Compound, pharmaceutical composition containing same and application thereof

Abstract

The invention relates to a compound with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, and also relates to a pharmaceutical composition containing the compound, a preparation method and application thereof.

Description

A compound, a pharmaceutical composition containing the same and its use Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and biopharmaceuticals. Specifically, the present invention relates to a compound having a novel structure of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, and use thereof in the preparation of a medicament for preventing or treating diseases of extracellular matrix protein abnormalities and diseases associated with elevated intraocular pressure. Background Art

[0002] Glycoside compounds can play a relatively good role in anti-oxidation, anti-inflammation, anti-ischemia-reperfusion injury, vascular smooth muscle relaxation, nerve protection, anti-fatigue, anti-aging, immune regulation, relief of corneal epithelial cell oxidative damage caused by dry eye, and anti-liver, lung and kidney fibrosis.

[0003] Nitric oxide (NO) is an important intercellular signaling factor. Nitric oxide (NO) can be synthesized in vivo by nitric oxide synthase or released by drugs (such as nitroglycerin). NO binds to soluble guanylate cyclase (sGC) and then converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP). cGMP is a second messenger that regulates smooth muscle relaxation and vasodilation as well as many other important biological processes, such as platelet inhibition and cell growth and differentiation. Nitric oxide plays an important physiological role in regulating optic nerve head blood flow and intraocular pressure (IOP). In the optic nerve head, NO donors reduce vascular resistance by relaxing smooth muscle, resulting in local vasodilation and increased optic nerve head blood flow. Conversely, damage to the NO pathway reduces blood flow to the optic nerve head, leading to ischemia and optic nerve damage.

[0004] Glaucoma is a group of eye diseases characterized by retinal ganglion cell degeneration, specific optic nerve atrophy, and progressive visual field loss. It is primarily associated with pathologically elevated intraocular pressure and is the most common cause of irreversible blindness. The signaling pathways involved in the pathogenesis of glaucoma are complex, and downstream signaling factors often intersect with each other. However, they primarily regulate the development of glaucoma by upregulating the expression of pro-apoptotic genes, downregulating neuroprotective and regenerative factors, and promoting trabecular meshwork fibrosis, leading to aqueous humor drainage obstruction and ultimately glaucoma. Current clinical medications for primary open-angle glaucoma primarily aim to lower intraocular pressure by reducing aqueous humor production and / or promoting aqueous humor outflow. None of these medications directly target the pathological mechanism of aqueous humor outflow obstruction in glaucoma, effectively treating the symptoms rather than the root cause. Therefore, a drug that can improve trabecular meshwork fibrosis while simultaneously lowering intraocular pressure is urgently needed to address both the symptoms and the root cause.

[0005] CN109045049A discloses the use of a glycoside compound in the preparation of a disease inhibitor drug for treating and preventing ophthalmic fibrosis, extracellular matrix protein abnormalities, high intraocular pressure, and the like. Summary of the Invention

[0006] In a first aspect, the present invention provides a compound having the structure of the following formula (I):

[0007] or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] R 1 、R 2 、R 3 、R 4 and R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, acyl, -NO2 and -L-R', wherein each alkyl, alkenyl, alkynyl is unsubstituted or substituted by at least one independently selected R X Substituents substituted;

[0010] -L- is -(CH2) o -, wherein each -(CH2)- is independently optionally replaced by a carbonyl group or -O-;

[0011] R' is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NO2, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl is unsubstituted or substituted by at least one independently selected R X Substituents substituted;

[0012] Among them, the R 1 、R 2 、R 3 、R 4 、R 5 and R' at least one is NO2;

[0013] R 6 、R 7 、R 8 and R 9 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-SC 1-6Alkyl, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X Substituents substituted;

[0014] Each R 10 、R 11 、R 12 and R 13 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1- 6-Alkyl-SC 1-6 Alkyl, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X Substituents substituted;

[0015] R X Selected from hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl and 5-10 membered heteroaryl, wherein each hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, heteroaryl is unsubstituted or substituted by at least one independently selected R Y Substituents substituted;

[0016] R Y Selected from hydroxyl, halogen, cyano, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0017] 1* C. 2* C. 3* C. 4* C and 5* C represents a carbon atom that may have chirality in the compound of formula (I);

[0018] o, m and n are each independently selected from integers of 0-6.

[0019] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0020] In a third aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, improving or preventing diseases of abnormal extracellular matrix proteins, such as ophthalmic fibrosis, and diseases associated with high intraocular pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figures 1A-1C show the effects of different concentrations of the compound RM-G-002M of the present invention on the extracellular matrix of the human trabecular meshwork induced by dexamethasone. Figure 1A shows the effects of different concentrations of the compound RM-G-002M of the present invention on fibronectin (FN) mRNA levels; Figure 1B shows the effects of different concentrations of the compound RM-G-002M of the present invention on type IV collagen (COL-IV) mRNA levels; Figure 1C shows the effects of different concentrations of the compound RM-G-002M of the present invention on laminin (LN) mRNA levels.

[0022] Figures 2A-2C show the effects of different concentrations of the compound RM-G-003M of the present invention on dexamethasone-induced human trabecular meshwork extracellular matrix. Figure 2A shows the effects of different concentrations of the compound RM-G-003M of the present invention on FN mRNA levels; Figure 2B shows the effects of different concentrations of the compound RM-G-003M of the present invention on COL-IV mRNA levels; and Figure 2C shows the effects of different concentrations of the compound RM-G-003M of the present invention on LN mRNA levels.

