable and at each occurrence of multiple variables in a formula, any variable is defined independently.

In one 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 variant thereof, and mixtures thereof:

in:

L is selected from a chemical bond, -CR'=CR"- or -C≡C-; wherein R' and R" are independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl or 3-7 membered heterocyclyl;

X is selected from a chemical bond, CR _b R _c , NR _a , O or S(O) _q ;

R ₁ is selected from H, halogen, -CN, -NO ₂ , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl; and R ₁ is optionally substituted with 1 , 2, or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ₂ and R ₂ 'are independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or, R ₂ and R ₂ 'may form oxo or thio;

R ₃ and R ₃ 'are independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or, R ₃ and R ₃ 'may form oxo or thio;

_R4 and _R4 ' are independently selected from H, halogen, -CN, _-NO2 , -( _C0-6 alkylene) _-ORd , -( _C0-6 alkylene) _{-NReRf ,} -( _C0-6 alkylene)-C(O) _Rd , -( _C0-6 alkylene)-C(O) _ORd , -( _C0-6 alkylene)-C(O) _{NReRf ,} -( _C0-6 alkylene)-OC(O) _Rd , -( _C0-6 alkylene)-N( _Re )-C(O) _Rd , -( _C0-6 alkylene)-S(O) _pRd , -( _C0-6 alkylene) _-S (O) _{pORd ,} -( _C0-6 alkylene)-S(O) _{pNReRf ,} -(C0-6 alkylene ₎ - _R4 and _{R4 ' can each} form _{an oxo} group _{or a thio group} ;

Alternatively, R ₂ and R ₃ combine to form a double bond, a C _3-7 carbocyclic group, a 3-7 membered heterocyclic group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group;

Alternatively, when X is CR _b R _c or NR _a , R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a double bond, a C _3-7 carbocyclic group, a 3-7 membered heterocyclic group, a C _6-10 aryl group or a 5-10 membered heteroaryl group;

_R5 is selected from H, halogen, -CN, _-NO2 , -(Co _-6 alkylene) _-ORd , -(Co _-6 alkylene) _-NReRf , -(Co _-6 alkylene)-C(O) _{Rd ,} -(Co _-6 alkylene)-C(O) _ORd , -(Co _-6 alkylene) _-C (O) _NReRf , -(Co _-6 alkylene)-OC(O) _Rd , -(Co _-6 alkylene)-N( _Re )-C(O) _Rd , -(Co _-6 alkylene)-S(O) _{pRd ,} -(Co _-6 alkylene) _-S (O) _{pORd ,} -(Co- ₆ alkylene) _-S (O) _{pNReRf ,} -(Co _-6 alkylene)-OS(O) _pRd , -(C _0-6 alkylene)-N(R _e )-S(O) _p R _d , C _1-6 alkyl or C _1-6 haloalkyl;

_R6 and _R7 are independently selected from H, halogen, -CN, _C1-6 alkyl or _C1-6 haloalkyl;

_Ra , _Rb , _Rc , _Rd , _Re and _Rf are independently selected from H, _C1-6 alkyl or _C1-6 haloalkyl;

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

n = 0, 1 or 2;

p = 1 or 2;

q = 0, 1 or 2;

Provided that when L is a chemical bond, R ₁ is selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

Preferably, wherein:

L is selected from a chemical bond, -CR'=CR"- or -C≡C-; wherein R' and R" are independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl or 3-7 membered heterocyclyl;

X is selected from a chemical bond, CR _b R _c , NR _a , O or S(O) _q ;

R ₁ is selected from H, halogen, -CN, -NO ₂ , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl; and R ₁ is optionally substituted with 1 , 2, or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ₂ , R ₂ ', R ₃ , R ₃ ', R ₄ and R ₄ ' are independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or, R ₂ and R ₂ ', R ₃ and R ₃ ', R ₄ and R ₄ ' may respectively form oxo or thio;

Alternatively, R ₂ and R ₃ combine to form a double bond, a C _3-7 carbocyclic group, a 3-7 membered heterocyclic group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group;

Alternatively, when X is CR _b R _c or NR _a , R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a double bond, a C _3-7 carbocyclic group, a 3-7 membered heterocyclic group, a C _6-10 aryl group or a 5-10 membered heteroaryl group;

_R5 is selected from H, halogen, -CN, _-NO2 , -(Co _-6 alkylene) _-ORd , -(Co _-6 alkylene) _-NReRf , -(Co _-6 alkylene)-C(O) _{Rd ,} -(Co _-6 alkylene)-C(O) _ORd , -(Co _-6 alkylene) _-C (O) _NReRf , -(Co _-6 alkylene)-OC(O) _Rd , -(Co _-6 alkylene)-N( _Re )-C(O) _Rd , -(Co _-6 alkylene)-S(O) _{pRd ,} -(Co _-6 alkylene) _-S (O) _{pORd ,} -(Co- ₆ alkylene) _-S (O) _{pNReRf ,} -(Co _-6 alkylene)-OS(O) _pRd , -(C _0-6 alkylene)-N(R _e )-S(O) _p R _d , C _1-6 alkyl or C _1-6 haloalkyl;

R ₆ and R ₇ are independently selected from H, halogen, -CN, -NO ₂ , -OR _a , -NR _b R _c , C _1-6 alkyl or C _1-6 haloalkyl;

_Ra , _Rb , _Rc , _Rd , _Re and _Rf are independently selected from H, _C1-6 alkyl or _C1-6 haloalkyl;

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

n = 0, 1 or 2;

p = 1 or 2;

q = 0, 1 or 2;

Provided that when L is a chemical bond, R ₁ is selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl.

L

In one embodiment, L is a chemical bond; in another embodiment, L is -CR'=CR"-; in another embodiment, L is -C≡C-.

In one embodiment, R' is H; in another embodiment, R' is halogen; in another embodiment, R' is C _1-6 alkyl; in another embodiment, R' is C _1-6 haloalkyl; in another embodiment, R' is C _3-7 carbocyclyl; in another embodiment, R' is 3-7 membered heterocyclyl.

In one embodiment, R" is H; in another embodiment, R" is halogen; in another embodiment, R" is C _1-6 alkyl; in another embodiment, R" is C _1-6 haloalkyl; in another embodiment, R" is C _3-7 carbocyclyl; in another embodiment, R" is 3-7 membered heterocyclyl.

X

In one embodiment, X is a chemical bond; in another embodiment, X is CR _b R _c ; in another embodiment, X is NR _a ; in another embodiment, X is O; in another embodiment, X is S(O) _q .

R ₁

In one embodiment, R ₁ is H; in another embodiment, R ₁ is halogen; in another embodiment, R ₁ is -CN; in another embodiment, R ₁ is -NO ₂ ; in another embodiment, R ₁ is -C(O)R _a ; in another embodiment, R ₁ is -C(O)OR _a ; in another embodiment, R ₁ is -C(O)NR _b R _c ; in another embodiment, R ₁ is C _1-6 alkyl; in another embodiment, R ₁ is C _1-6 haloalkyl; in another embodiment, R ₁ is C _2-8 alkenyl; in another embodiment, R ₁ is C _2-8 alkynyl; in another embodiment, R ₁ is C _3-7 carbocyclyl; in another embodiment, R ₁ is 3-7 membered heterocyclyl; in another embodiment, R ₁ is C _6-10 aryl; in another embodiment, R ₁ is 5-10 membered heteroaryl.

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

In one embodiment, R is independently H; in another embodiment, R is independently halogen; in another embodiment, R is independently -CN; in another embodiment, R is independently -NO ₂ ; in another embodiment, R is independently -OR _a ; in another embodiment, R is independently -NR _b R _c ; in another embodiment, R is independently -C(O)OR _a ; in another embodiment, R is independently -C(O)NR _b R _c ; in another embodiment, R is independently C _1-6 alkyl; in another embodiment, R is independently C _1-6 haloalkyl; in another embodiment, R is independently C _3-7 carbocyclyl; in another embodiment, R is independently 3-7 membered heterocyclyl; in another embodiment, R is independently C _6-10 aryl; in another embodiment, R is independently 5-10 membered heteroaryl.

R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ and R ₄ ′

In one embodiment, R ₂ and R ₂ 'are independently H; in another embodiment, R ₂ and R ₂ 'are independently halogen; in another embodiment, R ₂ and R ₂ 'are independently -CN; in another embodiment, R ₂ and R ₂ 'are independently -NO ₂ ; in another embodiment, R ₂ and R ₂ 'are independently -OR _a ; in another embodiment, R ₂ and R ₂ 'are independently -NR _b R _c ; in another embodiment, R ₂ and R ₂ 'are independently -C(O)OR _a ; in another embodiment, R ₂ and R ₂ 'are independently -C(O)NR _b R _c ; in another embodiment, R ₂ and R ₂ 'are independently C _1-6 alkyl; in another embodiment, R ₂ and R ₂ 'are independently C _1-6 haloalkyl; in another embodiment, R ₂ and R ₂ 'are independently C _3-7 membered carbocyclyl; in another specific embodiment, R ₂ and R ₂ 'are independently 3-7 membered heterocyclyl; in another specific embodiment, R ₂ and R ₂ 'are independently C _6-10 aryl; in another specific embodiment, R ₂ and R ₂ 'are independently 5-10 membered heteroaryl; in another specific embodiment, R ₂ and R ₂ 'may form oxo; in another specific embodiment, R ₂ and R ₂ 'may form thioxo.

