A class of heterocyclic l(p) inhibitors

Abstract

The present application provides a class of heterocyclic compounds as Lp(a) inhibitors, which are compounds represented by formula (I), isotopic variants, tautomers or stereoisomers. The present application also provides pharmaceutical compositions comprising the compounds, and their use in treating diseases associated with Lp(a).

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to Lp(a) inhibitors. Background Technology

[0002] Lipoprotein(a) (Lp(a)) is a lipoprotein particle formed by the interaction of low-density lipoprotein (LDL) particles and apolipoprotein(a) (apo(a)). Studies have shown that Lp(a) has properties that promote atherosclerosis, thrombosis, and inflammation, and is an independent risk factor for cardiovascular disease.

[0003] Epidemiological studies show that approximately 20% of the population has elevated serum Lp(a) levels (Lp(a) > 125 nmol / L (or approximately 50 mg / dL)). Expert consensus from multiple countries and regions agrees that lowering Lp(a) levels will help reduce the risk of cardiovascular disease and improve clinical outcomes. However, currently available methods for lowering Lp(a) include statins, PCSK9 inhibitors, and LDL apheresis, but their effectiveness is limited. Therefore, drugs that specifically lower Lp(a) are needed. Currently, no drugs specifically lowering Lp(a) have been approved for marketing. Several drugs are in clinical trials, primarily small nucleic acid drugs, with only one small molecule drug, muvalaplin, among them.

[0004] In conclusion, there is still a need to develop more highly active drugs that specifically reduce Lp(a) to meet the clinical needs of diseases associated with elevated Lp(a). Summary of the Invention

[0005] In this invention, we discovered a series of small molecule inhibitors that can significantly inhibit Lp(a) assembly and reduce Lp(a) levels.

[0006] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0007] (I)

[0008] in,

[0009] X, Y, and Z are independently selected from -CH2-, -CH2CH2-, -CH2CH2-O-, -CH2CH2-S-, -(C=O)-, -(SO2)-, and -(C=O)-NH-.

[0010] , , Independently selected from phenyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic groups, said group being R 1 R 2 R 3 replace;

[0011] R 1 R 2 R 3 Selected independently , , , Halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, phosphoxy, sulfonyl, , ;

[0012] And R 1 R 2 R 3 At least one of them is selected from , , , , -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups, -SF5;

[0013] R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups;

[0014] R b Selected from -(CH2) p -4-8 membered heterocyclic group, 5-6 membered heteroaryl group, C 3-8 cycloalkyl groups, the 4-8 membered heterocyclic groups, 5-6 membered heteroaryl groups, C 3-8 Cycloalkyl groups can be further converted by halogens, amino groups, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC1-6 Halogenated alkyl substitution;

[0015] m, n, and o are selected from 1, 2, 3, and 4;

[0016] p is selected from 0, 1, 2.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0018] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0019] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating diseases related to Lp(a).

[0020] In another aspect, the present invention provides a method for treating a disease related to Lp(a) in a subject, comprising administering a compound or composition of the present invention to the subject.

[0021] In another aspect, the present invention provides compounds or compositions thereof for the treatment of diseases associated with Lp(a).

[0022] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0023] definition

[0024] Chemical definition

[0025] The definitions of specific functional groups and chemical terms are described in more detail below.

[0026] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 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.

[0027] “C1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0028] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0029] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0030] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl and C 3-5 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linkage is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] "3-10 membered heterocyclic groups" refer to groups with a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 4-9 membered heterocyclic group is preferred, which is a 4-9 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5-8 membered heterocyclic group is preferred, which is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-8 membered heterocyclic group is preferred, which is a 3-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-7 membered heterocyclic group is preferred, which is a 4-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, 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, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl.Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring (e.g., having 6 or 10 shared π electrons arranged in a ring) having a ring carbon atom 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 bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point 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, 5-9-membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-9-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. 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 (e.g., 1,2,4-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: pyridinyl. 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 tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0035] The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0036] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb 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 SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa)3、-OSi(R aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0037] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or =NOR cc replace;

[0038] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0039] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0040] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0041] R ddEach is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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 -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R 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 SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R 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)2Ree -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0042] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0043] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0044] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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 - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 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)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0045] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0046] Other definitions

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0048] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women 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, such as 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.