[0023] Figures 3A-3C show the effects of different concentrations of the compound RM-G-004M of the present invention on dexamethasone-induced human trabecular meshwork extracellular matrix. Figure 3A shows the effects of different concentrations of the compound RM-G-004M of the present invention on FN mRNA levels; Figure 3B shows the effects of different concentrations of the compound RM-G-004M of the present invention on COL-IV mRNA levels; and Figure 3C shows the effects of different concentrations of the compound RM-G-004M of the present invention on LN mRNA levels.

[0024] Figures 4A-4C show the effects of different concentrations of the compound RM-G-005M of the present invention on dexamethasone-induced human trabecular meshwork extracellular matrix. Figure 4A shows the effects of different concentrations of the compound RM-G-005M of the present invention on FN mRNA levels; Figure 4B shows the effects of different concentrations of the compound RM-G-005M of the present invention on COL-IV mRNA levels; and Figure 4C shows the effects of different concentrations of the compound RM-G-005M of the present invention on LN mRNA levels.

[0025] Figures 5A-5C show the effects of different concentrations of the compound RM-G-006M of the present invention on dexamethasone-induced human trabecular meshwork extracellular matrix. Figure 5A shows the effects of different concentrations of the compound RM-G-006M of the present invention on FN mRNA levels; Figure 5B shows the effects of different concentrations of the compound RM-G-006M of the present invention on COL-IV mRNA levels; and Figure 5C shows the effects of different concentrations of the compound RM-G-006M of the present invention on LN mRNA levels.

[0026] Figures 6A-6C show the effects of different concentrations of the compound RM-G-007M of the present invention on dexamethasone-induced human trabecular meshwork extracellular matrix. Figure 6A shows the effects of different concentrations of the compound RM-G-007M of the present invention on FN mRNA levels; Figure 6B shows the effects of different concentrations of the compound RM-G-007M of the present invention on COL-IV mRNA levels; and Figure 6C shows the effects of different concentrations of the compound RM-G-007M of the present invention on LN mRNA levels.

[0027] Figures 7A-7C show the effects of different concentrations of the compound RM-G-008M of the present invention on the extracellular matrix of the human trabecular meshwork induced by dexamethasone. Figure 7A shows the effects of different concentrations of the compound RM-G-008M of the present invention on FN mRNA levels; Figure 7B shows the effects of different concentrations of the compound RM-G-008M of the present invention on COL-IV mRNA levels; Figure 7C shows the effects of different concentrations of the compound RM-G-008M of the present invention on LN mRNA levels.

[0028] Figures 8A-8C show the effects of different concentrations of the compound RM-G-009M of the present invention on dexamethasone-induced extracellular matrix in the human trabecular meshwork. Figure 8A shows the effects of different concentrations of the compound RM-G-009M of the present invention on FN mRNA levels; Figure 8B shows the effects of different concentrations of the compound RM-G-009M of the present invention on COL-IV mRNA levels; and Figure 8C shows the effects of different concentrations of the compound RM-G-009M of the present invention on LN mRNA levels.

[0029] Figures 9A-9C show the effects of different concentrations of the compound RM-G-010M of the present invention on dexamethasone-induced human trabecular meshwork extracellular matrix. Figure 8A shows the effects of different concentrations of the compound RM-G-010M of the present invention on FN mRNA levels; Figure 8B shows the effects of different concentrations of the compound RM-G-010M of the present invention on COL-IV mRNA levels; and Figure 8C shows the effects of different concentrations of the compound RM-G-010M of the present invention on LN mRNA levels.

[0030] Figures 10A-10C show the effects of different concentrations of the compound RM-G-011M of the present invention on dexamethasone-induced extracellular matrix in the human trabecular meshwork. Figure 8A shows the effects of different concentrations of the compound RM-G-011M of the present invention on FN mRNA levels; Figure 8B shows the effects of different concentrations of the compound RM-G-011M of the present invention on COL-IV mRNA levels; and Figure 8C shows the effects of different concentrations of the compound RM-G-011M of the present invention on LN mRNA levels.

[0031] Figures 11A-11C show the effects of different concentrations of the compound RM-G-027M of the present invention on dexamethasone-induced extracellular matrix in the human trabecular meshwork. Figure 8A shows the effects of different concentrations of the compound RM-G-027M of the present invention on FN mRNA levels; Figure 8B shows the effects of different concentrations of the compound RM-G-027M of the present invention on COL-IV mRNA levels; and Figure 8C shows the effects of different concentrations of the compound RM-G-027M of the present invention on LN mRNA levels.

[0032] FIG12 shows the effects of the compounds RM-G-002M to RM-G-009M of the present invention on the intraocular pressure of beagle dogs.

[0033] FIG13 shows the effects of the compounds RM-G-010M, RM-G-011M, and RM-G-027M of the present invention on intraocular pressure in beagle dogs.

[0034] FIG14 shows the effects of the compounds RM-G-004M, RM-G-010M, RM-G-011M and RM-G-027M of the present invention on the intraocular pressure of rats.

[0035] FIG15 shows the effects of the compounds RM-G-004M, RM-G-010M, RM-G-011M and RM-G-027M of the present invention on intraocular pressure in rats. DETAILED DESCRIPTION

[0036] The present invention will be described in further detail below. This description is for illustrative purposes only and is not intended to limit the present invention. Those skilled in the art will readily appreciate the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through various other specific embodiments. Those skilled in the art may make various modifications and alterations without departing from the spirit of the present invention.