In one embodiment, R ₃ and R ₃ 'are independently H; in another embodiment, R ₃ and R ₃ 'are independently halogen; in another embodiment, R ₃ and R ₃ 'are independently -CN; in another embodiment, R ₃ and R ₃ 'are independently -NO ₂ ; in another embodiment, R ₃ and R ₃ 'are independently -OR _a ; in another embodiment, R ₃ and R ₃ 'are independently -NR _b R _c ; in another embodiment, R ₃ and R ₃ 'are independently -C(O)OR _a ; in another embodiment, R ₃ and R ₃ 'are independently -C(O)NR _b R _c ; in another embodiment, R ₃ and R ₃ 'are independently C _1-6 alkyl; in another embodiment, R ₃ and R ₃ 'are independently C _1-6 haloalkyl; in another embodiment, R ₃ and R ₃ 'are independently C In another embodiment, R ₃ and R ₃ 'are independently _3-7 membered heterocyclyl; in another embodiment, R ₃ and R ₃ 'are independently C _6-10 aryl; in another embodiment, R ₃ and R ₃ 'are independently 5-10 membered heteroaryl; in another embodiment, R ₃ and R ₃ 'may form oxo; in another embodiment, R ₃ and R ₃ 'may form thioxo.

In one embodiment, R ₄ and R ₄ 'are independently H; in another embodiment, R ₄ and R ₄ 'are independently halogen; in another embodiment, R ₄ and R ₄ 'are independently -CN; in another embodiment, R ₄ and R ₄ 'are independently -NO ₂ ; in another embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-OR _a ; in another embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-NR _b R _c ; in another embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-C(O)R _a ; in another embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-C(O)OR _a ; in another embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-C(O)NR _b R _c ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-OC(O)R _a ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-N(R _b )-C(O)R _a ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C 0-6 alkylene)-S(O) _p R _a ; in another specific embodiment, R 4 and R 4 'are independently -(C _0-6 alkylene)-S(O) _p OR _a ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-S(O) p NR b R c ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-S(O) _p NR _b R _c ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C _0-6 alkylene)-OS(O) _p R _a ; in another specific embodiment, R ₄ and R ₄ 'are independently -(C In another embodiment, R ₄ and R ₄ 'are independently -OR _a ; In another embodiment, R 4 and R 4 'are independently -NR _b R _c ; In another embodiment, R ₄ and R ₄ 'are independently _-C (O) _{OR a} ; In another embodiment, R ₄ and R ₄ 'are independently -C(O)NR _{b R c} ; In another embodiment, R ₄ and R ₄ 'are independently C _1-6 alkyl; In another embodiment, R ₄ and R ₄ 'are independently C _1-6 haloalkyl; In another embodiment, R ₄ and R ₄ ' _are independently C _3-7 carbocyclyl _{; In another embodiment, R 4 and R 4 'are independently 3-7 membered heterocyclyl; In another embodiment, R 4 and R 4 ' are} independently C In another embodiment, R ₄ and R ₄ 'are independently _5-10 membered heteroaryl; in another embodiment, R ₄ and R ₄ 'may form oxo; in another embodiment, R ₄ and R ₄ 'may form thio.

In another specific embodiment, _R2 and _R3 combine to form a double bond; in another specific embodiment, _R2 and _R3 combine to form a _C3-7 carbocyclyl; in another specific embodiment, _R2 and _R3 combine to form a 3-7 membered heterocyclyl; in another specific embodiment, _R2 and _R3 combine to form a _C6-10 aryl; in another specific embodiment, _R2 and _R3 combine to form a 5-10 membered heteroaryl.

When X is CR _b R _c or NR _a , in another specific embodiment, R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a double bond; in another specific embodiment, R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a C _3-7 carbocyclyl; in another specific embodiment, R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a 3-7 membered heterocyclyl; in another specific embodiment, R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a C _6-10 aryl; in another specific embodiment, R ₃ or R ₄ may combine with one of _Ra , R _b and R _c to form a 5-10 membered heteroaryl.

R ₅

In one embodiment, R ₅ is H; in another embodiment, R ₅ is halogen; in another embodiment, R ₅ is -CN; in another embodiment, R ₅ is -NO ₂ ; in another embodiment, R ₅ is -(C _0-6 alkylene)-OR _a ; in another embodiment, R ₅ is -(C _0-6 alkylene)-NR _b R _c ; in another embodiment, R ₅ is -(C _0-6 alkylene)-C(O)R _a ; in another embodiment, R ₅ is -(C _0-6 alkylene)-C(O)OR _a ; in another embodiment, R ₅ is -(C _0-6 alkylene)-C(O)NR _b R _c ; in another embodiment, R ₅ is -(C _0-6 alkylene)-OC(O)R _a ; in another embodiment, R ₅ is -(C _0-6 alkylene)-N(R _b )-C(O)R _a ; in another embodiment, R In another specific embodiment, _R is -(C _0-6 alkylene)-S(O) _{p Ra} ; in another specific embodiment, _R is -(C _0-6 alkylene)-S(O) _p OR _a ; in another specific embodiment, _R is -(C _0-6 alkylene)-S(O) _p NR _b R _c ; in another specific embodiment, _R is -(C _0-6 alkylene)-OS(O) _{p Ra} ; in another specific embodiment, R _is -(C _0-6 alkylene)-N(R _{b )} -S(O) _{p Ra} ; in another specific embodiment, R is C _1-6 alkyl; in another specific embodiment, _R is C _1-6 haloalkyl.

_R6 and _R7

In one embodiment, R ₆ and R ₇ are independently H; in another embodiment, R ₆ and R ₇ are independently halogen; in another embodiment, R ₆ and R ₇ are independently -CN; in another embodiment, R ₆ and R ₇ are independently -NO ₂ ; in another embodiment, R ₆ and R ₇ are independently -OR _a ; in another embodiment, R ₆ and R ₇ are independently -NR _b R _c ; in another embodiment, R ₆ and R ₇ are independently C _1-6 alkyl; in another embodiment, R ₆ and R ₇ are independently C _1-6 haloalkyl.

_Ra , _Rb and _Rc

In one embodiment, _Ra , _Rb and _Rc are independently H; in another embodiment, _Ra , _Rb and _Rc are independently _C1-6 alkyl; in another embodiment, _Ra , _Rb and _Rc are independently _C1-6 haloalkyl.

m

In one embodiment, m=0; in another embodiment, m=1; in another embodiment, m=2; in another embodiment, m=3; in another embodiment, m=4; in another embodiment, m=5.

n

In one embodiment, n=0; in another embodiment, n=1; in another embodiment, n=2.

p

In one embodiment, p=1; in another embodiment, p=2.

q

In one embodiment, q=0; in another embodiment, q=1; in another embodiment, q=2.

In a specific embodiment, Selected from the following groups:

In another specific embodiment, Selected from the following groups:

Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of L can be combined with any technical solution or any combination thereof of X, R ₁ -R ₇ , R ₂ '-R ₄ ', m and n. The present invention is intended to include all combinations of these technical solutions, which are not listed one by one due to space limitations.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (II-1), (II-2), (II-3), (II-4) or (II-5):

in,

R ₁ is selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C 1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 carbocyclyl, _3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

R ₆ ′ and R ₆ ″ are halogen and methyl; preferably, R ₆ ′ is F, and R ₆ ″ is Cl or Br;

X, R ₂ -R ₇ , R ₃ ′, m and n are as defined above.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (II-3) or (II-4):

in,

R ₁ is selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl or C _1-6 haloalkyl;

_R2 and _R3 are H;

R ₅ is -(C _0-6 alkylene)-C(O)OR _d ;

R ₆ ′ and R ₆ ″ are halogen and methyl;

_Rd is selected from H, _C1-6 alkyl or _C1-6 haloalkyl;

Preferably,

R ₁ is selected from H, halogen or C _1-6 haloalkyl;

_R2 and _R3 are H;

R ₅ is -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₆ ′ is F, and R ₆ ″ is Cl or Br;

_Rd is selected from H, _C1-6 alkyl or _C1-6 haloalkyl;

Preferably,

R ₁ is selected from H, halogen, CF ₃ or CHF ₂ ; preferably, R ₁ is CF ₃ ;

_R2 and _R3 are H;

R ₅ is -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₆ ′ is F, and R ₆ ″ is Cl or Br;

R _d is selected from H, C _1-6 alkyl or C _1-6 haloalkyl.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (II-5):

in,

X is a chemical bond or O;

R ₁ is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

_R3 is selected from H, halogen or _C1-6 alkyl;

R ₃ 'is selected from H or halogen;

_R4 is selected from H or _C1-6 alkyl;

R ₅ is selected from H, -(C _0-6 alkylene)-OR _d , -(C _0-6 alkylene)-NR _e R _f , -(C _0-6 alkylene)-C(O)R _d , -(C _0-6 alkylene)-C(O)OR _d , -(C _0-6 alkylene)-C(O)NR _e R _f , -(C _0-6 alkylene)-OS(O) ₂ R _d or -(C _0-6 alkylene)-N(R _e )-S(O) ₂ R _d ; preferably, R ₅ is in (S) configuration; preferably, when R ₅ is -COOH, at least one of R ₃ , R ₃ 'and R ₄ is not H;