[0049] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0050] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0051] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation

[0052] In this document, “compounds of the present invention” refers to compounds of formula (I) (including sub-formulas, such as formulas (II), (III) etc.) or isotopic variants, tautomers or stereoisomers, and mixtures thereof.

[0053] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or isotopic variant, tautomer or stereoisomer thereof:

[0054] (I)

[0055] in,

[0056] X, Y, and Z are independently selected from -CH2-, -CH2CH2-, -CH2CH2-O-, -CH2CH2-S-, -(C=O)-, -(SO2)-, and -(C=O)-NH-.

[0057] , , Independently selected from phenyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic groups, said group being R 1 R 2 R 3 replace;

[0058] R 1 R 2 R 3 Selected independently , , , Halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, phosphoxy, sulfonyl, , ;

[0059] And R 1 R 2 R 3 At least one of them is selected from , , , , -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups, -SF5;

[0060] R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups;

[0061] R b Selected from -(CH2) p -4-8 membered heterocyclic group, 5-6 membered heteroaryl group, C 3-8cycloalkyl groups, the 4-8 membered heterocyclic groups, 5-6 membered heteroaryl groups, C 3-8 Cycloalkyl groups can be further converted by halogens, amino groups, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl substitution;

[0062] m, n, and o are selected from 1, 2, 3, and 4;

[0063] p is selected from 0, 1, 2.

[0064] In another embodiment, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the following general formula structure:

[0065] (II)

[0066] in,

[0067] X, Y, Z, R 1 R 2 R 3 The ranges of m, n, and o are the same as in claim 1.

[0068] In another embodiment, the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the following general formula structure:

[0069] (III)

[0070] Where X, Y, Z, R 1 R 2 R 3 The ranges of m, n, and o are the same as in claim 1.

[0071] In another embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein said compound is selected from:

[0072] , , , , , , , , , , , , , , .

[0073] Those skilled in the art will understand that the present invention also includes isotopically labeled compounds (isotope variants) that are equivalent to those described in formula (A), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those 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, respectively, for example... 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. Compounds of the present invention containing the aforementioned isotopes and / or other isotopes, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, such as those incorporating radioactive isotopes (e.g., 3H and 14C), can be used for drug and / or substrate tissue distribution assays. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0074] Pharmaceutical Compositions and Kits

[0075] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0076] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0077] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0078] Dosage

[0079] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0080] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0081] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0082] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0083] 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 bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0084] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, for the purpose of precise dosing, the compositions are provided in unit dose form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0085] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0086] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically chosen in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0087] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0088] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0089] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0090] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0091] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0092] The above-described components for oral, injectable, or topical administration are merely representative. 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.

[0093] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0094] This invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether-substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0095] Example

[0096] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using common methods known in the art.

[0097] Abbreviations: PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; MeCN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; THF = tetrahydrofuran; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1-propyl phosphate cyclohydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride; DMA = N,N-dimethylacetamide.

[0098] Example 1: Preparation of key intermediates

[0099] Composition of intermediate int 1

[0100]

[0101] Step 1: Under nitrogen protection, int 1-1 (20.0 g, 87.23 mmol) was added to THF (200 mL) at 10 °C, followed by the addition of TEA (13.2 g, 130.8 mmol). After stirring for 5 minutes, Pivaloyl chloride (13.2 g, 109.04 mmol) was added. After stirring for another 15 minutes, LiCl (4.6 g, 109.04 mmol) and int 1-2 (15.5 g, 87.23 mmol) diluted in THF (200 mL) were added. The mixture was heated to room temperature and stirred for 24 h. 1N HCl aqueous solution (200 mL) was added to separate the organic phase from the aqueous phase. The organic phase was washed with 1N NaOH aqueous solution (200 mL) and saturated NaCl aqueous solution (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude solid was added to a methanol / water mixture (1:2, 575 mL) and stirred at room temperature for 2 days. The solid was filtered off, washed with n-hexane (2 × 150 mL), and dried to give compound int 1-3 (30.0 g, yield 88.5%). LCMS: ESI-MS (m / z): [M+H] + -56=333.