[0037] General Terms and Definitions

[0038] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. In the event of a conflict, the definitions provided herein shall prevail. The technology used herein refers to technology generally understood in the art, including variants and equivalent replacements apparent to those skilled in the art. Although it is believed that the following terms are readily understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention. When a trade name appears herein, it refers to the corresponding commodity or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0039] When a certain amount, concentration or other numerical value or parameter is described in the form of a range, preferred range or preferred upper limit or preferred lower limit, it should be understood to be equivalent to specifically disclosing any range formed by combining any upper limit or preferred value with any lower limit or preferred value, regardless of whether the range is clearly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. For example, the expression "m is an integer from 0 to 6" means that m is any integer from 0 to 6, for example, m can be 0, 1, 2, 3, 4, 5 or 6. Other similar expressions such as n and o should also be understood in a similar manner.

[0040] Unless the context clearly dictates otherwise, singular forms such as "a", "an", and "the" include plural forms. The expression "one or more" or "at least one" may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0041] The terms "about" and "approximately" when used with a numerical variable generally mean that the value of the variable and all values ​​of the variable are within the range of experimental error (e.g., within a 95% confidence interval about the mean) or within ±10% or more of the stated value.

[0042] The expressions "comprising," "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any elements, steps, or ingredients not specified. The expression "consisting essentially of means that the scope is limited to the specified elements, steps, or ingredients, as well as the optional presence of elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of."

[0043] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. 1-20 Alkyl", such as C 1-6 Alkyl, C1-4 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 3-6 Alkyl. "C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 Alkyl, C 1-4 Alkyl, C 1- 3 alkyl, C 1-2 Alkyl, C 2-6 Alkyl, C 2-4 C6 alkyl, C5 alkyl, etc. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or isomers thereof.

[0044] A divalent group refers to a group obtained by removing a hydrogen atom from a carbon atom with free valence electrons of a corresponding monovalent group. A divalent group has two attachment sites connected to the rest of the molecule. For example, "alkylene" or "alkylene group" refers to a saturated straight or branched divalent hydrocarbon group. Examples of "alkylene" include, but are not limited to, methylene (-CH2-), ethylene (-C2H4-), propylene (-C3H6-), butylene (-C4H8-), pentylene (-C5H8-), and alkylene (-C5H6-). 10 -), hexamethylene (-C6H 12 -), 1-methylethylene (-CH(CH3)CH2-), 2-methylethylene (-CH2CH(CH3)-), methylpropylene or ethylpropylene, etc. For example, as used herein, -(CH2) o - belongs to the case of divalent groups.

[0045] Unless otherwise specified, "cycloalkyl" includes any stable cyclic alkyl group, including monocyclic, bicyclic, or tricyclic ring systems, including spirocyclic, fused, and bridged rings. It may be monosubstituted or polysubstituted and may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like.

[0046] Unless otherwise specified, the term "heterocycloalkyl" by itself or in combination with other terms refers to a cyclized "heteroalkyl" group, which includes monocyclic, bicyclic, and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, fused, and bridged rings. In addition, with respect to such "heterocycloalkyl" groups, a heteroatom may occupy the position at which the heterocycloalkyl group is attached to the rest of the molecule. In some embodiments, the heterocycloalkyl group is a 3-10 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-8 membered heterocycloalkyl group. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxepanyl, hexylhydrofuro[3,2-b]furanyl.

[0047] The term "alkenyl" is used to refer to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, which may be located at any position of the group. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0048] The term "alkynyl" is used to refer to a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, which may be located at any position of the group. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0049] The term "alkoxy" represents an alkyl group having a specific number of carbon atoms connected through an oxygen bridge. Non-limiting examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy. The term "C 1-6 "Alkoxy" means an alkyl group containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0050] Unless otherwise specified, the terms "aromatic ring" and "aryl" are used interchangeably. The term "aromatic ring" or "aryl" refers to a polyunsaturated carbocyclic ring system, which can be a monocyclic, bicyclic or polycyclic ring system, wherein at least one ring is aromatic, and the rings in the bicyclic and polycyclic ring systems are fused together. It can be monosubstituted or polysubstituted, and can be monovalent, divalent or polyvalent. Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0051] Unless otherwise specified, the terms "heteroaromatic ring" and "heteroaryl" as used herein are used interchangeably. The term "heteroaryl" refers to an aromatic group (or aromatic ring) containing 1, 2, 3 or 4 heteroatoms independently selected from B, N, O and S, which can be a monocyclic, bicyclic or tricyclic ring system, wherein the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined herein), and is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The heteroaryl group may be attached to the remainder of the molecule through a heteroatom. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group; in other embodiments, the heteroaryl group is a 5-6 membered heteroaryl group. Examples of the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), furyl, (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl and 6-quinolyl, etc.), pyrazinyl, purinyl, phenyloxazolyl, 1,2,5-oxadiazole-2-oxide.

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, fumarates, gluconates, glucuronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)). The compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, bismuth, and diethanolamine salts. Pharmaceutically acceptable salts are reviewed in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0053] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0054] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of the substituents may be any on a chemically feasible basis.

[0055] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0056] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0057] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0058] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0059] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0060] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0061] The term "pharmaceutically acceptable excipient" refers to carrier substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable excipients" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0062] The term "pharmaceutical composition" or "pharmaceutically active ingredient composition" refers to a composition comprising one or more active ingredients and optionally one or more pharmaceutically acceptable excipients.