R ₆ ′ and R ₆ ″ are halogen and methyl;

R _d , _Re and R _f are independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Preferably,

X is a chemical bond or O;

R ₁ is selected from H, halogen or C _1-6 haloalkyl; preferably, R ₁ is C _1-6 haloalkyl;

_R3 is selected from H, halogen or _C1-6 alkyl;

R ₃ 'is selected from H or halogen;

_R4 is selected from H or _C1-6 alkyl;

R ₅ is selected from H, -(C _0-6 alkylene)-C(O)OR _d , -(C _0-6 alkylene)-C(O)NR _e R _f , -(C _0-6 alkylene)-OS(O) ₂ R _d or -(C _0-6 alkylene)-N(R _e )-S(O) ₂ R _d ; preferably, R ₅ is selected from -(C _0-6 alkylene)-C(O)OH, -(C _0-6 alkylene)-C(O)NH ₂ or -(C _0-6 alkylene)-NH-S(O) ₂ R _d ; preferably, R ₅ is in (S) configuration; preferably, when R ₅ is -COOH, at least one of R ₃ , R ₃ 'and R ₄ is not H;

R ₆ ′ and R ₆ ″ are halogen and methyl;

R _d , _Re and R _f are independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Preferably,

X is a chemical bond or O;

R ₁ is selected from H, Br, CF ₃ or CHF ₂ ; preferably, R ₁ is CF ₃ ;

_R3 is H, F or isopropyl;

_R3 is H or F;

_R4 is H or methyl;

R ₅ is selected from H, -COOH, -CONH ₂ , -CH ₂ NHSO ₂ Me, -COOMe or -CH ₂ OH; preferably, R ₅ is selected from -COOH, -CONH ₂ or -CH ₂ NHSO ₂ Me; preferably, R ₅ is in (S) configuration; preferably, when R ₅ is -COOH, at least one of R ₃ , R ₃ ' and R ₄ is not H;

R ₆ ′ is F, and R ₆ ″ is Cl or Br.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8) or (III-9):

in,

R ₄ and R ₅ are -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₆ ′ and R ₆ ″ are halogen and methyl; preferably, R ₆ ′ is F, and R ₆ ″ is Cl or Br;

X, R ₁ -R ₇ , R′, R″, m and n are as defined above.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (III-5), (III-6), (III-7) or (III-8):

in,

R’ and R” are H;

R ₁ is selected from H, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl or -C(O)OR _a ; preferably, R ₁ is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl or -C(O)OR _a ;

_R2 and _R3 are H;

R ₄ and R ₅ are -C(O)OH or -CH ₂ CH ₂ C(O)OH;

_{Ra is} independently selected from H, _C1-6 alkyl or _C1-6 haloalkyl; preferably, Ra _is independently _C1-6 alkyl or _C1-6 haloalkyl;

R _d is independently selected from C _1-6 alkyl or C _1-6 haloalkyl;

R ₆ ′ and R ₆ ″ are halogen and methyl; preferably, R ₆ ′ is F and R ₆ ″ is Cl or Br.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (III-9):

in,

R ₁ is selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl or -C(O)OR _a ; preferably, R ₁ is selected from halogen or -C(O)OR _a ;

R ₄ is H or -(C _0-6 alkylene)-C(O)OR _d ; preferably, R ₄ is H or -(C _1-6 alkylene)-C(O)OH; preferably, R ₄ is (R) configuration;

R ₅ is H or -(C _0-6 alkylene)-C(O)OR _d ; preferably, R ₅ is H or -C(O)OR _d ; preferably, R ₅ is (S) configuration; preferably, at least one of R ₄ and R ₅ is a non-hydrogen group;

R ₆ ′ and R ₆ ″ are halogen and methyl;

R _a is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R _d is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Preferably,

_R1 is selected from Br, Cl or -C(O)Me;

R ₄ is H or -CH ₂ CH ₂ C(O)OH; preferably, R ₄ is in the (R) configuration;

R ₅ is H, -C(O)OH, -C(O)OMe or -CH ₂ CH ₂ C(O)OH; preferably, R ₅ is H, -C(O)OH or -C(O)OMe; preferably, R ₅ is in (S) configuration; preferably, at least one of R ₄ and R ₅ is a non-hydrogen group;

R ₆ ′ is F, and R ₆ ″ is Cl or Br.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6):

in,

R ₆ ′ and R ₆ ″ are halogen and methyl; preferably, R ₆ ′ is F, and R ₆ ″ is Cl or Br;

X, R ₁ -R ₇ , m and n are as defined above.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (IV-3), (IV-4) or (IV-5):

in,

R ₁ is selected from H, -C(O)OR _a , -C(O)NR _b R _c , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl, 3-7 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; and R ₁ is optionally substituted by 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO ₂ , -OR _a or -NR _b R _c ;

_R2 and _R3 are H, or _R2 and _R3 combine to form a double bond;

R ₄ is -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₅ is -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₆ ′ and R ₆ ″ are halogen and methyl;

_Ra , _Rb and _Rc are independently selected from H, _C1-6 alkyl or _C1-6 haloalkyl;

Preferably,

R ₁ is selected from H, -C(O)OR _a , C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl or 3-7 membered heterocyclyl; and R ₁ is optionally substituted by 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO ₂ , -OR _a or -NR _b R _c ;

Preferably, R ₁ is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 carbocyclyl or 3-7 membered heterocyclyl; and R ₁ is optionally substituted by 1, 2 or 3 R groups, wherein R is independently selected from -OR _a or -NR _b R _c ;

_R2 and _R3 are H;

R ₄ is -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₅ is -C(O)OH or -CH ₂ CH ₂ C(O)OH;

R ₆ ′ is F, and R ₆ ″ is Cl or Br;

_Ra , _Rb and _Rc are independently selected from H, _C1-6 alkyl or _C1-6 haloalkyl.

In a more specific embodiment, the present invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which has the general formula (IV-6):

in,

R ₁ is selected from H, C _1-6 alkyl, -C(O)OR _a or C _3-7 carbocyclyl, and wherein C _1-6 alkyl or C _3-7 carbocyclyl is optionally substituted by 1 -OR _a group;

R ₄ is H or -CH ₂ CH ₂ C(O)OH; preferably, R ₄ is in the (R) configuration;

R ₅ is H or -C(O)OR _a ; preferably, R ₅ is in (S) configuration;

R ₆ ′ and R ₆ ″ are halogen and methyl;

R _a is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Preferably,

R ₁ is selected from H, cyclopropyl, -C(O)OMe or -CH ₂ OH;

R ₄ is H or -CH ₂ CH ₂ C(O)OH; preferably, R ₄ is in the (R) configuration;

R ₅ is H, -C(O)OH or -C(O)OMe; preferably, R ₅ is H or -C(O)OH; preferably, R ₅ is in (S) configuration; preferably, at least one of R ₄ and R ₅ is a non-hydrogen group;

R ₆ ′ is F, and R ₆ ″ is Cl or Br.

In a more specific embodiment, the compound of the present invention is selected from the following compounds, but is not limited thereto:

The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and/or diastereoisomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. 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 its salt that is combined with a solvent, usually formed by a solvent decomposition reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by, for example, the general formula R·xH ₂ O, where R is the compound, and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R·0.5H ₂ O)) and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R·2H ₂ O) and a hexahydrate (R·6H ₂ O)).

The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can lead to a crystalline form dominating. The various polymorphs of a compound can be prepared by crystallization under different conditions.

The present invention also includes isotope-labeled compounds (isotope variants), which are equivalent to those described in Formulas I-VIII, but one or more atoms are replaced by atoms having atomic masses or mass numbers different from the atomic masses or mass numbers commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs all belong to the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as those that introduce radioactive isotopes (such as ³ H and ¹⁴ C), can be used for drug and/or substrate tissue distribution assays. Tritium, i.e., ³ H, and carbon-14, i.e., ¹⁴ C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes, such as deuterium, i.e., ² H, may be preferred in some cases because of greater metabolic stability, which may provide therapeutic benefits, such as increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of Formulas I-VIII of the present invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents when performing the processes disclosed in the following schemes and/or Examples and Preparations.

In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted into its active form having a medical effect in vivo, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

Prodrugs are any covalently bonded compounds of the present invention that release the parent compound in vivo when such prodrugs are administered to a patient. Prodrugs are usually prepared by modifying functional groups, and the modification is carried out in a manner that allows the modification to be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which hydroxyl, amino or sulfhydryl groups are bonded to any group, which can be cleaved to form hydroxyl, amino or sulfhydryl groups when administered to a patient. Therefore, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of hydroxyl, sulfhydryl and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl esters, ethyl esters, etc. can be used. Esters themselves can be active and/or can be hydrolyzed under human body conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or its salt.

The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of Formula I-VIII or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

Pharmaceutical compositions, preparations and kits

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

The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

The present invention also includes a kit (e.g., a pharmaceutical package). The kit provided may include a compound of the invention, other therapeutic agents, and a first and second container (e.g., a vial, an ampoule, a bottle, a syringe and/or a dispersible package or other suitable container) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and/or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first container and the second container are combined to form a unit dosage form.

Drug administration

Pharmaceutical composition provided by the invention can be administered by many ways, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial cavity administration, intrasternal administration, intrathecal administration, intralesional administration and intracranial injection or infusion technology.