[0102] Step 2: Under nitrogen protection, LiHMDS (16.0 g, 95.76 mmol) was slowly added dropwise to int 1-3 (31.0 g, 79.80 mmol) dissolved in THF (1.3 L) in an ice bath. The mixture was stirred in an ice bath for 50 min. Then, int 1-4 (23.9 g, 95.76 mmol) dissolved in THF (300 mL) was added dropwise. The reaction system was slowly heated to room temperature and reacted for 12 h. The reaction was monitored by LC-MS until completion. The reaction mixture was then cooled in an ice / water bath, and a saturated aqueous solution of NH4Cl (1 L) was added in portions. Water (1 L) was added to the mixture and extracted with MTBE (3.5 L). The organic layer was washed with a mixture of water (1 L) and a saturated aqueous solution of NaCl (500 mL), and then with a saturated aqueous solution of NaCl (500 mL). The organic matter was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (35% PE / EA) to obtain orange oil int 1-5 (22.0 g, 49.5%). LCMS: ESI / MS (m / z): [M+H] + -56 = 501 / 503.

[0103] Step 3: Under nitrogen protection, H₂O₂ (1.5 g, 43.05 mmol) was added in one batch to int 1-5 (16 g, 28.70 mmol) dissolved in THF (10 mL). Then, LiOH (1.81 g, 43.05 mmol) dissolved in H₂O (2 mL) was added in portions, and the reaction temperature was raised to room temperature. The reaction was stirred at room temperature for 2.5 h, and the reaction was monitored for completion by LC-MS. Then, an aqueous solution of sodium bisulfite was slowly added dropwise under ice bath conditions. Subsequently, an aqueous solution of NaOH (5N) was added to the reaction mixture until the pH was approximately 12, followed by the addition of water (100 mL) and MTBE (400 mL). The layers were separated, and the aqueous layer was extracted with MTBE (200 mL). The organic matter was combined, and MTBE (300 mL) was added. The aqueous solution was stirred, and the mixture was cooled to 5°C. An aqueous solution of hydrochloric acid (5N) was then added to bring the pH of the mixture to approximately 3. The layers were separated and the organic layer was washed with a mixture of saturated NaCl aqueous solution (100 mL) and water (500 mL). The organic matter was dried over Na₂SO₄, filtered, and concentrated to give int 1-6 (14.0 g, 22.5%) as a white solid. LCMS: ESI / MS (m / z): [M+H] + -56 = 342 / 344.

[0104] Step 4: Under nitrogen protection, int 1-6 (10.0 g, 25.1 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL), and int 1-7 (18.0 g, 87.9 mmol) was added. The mixture was stirred at 65 °C for 3 hours. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, the solid was filtered off, and the organic layer was washed with saturated NaHCO3 aqueous solution (300 mL). The organic layer was concentrated to obtain a solid product. MTBE (300 mL) was added to the solid product, stirred, and filtered. The filtrate was concentrated to give int 1-8 (8.9 g, 78.0%) as a white solid. LCMS: ESI / MS (m / z): [M+H] + -112 = 342 / 344.

[0105] Step 5: Under nitrogen protection, int 1-8 (8.7 g, 19.15 mmol) was dissolved in 1,4-Dioxane (87 mL) and H2O (2 mL), followed by int 1-9 (3.5 g, 22.98 mmol), Pd(PPh3)4 (2.2 g, 1.92 mmol), and K2CO3 (7.9 g, 57.45 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction was monitored by LC-MS until complete. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with EA, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography (60% PE / EA) to obtain a white solid, int 1-10 (3.7 g), yield: 48.1%. LCMS: ESI-MS (m / z): [M+H] + =402.

[0106] Step 6: Under nitrogen protection, int 1-10 (3.0 g, 7.47 mmol) was dissolved in 1,4-Dioxane (30 mL), K₂O₅O₄ (0.28 g, 0.75 mmol) was added, and the mixture was stirred for 15 minutes. Then, an aqueous solution of NaIO₄ (3.2 g, 14.94 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, diluted with water, extracted three times with EA, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography (60% PE / EA) to obtain an oily compound, int 1-11 (2.5 g), yield: 82.9%. LCMS: ESI-MS (m / z): [M+H] + =404.

[0107] Step 7: Under nitrogen protection, compound int 1-11 (4.0 g, 9.91 mmol), pyridine (1.6 g, 19.82 mmol), and NH2OH·HCl (1.0 g, 14.87 mmol) were dissolved in EtOH (5 mL). The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, diluted with water, extracted three times with EA, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography (60% PE / EA) to give the oily compound int 1-12 (1.8 g), yield: 43.4%. LCMS: ESI-MS (m / z): [M+H] + -56 = 319.