[0063] Compounds of the present invention

[0064] The present invention provides a compound having the structure of the following formula (I):

[0065] or a pharmaceutically acceptable salt thereof,

[0066] in,

[0067] R 1 、R 2 、R3 、R 4 and R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, acyl, -NO2 and -L-R', wherein each alkyl, alkenyl, alkynyl is unsubstituted or substituted by at least one independently selected R X Substituents substituted;

[0068] -L- is -(CH2) o -, wherein each -(CH2)- is independently optionally replaced by a carbonyl group or -O-;

[0069] R' is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NO2, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl is unsubstituted or substituted by at least one independently selected R X Substituents substituted;

[0070] Among them, the R 1 、R 2 、R 3 、R 4 、R 5 and R' at least one is NO2;

[0071] R 6 、R 7 、R 8 and R 9 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-SC 1-6 Alkyl, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X Substituents substituted;

[0072] Each R 10 、R 11 、R 12 and R 13 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1- 6-Alkyl-SC 1-6 Alkyl, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X Substituents substituted;

[0073] R X Selected from hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl and 5-10 membered heteroaryl, wherein each hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, heteroaryl is unsubstituted or substituted by at least one independently selected R Y Substituents substituted;

[0074] R Y Selected from hydroxyl, halogen, cyano, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0075] 1* C. 2* C. 3* C. 4* C and 5* C represents a carbon atom that may have chirality in the compound of formula (I);

[0076] o, m and n are each independently selected from integers of 0-6.

[0077] In one embodiment, R 1 In a preferred embodiment, R 1 In another preferred embodiment, R 1 -L-R', wherein -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o -The other end is replaced by -O-, R' is -NO2 and is connected to -O-. In a specific embodiment, R 1 for In a preferred embodiment, R 1 -L-R', wherein -L- is -(CH2) o -, where o is 3, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o The other end of - is replaced by -O-, and R' is C 1-6 Alkyl and connected to -O-, which is further R X Replacement, R X To be R Y Substituted 5-10 membered heteroaryl, R Y In a specific embodiment, R1 for In a preferred embodiment, R 1 -L-R', wherein -L- is -(CH2) o -, where o is 3, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o -The other end is replaced by -O-, R' is In a specific embodiment, R 1 for In a preferred embodiment, R 1 -L-R', wherein -L- is -(CH2) o -, where o is 2, and -(CH2) o - is replaced by carbonyl and -O-, R' is a 3-10 membered heterocycloalkyl group and is connected to -O-, which is further replaced by R X Replacement, R X To be R Y Substituted hydroxyl, R Y In a specific embodiment, R 1 for

[0078] In one embodiment, R 2 In a preferred embodiment, R 2 In another preferred embodiment, R 2 It is acetyl.

[0079] In one embodiment, R 3 is selected from hydrogen, acyl and -L-R'. In a preferred embodiment, R 3 In another preferred embodiment, R 3 In another preferred embodiment, R 3 -L-R', wherein -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o -The other end is replaced by -O-, R' is -NO2 and is connected to -O-. In a specific embodiment, R 3 for

[0080] In one embodiment, R 4 is selected from hydrogen, acyl and -L-R'. In a preferred embodiment, R 4 In another preferred embodiment, R 4In another preferred embodiment, R 4 is -L-R', -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o -The other end is replaced by -O-, R' is -NO2 and is connected to -O-. In a specific embodiment, R 4 for

[0081] In one embodiment, R 5 In a preferred embodiment, R 5 In another preferred embodiment, R 5 In another preferred embodiment, R 5 is -L-R', -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o -The other end is replaced by -O-, R' is -NO2 and is connected to -O-. In a specific embodiment, R 5 for

[0082] In one embodiment, R 6 In one embodiment, R 7 In one embodiment, R 8 In one embodiment, R 9 In one embodiment, R 10 In one embodiment, R 11 In one embodiment, R 12 In one embodiment, R 13 For hydrogen.

[0083] In one embodiment, m is 2. In one embodiment, n is 1. In one embodiment, o is 4. When m and n are integers greater than 1, each R 10 、R 11 、R 12 and R 13 Can be the same or different.

[0084] In one embodiment, the chiral carbon atom 1* C is in R configuration. In one embodiment, the chiral carbon atom 2* C is in R or S configuration. In one embodiment, the chiral carbon atom 3* C is in S configuration. In one embodiment, the chiral carbon atom4* C is in R configuration. In one embodiment, the chiral carbon atom 5* C is in R configuration.

[0085] The compound provided by the present invention is selected from the following structures:

[0086] or a pharmaceutically acceptable salt thereof.

[0087] In a preferred embodiment, the compounds of the present invention are selected from

[0088] or a pharmaceutically acceptable salt thereof.

[0089] In a more preferred embodiment, the compound of the present invention is selected from

[0090] Pharmaceutically acceptable salts of the compounds of the present invention

[0091] Those skilled in the art will appreciate that the compound according to the present invention can exist in the form of a pharmaceutically acceptable salt. As a pharmaceutically acceptable salt, for example, the following examples can be provided: metal salts, ammonium salts, salts formed with organic bases, inorganic acids, organic acids, alkaline or acidic amino acids, etc. Pharmaceutically acceptable salts according to the present invention can be prepared by conventional chemical methods by compounds containing acidic or basic groups. Usually, the compound can be prepared by reacting the suitable base or acid of stoichiometry in water, organic solvent or its mixture in the form of free acid or base. Usually, preferred non-aqueous media are such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, etc.

[0092] Administration, pharmaceutical compositions and kits

[0093] The compounds according to the present invention will be administered alone or in combination with additional therapeutic agents in an effective amount by any common and acceptable means known in the art. The effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors known to those skilled in the art.