Generally, an effective amount of the compounds provided herein is administered. The amount of the compound actually administered can be determined by a physician according to the relevant circumstances, including the condition being treated, the route of administration selected, 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 the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice of a physician and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a specific condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

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

Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by push injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The push dose depends on the target systemic level of the active component through the body, for example, the intramuscular or subcutaneous push dose slowly releases the active component, and the push injection (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly, so that the concentration of the active component in the blood is quickly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active component in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the push dose can be first given, and then continuous infusion.

Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is usually a relatively small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various carriers or excipients and processing aids useful for forming the desired administration form.

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

In order to provide blood levels similar to those using an injectable dose, or lower blood levels than using an injectable dose, a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

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

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, 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, and the remainder is an injectable excipient, etc.

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

The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or a variety of solid matrices.

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

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

The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present 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 substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

Combination therapy

The compounds or compositions of the present invention can be administered simultaneously with one or more additional agents, or before or after the one or more additional agents, as a combination therapy. Medicaments include therapeutic agents. Medicaments also include preventive agents. Medicaments include small organic molecules, such as pharmaceutical compounds (e.g., approved by the U.S. Food and Drug Administration, provided in the U.S. Federal Regulations (CFR) human or veterinary compounds), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules of connexins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In some embodiments, the additional agents are agents for treating and/or preventing diseases described herein. Each additional agent can be administered at a dose and/or schedule determined by the agent. The additional agents can 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 specific combination used in the regimen will take into account the compatibility of the compounds of the invention with the additional agents and/or the desired therapeutic and/or preventive effect to be achieved. Typically, the levels of the additional agents used in combination are no greater than their levels when used alone. In some embodiments, the levels used in combination will be lower than their levels when used alone.

In a specific embodiment, the additional agent is an antiviral agent selected from HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, capsid assembly regulators, reverse transcriptase inhibitors, TLR-agonists, and agents of different or unknown mechanisms, and combinations thereof.

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

In another embodiment, the reverse transcriptase inhibitor is at least one of the following: Zidovudine, Didanosine, Zalcitabine, ddA (2', 3'-dideoxyadenosine), Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atev irapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, tenofovir, adefovir, cidofovir, efavirenz, nevirapine, delavirdine, or etravirine.

In another embodiment, the additional agent is, for example, a T cell response activator AIC649; a biological agent of the interferon class such as interferon and pegylated interferon; a TLR modulator such as a TLR-7 agonist or a TLR-9 agonist such as SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenosine), AZD8848 ([3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purine-9- [3-(4-morpholinyl)propyl] [3-(4-morpholinyl)propyl] amino}methyl)phenyl] acetate), GS-9620 and RO6864018; therapeutic vaccines that stimulate HBV-specific immune responses; 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 dipivoxil.

Example

The following examples are provided so as to provide those skilled in the art with a complete disclosure and description of how to perform, prepare and evaluate the methods and compounds claimed herein and are intended to merely illustrate the invention and not to limit the scope of the invention.

In the following examples, all water-sensitive reactions were carried out under dry conditions. Benzene, tetrahydrofuran or dichloromethane were refluxed in the presence of sodium metal, dried, distilled and stored for later use. All intermediates were purified by silica gel chromatography. All final compounds were purified by preparative HPLC using a C18 reverse phase column with a mobile phase of (A: 0.1% trifluoroacetic acid in water; B: acetonitrile) or alkaline conditions (A: 0.1% ammonia solution; B: acetonitrile). Based on HPLC, LC-MS and 1H NMR analysis, the purity of all final compounds was greater than 95%. All reported yields were not optimized.

Example 1

Compound 1 :

30% sodium methoxide solution (2.55 mL, 14 mmol) was added dropwise to a 5 mL anhydrous methanol solution of thiazole-2-carbonitrile (1.50 g, 14 mmol) under stirring, and the reaction mixture was stirred at room temperature until the starting material disappeared. Ammonium chloride (1.50 g, 28 mmol) was then added in one portion, and the reaction mixture was stirred overnight. The undissolved material was filtered off, and the filtrate was concentrated in vacuo to obtain a gray solid of thiazole-2-carboxamidine hydrochloride 1 , which was directly used in the next step of condensation cyclization without further purification.

Compound 4 :

Thiazole-2-carboximidamide hydrochloride ( 1 , 150 mg, 1.0 mmol), 2-chloro-4-fluorobenzaldehyde ( 2 , 160 mg, 1.0 mmol), 2-trifluoromethylacetone ( 3 , 126 mg, 1.0 mmol) and _{potassium acetate (0.20 g, 2.0 mmol) were dissolved in 10 mL of CF3CH2OH solution} , and the reaction mixture was stirred and refluxed under nitrogen for 12 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate, the organic layer was washed with brine _, dried ( _Na2SO4 ), and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether: 1:4-1:2) to obtain a yellow solid product 4 (195 mg, 52%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.98 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.90 (dd, J=8.0, 4.0 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 2.47 (s, 3H).

Compound 5 :

NBS (200 mg, 1.1 mmol) was added to a solution of compound 4 (375 mg, 1.0 mmol) in CCl ₄ (5 mL), and the reaction solution was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the residue was purified by column chromatography to give compound 5 (390 mg, 86%). MS m/z 445 [M+H].

Compound 6 :

To a solution of compound 5 (49 mg, 0.11 mmol) and (3S)-morpholine-3-carboxylic acid hydrochloride (29 mg, 0.17 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (80 μL, 0.45 mmol) dropwise with stirring, and the reaction mixture was stirred at room temperature until the starting material 5 disappeared. After dilution with ethyl acetate (10 mL), the organic phase was washed with saturated ammonium chloride solution and brine, dried (Na ₂ SO ₄ ), concentrated, and the residue was purified by preparative HPLC to give a light yellow solid product 6 (28 mg, 50%). MS m/z 506 [M+H]; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.68 (br.s, 1H), 9.85 (s, 1H), 8.03 (d, J=4.0 Hz, 1H), 7.91 (d, J=4.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.11 (td, J=8.76, 2.62 Hz, 1H), 6.01 (s, 1H), 4.21 (d, J=20 Hz, 1H), 4.07-3.97 (m, 2H), 3.89-3.56 (m, 4H), 3.15-3.05 (m, 1H), 2.45-2.35 (m, 1H).

Using the same synthesis method as compound 6 , bromide 5 is subjected to nucleophilic substitution reaction with various morpholine derivatives to obtain the following compounds 7-16 :

MS m/z 506 [M+H]; 1H NMR (DMSO-d6, 400 MHz) δ 12.84 (br s, 1H), 9.85 (s, 1H), 8.08-7.88 (m, 2H), 7.44-7.26 (m, 2H), 7.16 (m, 1H), 6.01 (s, 1H), 4.18-4.02 (m, 2H), 3.90-3.80 (m, 2H), 3.77-3.58 (m, 2H), 3.47-3.24 (m, 1H), 3.14-2.99 (m, 1H), 1.38-1.12 (m, 1H).

MS m/z 506 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 8.01 (d, J = 3 Hz, 0.5H), 8.00 (d, J = 3 Hz, 0.5H), 7.91 (dd, J = 3 Hz, 0.5H), 7.90 (d, J = 3 Hz, 0.5H), 7.54 (m, 0.5H), 7.53 (m, 0.5H), 7.30 (m, 1H), 7.15-7.09 (m, 1H), 6.21 (s, 1H), 4.82-4.55 (m, 3H), 4.31-4.24 (m, 1H), 4.12-3.91 (m, 2H), 3.74-3.65 (m, 1H), 3.55-3.37 (m, 2H).

MS m/z 520 [M+H]; 1H NMR (MeOH-d4, 400 MHz): δ 8.00 (d, J = 3.14 Hz, 1H), 7.88 (d, J = 3.14 Hz, 1 nH), 7.51 (m, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 6.19 (s, 1H), 4.41 (d, J = 16.56 Hz, 1H), 4.20 (d, J = 16.44 Hz, 1H), 4.00-4.13 (m, 1H), 3.75-3.98 (m, 3H), 3.51 (d, J = 8.91 Hz, 1H), 3.06 (m, 1H), 1.36 (d, J = 6.27 Hz, 3H).

MS m/z 520 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 7.97 (d, J = 3.0 Hz, 1H), 7.74 (d, J = 3.3 Hz, 1H), 7.42 (m, 1H), 7.23 (m, 1H), 7.04 (m, 1H), 6.17 (s, 1H), 4.40 (d, J = 17.8 Hz, 1H), 3.96-4.15 (m, 3H), 3.76-3.88 (m, 4H), 3.13-3.31 (m, 3H), 2.50 (m, 1H).

MS m/z 505 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 7.97 (d, J = 3.01 Hz, 1H), 7.71-7.81 (m, 1H), 7.42 (m, 1H), 7.23 (m, 1H), 7.06 (m, 1H), 6.08-6.20 (m, 1H), 4.08-4.27 (m, 1H), 4.01 (dd, J = 3.26, 11.29 Hz, 1H), 3.67-3.92 (m, 4H), 3.35-3.43 (m, 1H), 3.00-3.09 (m, 1H), 2.50-2.68 (m, 1H).