[0108] Step 8: Under nitrogen protection, int 1-12 (1.8 g, 4.30 mmol) was dissolved in NH3-MeOH (7 M, 20 mL), and Ni (0.4 g, 6.02 mmol) was added. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, diluted with water, filtered, and the filter cake was washed three times with methanol. The filtrate was concentrated to obtain the oily compound int 1-13 (1.7 g), yield: 97.7%. LCMS: ESI-MS (m / z): [M+H] + =405.

[0109] Step 9: Under nitrogen protection, int 1-13 (1.5 g, 3.61 mmol) was dissolved in isopropanol (15 mL), and int 1-11 (1.5 g, 3.61 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.68 g, 10.83 mmol) was added, and stirring continued for 16 hours. The reaction was monitored by LC-MS until complete. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography (60% PE / EA) to obtain a white solid, int 1 (1.8 g), yield: 63.0%. LCMS: ESI-MS (m / z): [M+H] + =792.

[0110] 1H NMR (400 MHz, CDCl3, ppm) δ 7.25 - 7.19 (m, 2H), 7.18 - 7.09 (m,4H), 7.08 - 7.01 (m, 2H), 3.78 - 3.68 (m, 4H), 3.62 -3.49 (m, 2H), 3.48 -3.38 (m, 1H), 3.32 - 3.18 (m, 2H), 3.08 - 2.91 (m, 2H), 2.89 - 2.72 (m, 4H), 2.49 (s, 2H), 2.42 - 2.30 (m, 2H), 1.99 - 1.87 (m, 2H), 1.64 (s, 4H), 1.44(s, 18H), 1.26 (s, 18H).

[0111] Composition of intermediate int 2

[0112]

[0113] Step 1: Compound int 2-1 (500.0 mg, 2.67 mmol) and TEA (814.0 mg, 8.06 mmol) were dissolved in dichloromethane (5 mL). Methylsulfonyl chloride (306.0 mg, 2.69 mmol) was then added under ice bath conditions. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction was monitored by LC-MS until complete, at which point the reaction was stopped. The reaction solution was diluted with water upon cooling, extracted three times with DCM, and the organic phase was dried and concentrated to obtain crude int 2-2. The crude product was used directly in the next step of the reaction without purification; yield: 99%. LCMS: ESI-MS (m / z): [M+H] + -56 = 209.

[0114] Step 2: Compound int 2-2 (660.0 mg, 2.50 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of int 2-3 (495.0 mg, 2.50 mmol) and cesium carbonate (2.43 g, 7.50 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS until complete, at which point the reaction was stopped. The mixture was diluted with water, extracted three times with DCM, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE-60%EA) to obtain a colorless oily compound int 2 (643.0 mg), yield: 67%. LCMS: ESI-MS (m / z): [M+H] + -100 = 283.

[0115] Int 3 is synthesized using a method similar to that used to synthesize int 2.

[0116]

[0117] Composition of intermediate int 4

[0118]

[0119] Step 1: Under nitrogen protection, compound int 4-1 (1.0 g, 6.57 mmol) and trimethyl orthoacetate (1.1 g, 9.86 mmol) were added to the solvent MeOH (10 mL), followed by p-TsOH (0.1 g, 0.66 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The reaction solution was cooled to room temperature, diluted with water, extracted three times with EA, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (30% PE / EA) to obtain a white solid compound int 4-2 (1.1 g), yield: 95.0%. LCMS: ESI-MS (m / z): [M+H] + =199.

[0120] Step 2: Under nitrogen protection, compound int 4-2 (1.1 g, 5.50 mmol) was dissolved in MeOH (10 mL), and (NH4)2CO3 (2.6 g, 27.48 mmol) and iodophenyldiacetic acid (8.9 g, 27.48 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until complete. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with EA, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (45% PE / EA) to obtain compound int 4-3 (0.9 g), yield: 89.4%. LCMS: ESI-MS (m / z): [M+H] + =230.

[0121] Step 3: Under nitrogen protection, compound int 4-3 (0.2 g, 0.87 mmol) was dissolved in DCM (2 mL), and HCl-Dioxane (4 M, 2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the solution was purified by silica gel column chromatography (40% PE / EA) to obtain compound int 4 (0.1 g), yield: 62.8%. LCMS: ESI-MS (m / z): [M+H] + =184.