[0094] As a general example, a daily dosage of about 0.001 to about 100 mg / kg body weight can be used, or more particularly about 0.03 to 2.5 mg / kg body weight. In larger mammals, such as humans, the daily dosage can be in the range of about 0.5 mg to about 2000 mg.

[0095] The compounds of the present invention are typically administered in the form of a pharmaceutical composition comprising a pharmaceutically active ingredient and various other pharmaceutically acceptable components, for example, see Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred or desired form depends on the intended mode of administration and therapeutic application. Depending on the desired formulation, the composition may also include a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a carrier commonly used to formulate a pharmaceutical composition for administration to animals or humans. The choice of diluent does not affect the biological activity of the combination. Examples of diluents include, but are not limited to, distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0096] The compounds of the present invention can be administered in the form of pharmaceutical compositions by any conventional route; for example, enterally, such as orally, for example in the form of tablets, capsules or pills; parenterally, for example in the form of injectable solutions or suspensions; or topically, for example, ophthalmically, nasally, for example in the form of emulsions, gels, ointments or creams or in the form of suppositories.

[0097] Therefore, the present invention also provides a pharmaceutical composition comprising a compound having a structure of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The compound of the present invention may exist in free form or in the form of a pharmaceutically acceptable salt in combination with at least one pharmaceutically acceptable carrier, and may be prepared in a conventional manner, for example, by mixing, granulation, coating, dissolution or lyophilization processes.

[0098] In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. For a lyophilized composition comprising only the active ingredient or comprising the active ingredient and a carrier (such as mannitol), a dispersion or suspension can be prepared before use.

[0099] The limiting examples of carriers include fillers, such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, and / or if necessary, disintegrants, such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinyl pyrrolidones, alginic acid or its salts, such as sodium alginate. Other carriers include, but are not limited to, rheology modifiers and lubricants, such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate, and / or polyethylene glycol or its derivatives.

[0100] The present invention also provides a pharmaceutical combination, such as a kit, comprising a) a first agent, which is a compound having a structure of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, and b) at least one additional agent. The kit may further comprise instructions for administration thereof.

[0101] Methods of treatment and uses of the compounds of the present invention

[0102] The present invention provides a method for treating diseases caused by abnormal extracellular matrix proteins, such as ophthalmic fibrosis, trabecular meshwork cell and ganglion cell damage, oxidative damage to corneal epithelial cells caused by dry eye, and diseases associated with high intraocular pressure, comprising administering a therapeutically effective amount of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention to a subject in need thereof.

[0103] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for treating, improving or preventing diseases with abnormal extracellular matrix proteins, such as ophthalmic fibrosis, trabecular meshwork cell and ganglion cell damage, oxidative damage to corneal epithelial cells caused by dry eye, and diseases associated with high intraocular pressure.

[0104] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a drug for treating, ameliorating or preventing diseases with abnormal extracellular matrix proteins, such as ophthalmic fibrosis, trabecular meshwork cell and ganglion cell damage, oxidative damage to corneal epithelial cells caused by dry eye, and diseases associated with elevated intraocular pressure.

[0105] In one embodiment, diseases with abnormal extracellular matrix proteins (such as ophthalmic fibrosis, damage to trabecular meshwork cells and ganglion cells, oxidative damage to corneal epithelial cells caused by dry eye) and diseases associated with high intraocular pressure include but are not limited to glaucoma, subretinal fibrosis caused by age-related macular degeneration, diabetic retinopathy, and high intraocular pressure and tissue fibrosis caused by post-cataract.

[0106] In embodiment (1), the present invention provides a compound having the structure of the following formula (I):

[0107] or a pharmaceutically acceptable salt thereof,

[0108] in,

[0109] R 1 、R 2 、R 3 、R 4 and R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, acyl, -NO2 and -L-R', wherein each alkyl, alkenyl, alkynyl is unsubstituted or substituted by at least one independently selected R X Substituents substituted;

[0110] -L- is -(CH2) o -, wherein each -(CH2)- is independently optionally replaced by a carbonyl group or -O-;

[0111] R' is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and NO2, wherein each alkyl, alkenyl, alkynyl is unsubstituted or substituted by at least one independently selected R X Substituents substituted;

[0112] Among them, the R 1 、R 2 、R 3 、R 4 、R 5 and R' at least one is NO2;

[0113] R 6 、R 7 、R 8 and R 9 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-SC 1-6 Alkyl, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X Substituents substituted;

[0114] Each R 10 、R 11 、R 12 and R 13 are each independently selected from hydrogen, C1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1- 6-Alkyl-SC 1-6 Alkyl, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X Substituents substituted;

[0115] R X Selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein each alkyl, alkoxy, alkenyl, alkynyl is unsubstituted or substituted by at least one independently selected R Y Substituents substituted;

[0116] R Y Selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0117] 1* C. 2* C. 3* C. 4* C and 5* C represents a carbon atom that may have chirality in the compound of formula (I);

[0118] o, m and n are each independently selected from integers of 0-6.

[0119] In another embodiment (2), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein R 1 selected from -NO2 and -L-R';

[0120] Preferably,

[0121] R 1 is -NO2; or

[0122] R 1 -L-R', wherein -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o The other end of - is replaced by -O-, and R' is -NO2 and is connected to -O-.

[0123] In another embodiment (3), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein R 2 is selected from hydrogen and acyl;

[0124] Preferably,

[0125] R 2 is hydrogen; or

[0126] R 2 It is acetyl.