MS m/z 492 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 7.98-8.02 (m, 1H), 7.91 (dd, J = 3.01, 0.75 Hz, 1H), 7.57 (dd, J = 8.66, 5.90 Hz, 1H), 7.30 (dd, J = 8.66, 2.64 Hz, 1H) 7.12 (m, 1H), 6.19-6.23 (m, 1H), 4.85 (d, J = 6.53 Hz, 1H), 4.70 (m, 1H), 4.05-4.18 (m, 3H), 3.90-4.01 (m, 3H), 3.70-3.79 (m, 2H), 3.43-3.53 (m, 1H).

MS m/z 569 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 8.19 (brs, 1H), 7.96 (d, J = 3.01 Hz, 1H), 7.76 (d, J = 3.26 Hz, 1H), 7.48 (m, 1H), 7.22 (m, 1H), 7.04 (m, 1H), 6.18 (s, 1H), 4.13-4.34 (m, 2H), 3.93 (m, 1H), 3.77-3.83 (m, 2H), 3.72 (m, 1H), 3.36-3.46 (m, 2H), 2.98 (s, 3H), 2.85-2.92 (m, 1H), 2.80 (m, 1H), 2.53-2.62 (m, 1H).

MS m/z 569 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 8.01 (d, J = 3.14 Hz, 1H), 7.70-7.95 (m, 1H), 7.50 (m, 1H), 7.28 (mz, 1H), 7.10 (m, 1H), 6.02-6.27 (m, 1H), 4.35-4.61 (m, 1H), 4.21-4.35 (m, 1H), 4.11 (m, 1H), 3.72-3.97 (m, 2H), 3.67-3.71 (m, 1H), 3.35-3.46 (m, 1H), 2.95-3.17 (m, 1H), 2.10 (m, 1H), 1.07 (m, 6H).

MS m/z 462[M+H].

MS m/z 526 [M+H]; 1H NMR (MeOH-d4, 400 MHz) δ 8.20 (s, 2H), 7.63-7.60 (m, 1H), 7.38-7.35 (m, 1H), 7.22-7.18 (m, 1H), 6.29 (s, 1H), 4.57 (d, J=16 Hz, 1H), 4.13-4.08 (m, 2H), 3.70-3.67 (m, 1H), 3.33-3.28 (m, 1H), 2.92-2.82 (m, 1H), 2.63-2.56 (m, 1H).

Example 2

Compound 18 :

2-Chloro-4-fluorobenzaldehyde (9.00 g, 56.761 mmol, 1.0 equiv), 1,3-thiazole-2-carboximidamide hydrochloride (9.29 g, 56.778 mmol, 1.0 equiv), compound 17 (8.98 g, 56.761 mmol, 1.0 equiv), KOAc (16.7 g, 170.283 mmol, 3.00 equiv) and methanol (300 mL) were added to a 500 mL round-bottom flask. The resulting solution was stirred overnight at 80 ° C in an oil bath, the reaction mixture was cooled to 20 ° C with a water bath, and then quenched by adding 500 mL of water/ice. The resulting solution was extracted with 3×500 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After the ethyl acetate solution was concentrated, the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether 0-20%) to obtain 9.0 g of compound 18 (33.04%) as a yellow solid. MS m/z 408 [M+H].

Compound 19 :

Compound 18 (9.00 g, 22.065 mmol, 1.00 equiv) and HCl in dioxane (100 mL, 4 N) were added to a 500 mL round-bottom flask. The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated and washed with ether to give 5.0 g (64.42%) of compound 19 as a yellow solid. MS m/z 352 [M+H].

Compound 20 :

Compound 19 (5.00 g, 14.213 mmol, 1.00 equiv), Na ₂ CO ₃ (3.01 g, 28.426 mmol, 2.00 equiv), NaI (10.66 g, 71.065 mmol, 5.0 equiv), 150.00 ml each of methanol, acetonitrile and water were added to a 1000 mL round-bottom flask. Oxone (4.37 g, 7.106 mmol, 0.50 equiv) was then added in batches under stirring at room temperature. The resulting solution was stirred at room temperature for 30 minutes, and then 200 mL of NaHSO 3 aqueous solution was added to quench the reaction. The resulting solution was extracted with 3×200 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column to obtain 3.5 g of compound 20 (56.78%) as a yellow oil. MS m/z 434 [M+H].

Compound 21 :

Compound 20 (3.50 g, 8.071 mmol, 1.0 equivalent), DCM (100.00 mL), Et ₃ N (2450.01 g, 24.212 mmol, 3.0 equivalent), DMAP (98.60 g, 0.807 mmol, 0.1 equivalent) were added to a 500 mL round-bottom flask, and then Boc ₂ O (1761.39 g, 8.071 mmol, 1.0 equivalent) was added dropwise under stirring at room temperature. The reaction solution was stirred at room temperature overnight. 200 mL of water was added to quench the reaction, and the resulting solution was extracted with 3×200 mL of ethyl acetate. The organic phases were combined, dried, and concentrated. The resulting residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether 0-50%) to obtain 4.0 g (92.85%) of compound 21 as a yellow solid. MS m/z 534 [M+H].

Compound 22 :

Compound 21 (4.00 g, 7.494 mmol, 1.0 equivalent), methyl acrylate (2.26 g, 26.228 mmol, 3.5 equivalent), N-cyclohexyl-N-methylcyclohexylamine (1.76 g, 9.009 mmol, 1.2 equivalent), Pd ₂ (dba) ₃ (686.45 mg, 0.749 mmol, 0.1 equivalent) and PBu ^t ₃ .HBF ₄ (0.44 g, 1.517 mmol, 0.2 equivalent) were added to a 250 mL round-bottom flask purged with inert nitrogen, and the resulting solution was stirred at 95° C. overnight. 100 mL of water was added to quench the reaction, and then extracted with 3×100 mL of ethyl acetate. The combined organic phases were dried and concentrated, and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether 0-50%) to obtain 2.6 g (70.53%) of compound 22 as a yellow solid. MS m/z 492[M+H].

Compound 23 :

Compound 22 (2.10 g, 4.269 mmol, 1.00 equiv), NBS (911.70 mg, 5.122 mmol, 1.20 equiv), AIBN (140.19 mg, 0.854 mmol, 0.20 equiv) and chlorobenzene (100.00 mL) were added to a 250 mL round-bottom flask. The solution was stirred in an oil bath at 85 °C for 2 hours, and then 200 mL of water was added to quench the reaction. The resulting solution was extracted with 3×200 mL of ethyl acetate, the organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether 0-30%) to obtain 380 mg (15.59%) of bromide 23 as a yellow solid. MS m/z 570 [M+H].

Compound 24 :

(3S)-morpholine-3-carboxylic acid hydrochloride (278.90 mg, 1.664 mmol, 2.50 equiv), bromide 23 (380.00 mg, 0.666 mmol, 1.00 equiv), DIPEA (430.16 mg, 3.328 mmol, 5.00 equiv) and acetonitrile (50 mL) were added to a 100 mL round bottom flask and the reaction solution was stirred at room temperature overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The organic phases were combined, dried, concentrated, and then the crude product was purified by Flash-Prep-HPLC. The chromatographic conditions were as follows (IntelFlash-1): C18 silica gel column; mobile phase A: CH ₃ CN, mobile phase B: pure water containing 0.05% TFA. The acetonitrile content increased from 10% to 80% within 40 minutes; UV detector wavelength 254 nm. The product 24 was isolated as a yellow solid (330 mg, 79.82%). MS m/z 621 [M+H].

Compound 25 :

Compound 24 (330.00 mg, 0.531 mmol, 1.00 equivalent) was added to 4N HCl in dioxane (2.66 mL, 10.62 mmol, 20 equivalent) and stirred overnight at room temperature. The solvent was dried under reduced pressure and the residue was purified by preparative HPLC under the following chromatographic conditions: stationary phase, C18 silica gel column; mobile phase A: MeOH, mobile phase B: aqueous solution containing 0.05% HCl, mobile phase A increased from 10% to 50% gradient within 10 minutes; UV detector wavelength 254 nm. Compound 25 (141.7 mg, 49.9% yield) was obtained as a red solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.12-8.04 (m, 2H), 7.60-7.70 (m, 1H), 7.50-7.55 (m, 2H), 7.18-7.27 (m, 1H), 5.99 (s, 1H), 5.55-5.60 (m, 1H), 4.46-4.58 (m, 1H), 4.28-4.44 (m, 2H), 4.10-4.15 (m, 1H), 4.00-4.10 (m, 1H), 3.81-3.97 (m, 2H), 3.62 (s, 3H), 3.50-3.55 (m, 1H), 3.20-3.30 (m, 1H); MS (ES, m/z): [M+H]+＝521.

Compounds 26 and 27 were also prepared using a similar synthetic method:

1H NMR (400 MHz, MeOH-d4) δ 7.97 (m, 1H), 7.79 (m, 1H), 7.66-7.45 (m, 2H), 7.42 (m, 1H), 7.14-7.10 (m, 1H), 6.17 (s, 1H), 5.55-5.60 (m, 1H), 4.55-4.44 (m, 1H), 4.38-4.23 (m, 1H), 4.17-4.01 (m, 4H), 3.95-3.84 (m, 2H), 3.70 (d, J = 17.6 Hz, 1H), 3.53-3.36 (m, 1H), 2.84-2.73 (m, 1H), 1.15 (td, J = 7.1, 2.4 Hz, 3H).; MS (ES, m/z): [M+H] ⁺ 565,567.