[0122] Example 2 Preparation of the target compound

[0123] Preparation of target molecule P1

[0124]

[0125] Step 1: Under nitrogen protection, compound int 2 (38.0 mg, 0.10 mmol) was dissolved in isopropanol (3 mL), followed by int 1 (40.0 mg, 0.05 mmol) and two drops of acetic acid. After addition, the reaction system was stirred at room temperature for 1 h. Then, sodium cyanoborohydride (10.0 mg, 0.15 mmol) was added, and the reaction system was stirred at room temperature for 16 h. The reaction was stopped after TLC monitoring showed complete reaction. The product was diluted with water, extracted three times with EA, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by Prep-TLC (PE:EA = 1:1) to give a colorless oily product P 1-1 (40.0 mg), yield: 69%.

[0126] Step 2: Compound P1-1 (40.0 mg, 0.03 mmol) was dissolved in 3 mL of hydrochloric acid-dioxane solution. After the addition was complete, the reaction system was stirred at room temperature for 5 h. The reaction was stopped after LC-MS monitoring to ensure complete reaction. The solution in the reaction mixture was aspirated, washed with dioxane, concentrated, and dried to obtain a pale yellow solid compound P1 (20.0 mg), yield: 89%. LCMS: ESI-MS (m / z): [M+H] + = 746.

[0127] 1H NMR (400 MHz, D2O, ppm) δ 7.51 (d, J = 3.2 Hz, 2H), 7.47 – 7.41 (m,2H), 7.39 (d, J = 7.6 Hz, 3H), 7.32 (d, J = 1.6 Hz, 1H), 7.27 – 7.19 (m, 4H),4.55 (s, 2H), 4.36 (d, J = 7.6 Hz, 6H), 3.70 – 3.61 (m, 2H), 3.60 – 3.52 (m,1H), 3.51 – 3.41 (m, 3H), 3.33 – 3.21 (m, 4H), 3.20 – 3.14 (m, 4H), 3.11 (d,J = 11.2 Hz, 2H), 3.03 – 2.95 (m, 2H), 2.89 (t, J = 11.2 Hz, 2H), 2.80 – 2.75(m, 2H), 2.66 – 2.56 (m, 2H), 2.37 – 2.30 (m, 1H), 2.24 – 2.16 (m, 2H), 2.14 – 2.01 (m, 1H), 1.88 – 1.70 (m, 2H).

[0128] Following the synthetic route of compound P1, and using similar intermediate structures and methods, the following target molecules or key intermediates were synthesized:

[0129]

[0130] Preparation of target molecule P4

[0131]

[0132] Step 1: Compound int 5 (200.0 mg, 0.49 mmol) was dissolved in a mixed solvent of THF (4 mL) and H2O (1 mL), and LiOH·H2O (42.1 mg, 0.98 mmol) was added. The mixture was stirred at room temperature for 1 h, and the reaction was stopped after LC-MS monitoring to ensure completion. The mixture was diluted with water, and the pH of the reaction system was adjusted to weakly acidic with dilute hydrochloric acid (1N). The mixture was extracted three times with DCM, and the organic phase was dried and concentrated to give a white solid compound P4-1 (160 mg), yield: 83%. LCMS: ESI-MS (m / z): [MH] - =397.

[0133] Step 2: Compound P4-1 (160.0 mg, 0.40 mmol) and compound int 1 (318.3 mg, 0.40 mmol) were dissolved in DMF (3 mL), followed by the sequential addition of HATU (228.1 mg, 0.60 mmol) and DIPEA (156.0 mg, 1.20 mmol). After the addition was complete, the reaction mixture was reacted at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS until complete, at which point the reaction was stopped. The mixture was diluted with water, extracted three times with EA, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography (65% acetonitrile) to obtain a white solid compound P4-2 (60 mg), yield: 13%. LCMS: ESI-MS (m / z): [M+H] + =1172.

[0134] Step 3: Compound P4-2 (60.0 mg, 0.05 mmol) was dissolved in DCM (0.5 mL), and then 3 mL of hydrochloric acid-dioxane solution was added. After the addition was complete, the reaction system was stirred at room temperature for 1 h. The reaction was monitored by LC-MS until complete, and then the reaction was stopped. The reaction solution was concentrated under reduced pressure to obtain a white solid compound P4 (16.0 mg), yield: 42%. LCMS: ESI-MS (m / z): [M+H] + = 760.