[0127] In another embodiment (4), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein R 3 is selected from hydrogen, acyl, and -L-R';

[0128] Preferably,

[0129] R 3 is hydrogen;

[0130] R 3 is acetyl; or

[0131] R 3 -L-R', wherein -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o The other end of - is replaced by -O-, and R' is -NO2 and is connected to -O-.

[0132] In another embodiment (5), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein R 4 is selected from hydrogen, acyl, and -L-R';

[0133] Preferably,

[0134] R 4 is hydrogen;

[0135] R 4 is acetyl; or

[0136] R 4 is -L-R', -L- is -(CH2) o -, where o is 4, and -(CH2) o -One end is replaced by a carbonyl group, -(CH2) o The other end of - is replaced by -O-, and R' is -NO2 and is connected to -O-.

[0137] In another embodiment (6), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein R 5 is selected from hydrogen and acyl;

[0138] Preferably,

[0139] R 5 is hydrogen; or

[0140] R 5 It is acetyl.

[0141] In another embodiment (7), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently hydrogen.

[0142] In another embodiment (8), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein m is 2.

[0143] In another embodiment (9), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein n is 1.

[0144] In another embodiment (10), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in embodiment (1), wherein o is 4.

[0145] In another embodiment (11), the present invention provides a compound of the structure of formula (I) described in embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the chiral carbon atom 1* C is in R configuration.

[0146] In another embodiment (12), the present invention provides a compound of the structure of formula (I) described in embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the chiral carbon atom 2* C is in R or S configuration.

[0147] In another embodiment (13), the present invention provides a compound of the structure of formula (I) described in embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the chiral carbon atom 3* C is S configuration.

[0148] In another embodiment (14), the present invention provides a compound of the structure of formula (I) described in embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the chiral carbon atom 4* C is in R configuration.

[0149] In another embodiment (15), the present invention provides a compound of the structure of formula (I) described in embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the chiral carbon atom 5* C is in R configuration.

[0150] In another embodiment (16), the present invention provides a compound of the structure of formula (I) described in embodiment (1), which is selected from the following structures:

[0151] or a pharmaceutically acceptable salt thereof.

[0152] In another embodiment (17), the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to any one of embodiments (1) to (16) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0153] In another embodiment (18), the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (16) or the pharmaceutical composition according to embodiment (17) in the preparation of a drug for treating, improving or preventing diseases with abnormal extracellular matrix proteins and diseases associated with elevated intraocular pressure.

[0154] In another embodiment (19), the present invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (16) or a pharmaceutical composition according to embodiment (17) in the preparation of a medicament for preventing or treating glaucoma, subretinal fibrosis due to age-related macular degeneration, diabetic retinopathy, and high intraocular pressure and tissue fibrosis caused by post-cataract. Beneficial effects

[0155] The present invention provides a novel compound with a structure of formula (I), which can be used to treat, improve or prevent diseases with abnormal extracellular matrix proteins (such as ophthalmic fibrosis, trabecular meshwork cell and ganglion cell damage, and oxidative damage to corneal epithelial cells caused by dry eye), while also having the effect of reducing intraocular pressure. Therefore, the compound with a structure of formula (I) of the present invention can be used for treating diseases with abnormal extracellular matrix proteins (for example, for the pathological mechanism of tissue fibrosis caused by glaucoma trabecular meshwork aqueous humor outflow obstruction, age-related macular degeneration subretinal fibrosis, diabetic retinopathy, and post-cataract), and can also treat, improve or prevent related diseases with increased intraocular pressure (for example, glaucoma, ocular hypertension, etc.).

[0156] Example

[0157] The solution of the present invention is further described in detail below with reference to specific embodiments.

[0158] It should be noted that the following examples are merely examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the present invention. For those skilled in the art, other variations or modifications may be made based on the description of the present invention. It is not necessary and is not possible to exhaustively enumerate all embodiments herein, and the obvious variations or modifications derived therefrom are still within the scope of protection of the present invention. Unless otherwise indicated, the instruments, equipment, and reagents used herein are all commercially available.

[0159] Synthesis Example

[0160] Example 1 Synthesis of Compound RM-G-003M

[0161] Synthesis route:

[0162] 1.1 Synthesis of Compound A

[0163] Compound SM1 (100 g, 0.33 mol) was dissolved in THF (1 L). PPh3 (1.2 eq) was added with stirring at room temperature, followed by CBr4 (1.2 eq) in portions. The reaction was allowed to react overnight at room temperature. The THF was removed by concentration under reduced pressure, and the mixture was purified by column chromatography to afford Compound A (30 g, 25% yield) as an oil.

[0164] ESI-MS m / z 363.04[M+H] + .

[0165] 1 H NMR(600MHz,DMSO-d6)δ9.18(s,1H),7.04(d,J=7.7Hz,2H),6.66(d,J=7.7Hz,2H),5 .26(d,J=4.7Hz,1H),5.10(dd,J=12.2,4.0Hz,2H),4.26(d,J=7.7Hz,1H),3.83(dd,J =16.4,8.1Hz,1H),3.74(d,J=10.7Hz,1H),3.59(dt,J=17.6,9.2Hz,2H),3.32(t,J= 7.8Hz, 1H), 3.17 (s, 1H), 3.01 (ddd, J = 20.3, 13.0, 8.2Hz, 2H), 2.76 (d, J = 7.3Hz, 2H).