1H NMR (400 MHz, DMSO-d6) δ: 8.12-8.04 (m, 2H), 7.60-7.70 (m, 1H), 7.50-7.55 (m, 2H), 7.18-7.27 (m, 1H), 5.99 (s, 1H), 5.55-5.60 (m, 1H), 4.83-4.76 (m, 2H), 2.49 (s, 3H), 1.32 (d, 3H), 1.04-1.02 (m, 6H); MS (ES, m/z) [M+H] ⁺ 549.1.

Example 3

Compound 28 :

AIBN (0.49 g, 2.984 mmol, 0.20 equiv) and NBS (5.335 g, 29.974 mmol, 2.00 equiv) were added to a solution of compound 21 (8.0 g, 14.987 mmol, 1.00 equiv) in CCl ₄ (125 mL) at room temperature, and the reaction was stirred at 45° C. overnight. After cooling to room temperature, water (100 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated, and the residue was purified by silica gel column chromatography (0% to 20% ethyl acetate/petroleum ether) to give product 28 (6.6 g, 77.85% yield) as a yellow solid.

Compound 29 :

Compound 28 (6.60 g, 11.667 mmol, 1.00 equivalent) was dissolved in acetonitrile (90 mL), (S)-morpholine-3-carboxylic acid methyl ester hydrochloride (4.24 g, 23.335 mmol, 2.00 equivalent) and DIPEA (10.16 mL, 78.621 mmol, 5.00 equivalent) were slowly added at room temperature, and the reactants were stirred at 45 ° C overnight. After cooling to room temperature, water (50 mL) was added to quench the reaction, and then extracted with EA (3×80 mL). The organic layers were combined, dried, filtered and concentrated, and the crude product was purified by silica gel column chromatography (0% to 50% EA/PE) to obtain product 29 (5.3 g, 72.11% yield) as a yellow solid.

Compound 30 :

A solution of compound 29 (5.30 g, 8.414 mmol, 1.00 equiv), tert-butyl acrylate (3.24 g, 25.241 mmol, 3.00 equiv), Pd ₂ (dba) ₃ (0.77 g, 0.841 mmol, 0.10 equiv) and P( ^t Bu) ₃ .HBF ₄ (0.49 g, 1.683 mmol, 0.20 equiv) in dioxane (86.00 mL) was stirred at 120° C. overnight under nitrogen atmosphere. The mixture was cooled to room temperature and water (50 mL) was added to quench the reaction, and EA (3×80 mL) was extracted. 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 30 (4.5 g, 78.98%) as a yellow solid.

Compound 31 :

To a solution of compound 30 (5.30 g, 7.826 mmol, 1.00 equiv) in dioxane (50 mL) was added 4N HCl in dioxane (156.53 mL, 626.120 mmol, 80.00 equiv) at room temperature. The mixture was stirred for 3 hours and then concentrated under reduced pressure to give product 31 (3.3 g, 80.94%) as a yellow solid, which was directly used in the next step.

Compound 32 :

Compound 31 (3.30 g, 6.334 mmol, 1.00 equiv) was dissolved in a mixed solvent of MeOH (150.00 mL) and ACN (150.00 mL). A solution of Na2CO3 (1.34 g, 12.669 mmol, 2.00 equiv) and NaBr (3.26 g, 31.672 mmol, 5.00 equiv) in water (150.00 mL) was slowly added dropwise at room temperature. Then, a solution of Oxone (532.63 mg, 3.167 mmol, 0.50 equiv) in water (20.00 mL) was added dropwise to the above mixture over 20 minutes. After stirring for 1 hour, the reactant was quenched with brine and sodium sulfite, and the reactant was extracted with EA (3×150 mL). The combined organic layers were dried, filtered and concentrated, and the residue was purified by silica gel column chromatography (0% to 40% EA/PE) to give the product 32 (2.0 g, 56.80%) as a yellow solid.

Compound 33 :

Compound 32 (2.00 g, 3.598 mmol, 1.00 equivalent) was dissolved in a mixed solvent of THF (8.00 mL)-H ₂ O (8.00 mL)-MeOH (8.00 mL), and LiOH (258.50 mg, 10.794 mmol, 3.00 equivalent) was added in batches at room temperature. After the reaction solution was stirred overnight, EA (10 mL) was added to wash the resulting mixture. The aqueous phase was then acidified to pH = 5-6 with 1N HCl, and the mixture was finally extracted with EA (3×50 mL). The organic layer was then dried, filtered and concentrated, and the crude product was purified by preparative HPLC under the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL/min; gradient: mobile phase B increased from 38% to 56% in 7 minutes. After freeze-drying, the product 33 (711.2 mg, yield 35.06%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ8.20 (s, 2H), 7.62-7.70 (m, 1H), 7.36-7.42 (m, 1H), 7.18-7.26 (m, 2H), 6.57 (d, J＝13.6 Hz, 1H), 6.30 (d, J＝4.8 Hz, 1H), 4.12-4.50 (m, 4H), 3.95-4.05 (m, 2H), 3.82-3.94 (m, 1H), 3.56-3.68 (m, 1H), 3.12-3.26 (m, 1H); MS (ES, m/z): [M+H, M+H+2] ⁺ ＝540.95, 542.9

Using the above synthetic route, compounds 34a , 34b , 34c and 34d were also prepared:

¹ H NMR (400 MHz, CD ₃ OD) δ 7.96-7.98 (m, 1H), 7.78-7.80 (m, 1H), 7.66-7.45 (m, 2H), 7.42 (m, 1H), 7.14-7.10 (m, 1H), 6.17 (s, 1H), 4.10-4.49 (m, 4H), 3.95-4.05 (m, 2H), 3.82-3.94 (m, 1H), 3.56-3.68 (m, 1H), 3.12-3.26 (m, 1H).

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.20 (s, 1H), 8.16 (s, 1H), 7.62-7.70 (m, 1H), 7.18-7.42 (m, 3H), 6.55 (m, 1H), 6.30 (d, J=4.8 Hz, 1H), 4.16-4.03 (m, 2H), 3.58 (m, 1H), 3.45-3.53 (m, 1H), 2.75-2.80 (m, 2H), 2.35 (m, 1H), 2.02-2.30 (m, 3H), 1.57-1.68 (m, 2H), 1.09 (m, 3H); MS (ES, m/z): [M+H] ⁺ 569.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.10 (s, 1H), 8.01 (s, 1H), 7.60-7.70 (m, 1H), 7.36-7.42 (m, 1H), 7.00-7.26 (m, 2H), 6.54 (m, 1H), 6.10 (d, J=4.8 Hz, 1H), 4.33 (m, 1H), 3.50-3.54 (m, 1H), 3.00 (s, 1H), 2.64-2.90 (m, 3H), 2.46-2.50 (m, 2H), 2.35-2.42 (m, 1H), 1.13-1.68 (m, 4H); MS (ES, m/z): [M+H] ⁺ 569.

¹ H NMR (400 MHz, CD ₃ OD) δ8.21 (s, 1H), 8.10, 7.68-7.78 (m, 1H), 7.38-7.42 (m, 1H), 7.18-7.26 (m, 2H), 6.53 (d, 1H), 6.34 (d, 1H), 4.12-4.50 (m, 4H), 3.95-4.05 (m, 2H), 3.82-3.94 (m, 1H), 3.56-3.68 (m, 1H), 3.12-3.26 (m, 1H); MS (ES, m/z): [M+H] ⁺ 497.

Example 4

Compound 35 :

Compound 19 (1.5 g, 4.27 mmol, 1 eq) was added to 30 mL of dichloromethane, the temperature was raised to reflux, NBS (0.69 g, 3.84 mmol, 1 eq) was added in batches, and the mixture was stirred for 1 h before adding NBS (0.77 g, 4.27 mmol, 1 eq) in batches. After the reaction was completed by TLC, water (40 mL) was added to quench the reaction, and the mixture was extracted with DCM (30 mL x 3) and dried and concentrated. The crude product 35 was directly used in the next step.

Compound 36 :

Compound 35 (2.0 g, 4.34 mmol, 1.00 equivalent) was dissolved in acetonitrile (50 mL), (S)-morpholine-3-carboxylic acid methyl ester hydrochloride (1.58 g, 8.73 mmol, 2.00 equivalent) and DIPEA (2.8 mL, 21.7 mmol, 5.00 equivalent) were slowly added at room temperature, and the reactants were stirred at 45 ° C overnight. After cooling to room temperature, water (50 mL) was added to quench the reaction, and then extracted with ethyl acetate (3×80 mL). The organic layers were combined, dried, filtered and concentrated, and the crude product was purified by silica gel column chromatography (0% to 50% EA/PE) to obtain product 36 (1.1 g, two-step total yield 48.11%) as a yellow solid. MS (ES, m/z): [M+H] ⁺ = 529.8, 531.8.