[0135] 1H NMR (400 MHz, D2O) δ 7.53-7.51 (m, 2H), 7.47-7.45 (m, 2H), 7.38 (t,J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.20 (d,J = 8.0 Hz, 2H), 7.14 (s, 1H), 6.97-6.95 (m, 2H), 4.73-4.69 (m 3H), 4.53 (s,2H), 4.47 (d, J = 4.0 Hz, 2H), 3.66-3.59 (m 2H), 3.50-3.43 (m, 2H), 3.39-3.25(m, 4H), 3.18 – 3.07 (m, 3H), 3.10 (s, 3H), 3.01 – 2.87 (m, 5H), 2.81 – 2.71(m, 2H), 2.65-2.59 (m, 2H), 2.24– 2.17 (m, 3H), 2.02-1.94 (m, 1H), 1.86-1.78(m, 2H).

[0136] Example 3: Assay of the compound's ability to inhibit the assembly of Lp(a)

[0137] This method utilizes ELISA to detect the activity of compounds in inhibiting the assembly of Apo(a) and ApoB proteins into Lp(a).

[0138] Equimolar amounts of culture supernatant from wild-type HepG2 cells (endogenous ApoB source), recombinant Apo(a) protein, and the test compound (serially diluted) were mixed and incubated at 37°C for 2 hours. The reaction was then terminated by adding 150 mM 6-aminocaproic acid (EACA). The resulting solution was added to an ELISA plate pre-coated with ApoB-Capture antibody and incubated at room temperature for 2 hours, followed by 4 washes. Apo(a)-Detector antibody was added and incubated at room temperature for 1 hour. After washing, HRP-labeled secondary antibody was added and incubated at room temperature for 1 hour. After washing, chromogenic substrate 3,3,5,5'-tetramethylbenzidine (TMB) solution was added. After incubation at 37°C for 20-30 minutes, 1 M sulfuric acid was added to terminate the reaction. After mixing, the absorbance at 450 nm was immediately measured using a microplate reader. The 0% inhibition rate of Apo(a) and ApoB protein assembly corresponds to the OD value at a compound concentration of 0 (0.17% DMSO); the 100% inhibition rate of Apo(a) and ApoB protein assembly corresponds to the OD value at a reference compound (Muvalaplin) concentration of 3 nM.

[0139] Based on the inhibition rate data, curve fitting was performed to calculate IC. 50 Values. See Table 1 for specific experimental results.

[0140] Table 1. Inhibitory activity of compounds on Lp(a) assembly

[0141]

[0142] The structure of the compound Muvalaplin is as follows:

[0143]

[0144] The test results above show that the molecule of the present invention has an excellent inhibitory effect on the assembly of Lp(a) and is a highly active Lp(a) inhibitor.

Claims

1. A compound of formula (Ⅰ), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: (Ⅰ) in, X, Y, and Z are independently selected from -CH2-, -CH2CH2-, -CH2CH2-O-, -CH2CH2-S-, -(C=O)-, -(SO2)-, and -(C=O)-NH-. , , Independently selected from phenyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic groups, said group being R 1 R 2 R 3 replace; R 1 R 2 R 3 Selected independently , , , Halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, -SF5, phosphoxy, sulfonyl, , ; And R 1 R 2 R 3 At least one of them is selected from , , , , -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups, -SF5; R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups; R b Selected from -(CH2) p -4-8 membered heterocyclic group, 5-6 membered heteroaryl group, C 3-8 cycloalkyl groups, the 4-8 membered heterocyclic groups, 5-6 membered heteroaryl groups, C 3-8 Cycloalkyl groups can be further converted by halogens, amino groups, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl substitution; m, n, and o are selected from 1, 2, 3, and 4; p is selected from 0, 1, 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the following general formula: (ⅠI) in, X, Y, Z, R 1 R 2 R 3 The ranges of m, n, and o are the same as in claim 1.

3. The compound of claims 1 and 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the following general formula: (ⅠII) in, X, Y, Z, R 1 R 2 R 3 The ranges of m, n, and o are the same as in claim 1.

4. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator, optionally other therapeutic agents.

6. Use of any compound of claims 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, in the preparation of a medicament for the treatment and / or prevention of diseases associated with elevated Lp(a) levels.

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