[0166] 1.2 Synthesis of Compound A-1Ac

[0167] Compound A (30 g, 0.083 mol) was dissolved in pyridine (50 ml), and AcO (17 g, 0.17 mol) was added dropwise while maintaining the internal temperature below 30°C. After the addition was complete, the mixture was stirred overnight. Ethyl acetate was then added, and the pyridine was washed off with an aqueous copper sulfate solution. The product was concentrated under reduced pressure, dried, and purified by column chromatography to yield Compound A-1Ac (17 g, 51% yield) as an off-white solid.

[0168] ESI-MS m / z 405.05[M+H] + .

[0169] 1 H NMR (600MHz, DMSO-d6) δ7.31(d,J=7.6Hz,2H),7.02(d,J=7.6Hz,2H),5.26(d,J=5 .0Hz,1H),5.11(dd,J=23.1,4.5Hz,2H),4.29(d,J=7.6Hz,1H),3.91(dd,J=15.8, 7.9Hz,1H),3.72(dd,J=22.5,9.2Hz,2H),3.58(d,J=7.0Hz,1H),3.32(s,1H),3.1 8(dd,J=13.4,8.3Hz,1H),3.10–2.96(m,2H),2.89(t,J=6.7Hz,2H),2.25(s,3H).

[0170] 1.3 Synthesis of compound RM-G-003M

[0171] Under nitrogen protection, compound A-1Ac (17 g, 0.042 mol) and NaNO3 (50 g, 0.59 mol) were dissolved in N,N-dimethylformamide (DMF) (200 ml), heated to 80°C, and stirred for 16 hours. The reaction system was cooled to room temperature, filtered, concentrated under reduced pressure to dryness, and an appropriate amount of EA / MeOH = 5:1 mixed solution was added to dissolve the crude product. The solid was then filtered, and the filtrate was concentrated under reduced pressure to dryness and purified using silica gel column chromatography to obtain compound RM-G-003M (6.7 g, yield 41%) as a light yellow oil.

[0172] ESI-MS m / z 388.12[M+H] + .

[0173] 1H NMR (600MHz, DMSO-d6) δ7.27(d,J=7.6Hz,2H),7.02(d,J=7.6Hz,2H),5.37(s,1H),4.92(s,1H),4.73(d,J=5.8Hz,1H),4.53(s,1H),4.22(d,J=3.3Hz ,1H),4.09–3.92(m,2H),3.86(s,1H),3.63(t,J=7.1Hz,1H),3.54(dd,J=1 5.6, 7.8Hz, 1H), 3.43 (t, J = 8.5Hz, 1H), 2.82 (t, J = 6.8Hz, 2H), 2.25 (s, 3H).

[0174] Example 2 Synthesis of Compound RM-G-004M

[0175] Synthesis route:

[0176] RM-G-003M (6.6 g, 0.017 mol) was dissolved in a mixed solution of methanol (160 ml) and water (6.9 g), K2CO3 (4.4 g, 0.032 mol) was added, and the reaction mixture was stirred at room temperature overnight. TLC monitoring showed that the raw material reaction was complete, and then the mixture was filtered, washed with an appropriate amount of MeOH, and the pH of the filtrate was adjusted to about 6 using 4N HCl. It was concentrated under reduced pressure at 45°C to obtain a brown solid. It was then purified by column chromatography to obtain a light yellow solid, and further slurried using a mixture of PE / EA = 1:1 solvent to obtain a white solid compound RM-G-004M (3 g, yield 51%).

[0177] ESI-MS m / z 346.11[M+H] + .

[0178] 1 H NMR(600MHz, DMSO-d6)δ9.15(s,1H),7.04–6.99(m,2H),6.68–6.64(m,2H),5.36(s,1H),4.90(s,1H),4.72(s,1H),4.52(t,J= 4.9Hz,1H),4.21(d,J=4.4Hz,1H),4.07–4.00(m,1H),3.88(q,J=8.2,7.7Hz,1H),3.85(s,1H),3.64(t,J=7.4Hz,1H),3.46(dd J=7.9, 7.4Hz, 2H), 2.69 (t, J=7.4Hz, 2H).

[0179] Example 3 Synthesis of Compound RM-G-002M

[0180] Synthesis route:

[0181] 3.1 Synthesis of Compound A-Ac

[0182] Compound A (10 g, 0.028 mol) was dissolved in pyridine (70 ml) solution, 4-dimethylaminopyridine (DMAP) (30 mg, 0.25 mmol) was added, and the mixture was cooled to an internal temperature of about 0°C. Ac2O (14 g, 0.14 mol) was then added dropwise, and the internal temperature was controlled to be less than 5°C during the addition. After the addition was complete, the mixture was reacted at room temperature overnight, and TLC monitoring showed that the reaction of the raw material compound A was complete. MeOH (20 ml) was added, stirred for 0.5 hours, and concentrated under reduced pressure to obtain an oil. Ethyl acetate (EA) (100 ml) was then added, and the pH of the aqueous phase was adjusted to about 2 using 1N HCl. The layers were separated and the aqueous phase was extracted with EA (100 ml). The organic phase was washed with saturated NaCl, the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain an off-white solid compound A-Ac (8 g, yield 54%).

[0183] ESI-MS m / z:531.08[M+H] + .

[0184] 1 H NMR (600MHz, DMSO-d6) δ7.24(d,J=7.8Hz,2H),7.02(d,J=7.8Hz,2H),5.25(t,J=9.5Hz,1H),4.85(dd,J=12.5,8.3Hz,2H),4.76(t,J=8.8Hz,1H), 4.03–3.94(m,2H),3.70(dd,J=22.7,9.2Hz,2H),3.53(dd,J=10.8,6.8H z,1H),2.83(s,2H),2.25(s,3H),2.01(s,3H),1.92(s,3H),1.87(s,3H).