Compound 37 :

Compound 36 (212 mg, 0.4 mmol, 1.00 equiv) was dissolved in a mixed solvent of THF (3.00 mL)-H ₂ O (3.00 mL)-MeOH (3.00 mL), and LiOH (30 mg, 0.8 mmol, 2.00 equiv) was added in batches at room temperature. After the reaction solution was stirred overnight, EA (10 mL) was added to wash the resulting mixture. Then the aqueous phase was acidified to pH = 5-6 with 1N HCl, and finally the mixture was extracted with EA (3×50 mL). The organic layers were combined, dried, filtered and concentrated, and the crude product was purified by preparative HPLC. The chromatographic conditions were as follows: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL/min; gradient: mobile phase B increased from 30% to 60% in 10 minutes. After freeze drying, the product 37 (92 mg, yield 45%) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ: 12.87 (s, 1H), 8.96 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.43-7.52 (m, 2H), 7.24-7.28 (m, 1H), 5.86 (s, 1H), 3.49-3.87 (m, 7H), 3.02-3.06 (m, 1H), 2.48-2.50 (m, 1H); MS (ES, m/z): [M+H] ⁺ =516.98, 518.9.

Example 5

Compound 38

To a solution of compound 20 (430 mg, 1 mmol) in 20 mL of tetrahydrofuran was slowly added 0.44 mL of n-butyllithium n-hexane solution (2.5 M, 1.1 mmol) at -78°, and the reaction was stirred at low temperature for 2 h. An appropriate amount of saturated ammonium chloride solution was added to quench the reaction, and then extracted with ether. The mixture was washed with water three times and dried over anhydrous sodium sulfate. After filtration and concentration, 300 mg of a yellow-white solid was obtained, namely compound 38 , with a yield of 98%.

Compound 39

Compound 38 (306 mg, 1.0 mmol) was dissolved in CCl ₄ (5 mL), NBS (200 mg, 1.1 mmol) was slowly added, the reaction solution was stirred at room temperature for 3 hours, the solvent was removed in vacuo and the residue was purified by column chromatography to obtain compound 39 (308 mg, 80%). MS m/z [M+H] 388,390.

Compound 40

To a solution of compound 39 (40 mg, 0.11 mmol) and (3S)-morpholine-3-carboxylic acid hydrochloride (29 mg, 0.17 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (80 μL, 0.45 mmol) under stirring, and the reaction mixture was stirred at room temperature until the starting material disappeared. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain a light yellow solid product 40 (20 mg, 40%). MS m/z 437 [M+H].

Example 6

Compound 42

Compound 41 (10.0 g, 22.63 mmol, 1 eq) and dichloromethane (100 mL) were added to the reaction flask, and NBS (4.03 g, 22.63 mmol, 1 eq) was added in batches after stirring and dissolving. The addition was completed within 10 min, and the reaction was stirred at room temperature for 30 min. TLC showed that the product was generated, and trace amounts of raw materials remained. The reaction solution was evaporated under reduced pressure to remove the solvent, and the crude product 42 was directly used for the next step reaction.

Compound 43

The crude bromide 42 (5.9 g, 11.33 mmol, 1 eq), (S)-morpholine-3-carboxylic acid methyl ester hydrochloride (3.1 g, 17 mmol, 1.5 eq), potassium carbonate (3.1 g, 22.7 mmol, 2 eq) and ethanol (50 mL) were added to the reaction flask and stirred at 40°C for 4 h. The reaction of the raw materials was complete according to TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (PE:EA=4:1-2:1) to obtain the product 43 (4.1 g, yield 61.8%) as a yellow solid. MS-ESI m/z: 585.2 [M].

Compound 44

Add intermediate 43 (2.0 g, 3.42 mmol, 1 eq) and dichloromethane (20 mL) to the reaction flask, stir and dissolve, then add aluminum chloride (0.9 g, 6.84 mol, 2 eq) in batches, and stir at room temperature for 1 hour. Add 10 mL of ice water to the reaction solution under ice bath to quench, evaporate the solvent under reduced pressure, add 100 mL of 1N HCl to the residue and stir and dissolve, extract with 50 mL of ethyl acetate, discard the organic phase, adjust the pH of the aqueous phase to 5-6 with sodium carbonate, extract with ethyl acetate (50 mL x 2), wash the combined organic phase with saturated sodium chloride water, dry with anhydrous sodium sulfate, filter with diatomaceous earth, and spin dry the filtrate to obtain yellow foam solid product 44 (1.6 g, yield 94%). The product can be directly used in the next step without purification.

Compound 45

Add intermediate 44 (5.0 g, 10.1 mmol, 1 eq) and dichloromethane (50 ml) to the reaction flask, stir and dissolve, then add triethylamine (2.0 g, 20.2 mmol, 2 eq) and N-iodosuccinimide (3.41 g, 15.15 mmol, 1.5 eq), and stir the reaction solution at room temperature for 12 h. TLC detection shows that the reaction is complete, add 50 mL of saturated sodium sulfite solution to quench and wash, then wash with 50 mL of saturated sodium chloride, concentrate the organic phase, and separate the residue by column chromatography (PE: EA4: 1-2: 1) to obtain yellow solid product 45 (2.2 g, 3.81 mmol, yield 37%). MS-ESI m/z: 577.0 [M].

Compound 46

Iodide 45 (1.3 g, 2.25 mmol, 1 eq) and 15 ml of dichloromethane were added to the reaction flask, and after stirring and dissolving, Boc ₂ O (0.74 g, 3.38 mmol, 1.5 eq), triethylamine (0.45 g, 2.51 mmol, 1.1 eq) and DMAP (27 mg, 225 μmol, 0.1 eq) were added. After the addition, the mixture was stirred at room temperature for 4 h. 50 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated, and the residue was subjected to column chromatography (PE: EA 3: 1) to obtain a yellow solid product 46 (1.3 g, yield 85%). MS-ESI m/z: 676 [M].

Compound 48

The intermediate 46 (1.0 g, 1.48 mmol, 1 eq) and DMF (15 ml) were added to the reaction flask, and after stirring and dissolving, Pd(PPh ₃ ) ₄ (170 mg, 0.1 eq), CuI (28 mg, 0.1 eq), triethylamine (300 mg, 2 eq) and trimethylsilyl acetylene (195 mg, 2 eq) were added. The reaction solution was reacted at 60°C for 4 h under nitrogen protection. After the reaction was complete by TLC, 50 mL of water was added to quench the reaction, and then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, and the residue 47 obtained by filtration and concentration was directly used for the next step reaction.

The crude product 47 (710 mg, 1.1 mmol) was dissolved in dichloromethane (10 ml), and 5 mL of trifluoroacetic acid was slowly added. The reaction solution was stirred at room temperature overnight. The solvent was evaporated after concentration under reduced pressure, and 50 mL of dichloromethane and 20 mL of water were added to the residue. The pH of the aqueous phase was adjusted to 6-7 with saturated sodium bicarbonate solution under stirring. The organic phase was collected and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phase was washed with saturated sodium chloride, dried and concentrated, and the residue was separated by silica gel column chromatography (P: EA 1: 1) to obtain a yellow solid product 48 (392 mg, two-step yield 56%). MS-ESI m/z: 475 [M+H] ⁺ .

Compound 49

Intermediate 48 (300 mg, 0.63 mmol, 1 eq) was added to a mixed solvent of tetrahydrofuran (5 mL)-methanol (2 mL)-water (1 mL), stirred and dissolved, and then lithium hydroxide monohydrate (54 mg, 1.26 mmol, 2 eq) was added. The mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. 10 mL of water was added to the residue, and pH was adjusted to 5-6 with 1N HCl. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, filtered and concentrated, and the crude product was purified by preparative HPLC. The chromatographic conditions were as follows: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL/min; gradient: mobile phase B increased from 20% to 60% in 15 minutes. After freeze drying, a yellow solid product 49 (75 mg, yield 26%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (s, 1H), 7.50 (s, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H), 5.78 (s, 1H), 4.08-4.12 (m, 1H), 3.84-3.87 (m, 1H), 3.65-3.74 (m, 3H), 3.48-3.58 (m, 3H), 3.03-3.06 (m, 1H), 2.63-2.80 (m, 2H); MS (ES, m/z): [M+H] ⁺ ＝461.

Example 7

Compound 51a

The intermediate 46 (1.0 g, 1.48 mmol, 1 eq) and DMF (15 ml) were added to the reaction flask, and after stirring and dissolving, Pd(PPh ₃ ) ₂ Cl ₂ (103.7 mg, 148 μmol, 0.1 eq), CuI (28 mg, 148 μmol, 0.1 eq), triethylamine (300 mg, 2.95 mmol, 2 eq) and cyclopropylacetylene (195 mg, 2.95 mmol, 2 eq) were added. The reaction liquid was reacted at room temperature for 12 h under nitrogen protection. After TLC detection, 50 mL of water was added to quench the reaction, and then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, and the residue 50a obtained by filtration and concentration was directly used for the next step reaction.

Compound 50a (900 mg, 1.46 mmol) was dissolved in dichloromethane (10 ml), and 5 mL of trifluoroacetic acid was slowly added. The reaction solution was stirred at room temperature for 4 h. After TLC detection, the reaction was completed, and the solvent was evaporated. The residue was added with 50 mL of dichloromethane and 20 mL of water. The pH of the aqueous phase was adjusted to 6-7 with saturated sodium bicarbonate solution under stirring. The organic phase was collected and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phase was washed with saturated sodium chloride, dried and concentrated. The residue was separated by silica gel column chromatography (PE: EA1: 1) to obtain a yellow solid product 51a (700 mg, two-step total yield 61%). MS-ESI m/z: 515.1 [M] ⁺ .

Compound 52a

Intermediate 51a (700 mg, 1.36 mmol, 1 eq) was added to a mixed solvent of tetrahydrofuran (5 mL)-methanol (2 mL)-water (1 mL), stirred and dissolved, then lithium hydroxide monohydrate (115 mg, 2.7 mmol, 2 eq) was added, stirred at room temperature overnight, the solvent was evaporated under reduced pressure, 10 mL of water was added to the residue, and pH was adjusted to 5-6 with 1N HCl, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried, filtered and concentrated, and the crude product was purified by preparative HPLC. The chromatographic conditions were as follows: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL/min; gradient: mobile phase B increased from 20% to 60% in 15 minutes. After freeze drying, product 52a (210 mg, yield 31%) was obtained as a yellow solid. ¹ HNMR (400 MHz, CDCl ₃ )δ7.81(d, J＝2.8Hz,1H),7.50(s,1H),7.38-7.41(m,1H),7.11-7.15(m,1H),6.99-7.03(m,1H),5.78(s,1H),4.08-4.12(m,1H),3.84-3.87(m,1H),3.65-3.74(m,3H),3.48-3.58(m,3H),3.03-3.06(m,1H),2.67-2.70(m,1H),1.25-1.29(m,1H),0.77-0.79(m,2H),0.60-0.63(m,2H); MS(ES,m/z):[M] ⁺ ＝501.

Compounds 52b , 52c , 53a , 53b , 53c and 54 were also prepared using the same synthetic route:

MS (ES, m/z): [M+H] ⁺ =519.

¹ HNMR (400 MHz, CDCl ₃ ) δ7.81 (d, J=2.8 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H), 5.75 (s, 1H), 4.08-4.30 (m, 2H), 3.84-3.87 (m, 1H), 3.65-3.74 (m, 3H), 3.48-3.58 (m, 3H), 3.03-3.06 (m, 1H), 2.67-2.70 (m, 1H); MS (ES, m/z): [M+H] ⁺ ＝491.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (m, 1H), 7.50 (m, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H), 5.78 (s, 1H), 4.08-4.12 (m, 2H), 3.80-3.85 (m, 1H), 3.28-3.38 (m, 3H), 2.93-2.96 (m, 1H), 2.57-2.60 (m, 1H), 1.05-1.59 (m, 6H), 0.77-0.79 (m, 2H), 0.60-0.63 (m, 2H).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60-7.80 (m, 2H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H), 5.80 (s, 1H), 4.01-4.10 (m, 2H), 3.87-3.90 (m, 3H), 3.78-3.84 (m, 1H), 3.28-3.38 (m, 3H), 2.93-2.96 (m, 1H), 2.57-2.60 (m, 1H), 1.05-1.59 (m, 5H).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (m, 1H), 7.61 (m, 1H), 7.48-7.51 (m, 1H), 7.15-7.17 (m, 1H), 6.97-7.00 (m, 1H), 5.88 (s, 1H), 4.08-4.12 (m, 2H), 3.68-3.86 (m, 4H), 3.48-3.58 (m, 3H), 3.03-3.06 (m, 1H), 2.67-2.70 (m, 1H), 1.05-1.59 (m, 5H).

MS (ES, m/z): [M+H] ⁺ =489.

Example 8: In vitro anti-HBV activity test

experimental method:

HepG2.2.15 cells were used to detect the anti-HBV activity of the test compounds.

HepG2.2.15 cells were seeded into 96-well microplates at a density of 3×10 ⁴ cells in 0.1 mL of culture medium per well, and the multiwell plates were incubated overnight at 37°C. The test compound and the control compound (entecavir, ETV) were diluted threefold with DMSO solvent to 8 different concentration points, and two replicate wells were measured in parallel. The starting concentration of the test compound was 10 μM. 100 μL of the compound DMSO solution with decreasing concentrations was added to the microwells on the plate, so that the final concentration of DMSO in each well was 0.5%. After six days of compound treatment of cells, the content of HBV DNA in the supernatant was detected by quantitative PCR, and cell viability was detected by CellTiter Glo.

GraphPad Prism software was used to calculate the _EC50 and _CC50 values of the compounds.

Experimental results:

According to the above method, the ability of the compounds of the present invention to inhibit HBV replication in vitro was determined. The results are shown in the following table:

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

Experimental results

Preliminary in vitro activity experiments confirmed that most of the 5-alkyl-substituted dihydropyridine derivatives of the present invention had an EC ₅₀ of less than 0.1 μM, showing strong anti-HBV activity, and all compounds did not show any cytotoxicity at 10 μM; in addition, since the disadvantage of inactivation by 5-esterase hydrolysis was avoided, the compounds of the present invention had better metabolic stability as HBV capsid protein inhibitors. This type of compound has unexpected antiviral activity and can be used to treat diseases caused by HBV infection.

The above contents are further detailed descriptions of the present invention in combination with specific preferred embodiments, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the protection scope of the present invention.

Claims (33)

1. A compound of formula (III-5), (III-6) or (III-8), or a pharmaceutically acceptable salt thereof, and a mixture thereof, in, R' and R" are H; R ₁ is selected from halogen or -C(O)OR _a ; _R2 and _R3 are H; _R4 is -( _C1-6 alkylene)-C(O)OH; R _a is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; R _d is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; R ₆ ′ and R ₆ ″ are halogen. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein R ₁ is selected from Br, Cl or -C(O)OMe. 3. The compound according to claim 1, or a pharmaceutically acceptable salt _thereof , and a mixture thereof, wherein _R4 is _-CH2CH2C (O)OH. 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein Ra _is independently selected from _C1-6 alkyl or _C1-6 haloalkyl. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _{Rd is} independently selected from _C1-6 alkyl or _C1-6 haloalkyl. 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein R ₆ ′ is F, and R ₆ ″ is Cl or Br. 7. A compound of formula (III-9), or a pharmaceutically acceptable salt thereof, and a mixture thereof, in, R ₁ is selected from halogen or -C(O)OR _a ; R ₄ is H or -(C _1-6 alkylene)-C(O)OH; R ₄ is (R) configuration; R ₅ is H or -C(O)OR _d ; R ₅ is (S) configuration; At least one of _R4 and _R5 is a non-hydrogen group; R ₆ ′ and R ₆ ″ are halogen; R _a is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; R _d is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl. 8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R1 is selected from Br, Cl or -C(O)OMe. 9. The compound according to claim 7, or a pharmaceutically acceptable salt _thereof , and a mixture thereof, wherein _R4 is H or _-CH2CH2C (O)OH. 10. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein R ₅ is H, -C(O)OH or -C(O)OMe. 11. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein R ₆ ′ is F, and R ₆ ″ is Cl or Br. 12. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein Ra _is independently _C1-6 alkyl or _C1-6 haloalkyl. 13. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _Rd is H. 14. A compound of formula (IV-4) or (IV-5), or a pharmaceutically acceptable salt thereof, and a mixture thereof, in, R ₁ is selected from -C(O)OR _a , C _1-6 alkyl or C _3-7 carbocyclyl; _R4 is -( _C1-6 alkylene)-C(O)OH; R ₅ is -C(O)OR _d ; R ₆ ′ and R ₆ ″ are halogen; R _a is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; R _d is selected from H, C _1-6 alkyl or C _1-6 haloalkyl. 15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R1 is selected from _C1-6 alkyl or _C3-7 carbocyclyl. 16. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R1 is selected from H, cyclopropyl, -C(O)OMe or _-CH2OH . 17. The compound according to claim 14, or a pharmaceutically acceptable salt _thereof , and a mixture thereof, wherein _R4 is _-CH2CH2C (O)OH. 18. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R5 is -C(O)OH. 19. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein R ₆ ′ is F, and R ₆ ″ is Cl or Br. 20. The compound according to claim 14 or 15, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein Ra _is H. 21. A compound of formula (IV-6), or a pharmaceutically acceptable salt thereof, and a mixture thereof, in, R ₁ is selected from C _1-6 alkyl, -C(O)OR _a or C _3-7 carbocyclyl; R ₄ is -(C _1-6 alkylene)-C(O)OH; R ₄ is (R) configuration; R ₅ is H or -C(O)OR _a ; R ₅ is (S) configuration; At least one of _R4 and _R5 is a non-hydrogen group; R ₆ ′ and R ₆ ″ are halogen; _Ra is selected from H, _C1-6 alkyl or _C1-6 haloalkyl. 22. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R1 is selected from cyclopropyl or -C(O)OMe. 23. The compound according to claim 21, or a pharmaceutically acceptable salt _thereof , and a mixture thereof, wherein _R4 is H or _-CH2CH2C (O)OH. 24. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R5 is H, -C(O)OH or -C(O)OMe. 25. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein _R5 is H or -C(O)OH. 26. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein R ₆ ′ is F, and R ₆ ″ is Cl or Br. 27. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, and a mixture thereof, wherein Ra _is H. 28. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 30. The pharmaceutical composition according to claim 29, further comprising other therapeutic agents. 31. A kit comprising A first container containing a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof; and optionally, a second container containing other therapeutic agents; and optionally, a third container containing a pharmaceutical excipient for diluting or suspending the compound and/or other therapeutic agents. 32. Use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing viral infection. 33. The use of claim 32, wherein the virus is hepatitis B virus.