[0185] 3.2 Synthesis of compound RM-G-002M

[0186] Under nitrogen, compound A-Ac (8 g, 0.015 mol) and NaNO (3.8 g, 0.045 mol) were dissolved in MeCN (100 ml) and heated to 85°C with stirring for 72 hours. The reaction system was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound RM-G-002M (4 g, 52% yield) as a white solid.

[0187] ESI-MS m / z 514.15[M+H] + .

[0188] 1 H NMR (600MHz, DMSO-d6) δ7.22(d,J=7.6Hz,2H),7.02(d,J=7.7Hz,2H),5.26(t,J=9.5Hz,1H),4.88(dd,J=19.3,9.0Hz,2H),4.82–4.66(m,2H),4.61(dd,J =12.1,6.0Hz,1H),4.19–4.09(m,1H),3.99–3.89(m,1H),3.67(dd,J=15.4,7 .2Hz,1H),2.80(s,2H),2.25(s,3H),2.01(s,3H),1.94(s,3H),1.87(s,3H).

[0189] Example 4 Synthesis of Compound RM-G-005M

[0190] Synthesis route:

[0191] Under nitrogen, compound A-1Ac (8 g, 0.020 mol), 3-(nitrooxy)propionic acid (6.2 g, 0.046 mol), and NaCO (4.9 g, 0.046 mol) were dissolved in MeCN (100 ml) and heated to 85°C with stirring for 72 hours. The reaction system was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound RM-G-005M (1.8 g, 20% yield) as an oil.

[0192] ESI-MS m / z 482.13[M+Na] + .

[0193] 1H NMR(600MHz,DMSO-d6)δ7.29(d,J=8.0Hz,2H),7.05–6.97(m,2H),4.71(t,J=6.1Hz,2H),4. 34(d,J=11.7Hz,1H),4.24(d,J=7.8Hz,1H),4.11(dd,J=11.9,6.5Hz,1H),3.92–3.85(m,1H) ,3.71–3.65(m,1H),3.36(dd,J=9.5,6.9Hz,1H),3.16(t,J=8.8Hz,1H),3.08(t,J=9.2Hz,1 H), 2.97 (t, J = 8.4Hz, 1H), 2.84 (dq, J = 11.9, 6.2Hz, 4H), 2.25 (s, 3H), 2.07 (d, J = 1.8Hz, 2H).

[0194] Example 5 Synthesis of Compound RM-G-006M

[0195] Synthesis route:

[0196] Compound RM-G-005M (3.5 g, 0.0076 mol) was dissolved in a mixture of methanol (90 ml) and water (3.9 g), and KCO (2.5 g, 0.018 mol) was added. The reaction mixture was stirred at room temperature. TLC monitoring showed that the reaction of the starting compound RM-G-005M was complete. The pH of the reaction system was adjusted to approximately 6 using 4N HCl. After concentration under reduced pressure at 45°C, the mixture was purified by silica gel column chromatography to obtain the oily compound RM-G-006M (0.5 g, 16% yield).

[0197] ESI-MS m / z 440.11[M+Na] + .

[0198] 1H NMR(600MHz,DMSO-d6)δ9.15(s,1H),7.03(d,J=7.8Hz,2H),6.66(d,J=7.9Hz,2H),5.40–4.90(m, 3H),4.71(t,J=6.1Hz,2H),4.34(d,J=11.7Hz,1H),4.21(d,J=7.8Hz,1H),4.11(dd,J=11.9,6.5H z,1H),3.81(q,J=8.3Hz,1H),3.59(q,J=8.3Hz,1H),3.35(dd,J=9.5,6.8Hz,1H),3.16(t,J=8.9H z, 1H), 3.08 (t, J = 9.3Hz, 1H), 2.97 (t, J = 8.4Hz, 1H), 2.82 (q, J = 6.1Hz, 2H), 2.72 (q, J = 6.6Hz, 2H).

[0199] Example 6 Synthesis of Compounds RM-G-007M and RM-G-008M

[0200] Synthesis route:

[0201] 6.1 Synthesis of compounds TM3-1 and TM3-2

[0202] Compound 3-(nitrooxy)propionic acid (2.6 g, 0.019 mol) was dissolved in DCM (8 ml), DMF (0.22 g) was added, and the reaction system was cooled to 0°C, followed by the dropwise addition of SOCl2 (2.3 g, 0.019 mol). After the addition was complete, the mixture was reacted at room temperature for 2 hours to prepare an acyl chloride solution for use. Compound RM-G-005M (7.5 g, 0.016 mol) was dissolved in DCM (75 ml), pyridine (4.7 g) and DMAP (1.9 g) were added, and the reaction system was cooled to -5°C, followed by the dropwise addition of the acyl chloride solution prepared above, with the internal temperature being controlled below 0°C during the addition. After the addition was complete, the reaction system was warmed to room temperature and reacted for 12 hours. 1N HCl (45 ml) was then added, stirred for 0.5 hours, and the mixture was separated. The aqueous phase was extracted with DCM (80 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain oily compound TM3-1 (1.2 g, yield 13%) and oily compound TM3-2 (0.6 g, yield 7%).

[0203] 6.2 Synthesis of Compounds RM-G-007M and RM-G-008M

[0204] Compound TM3-1 (0.5 g, 0.87 mmol) was dissolved in a solution of methanol (10 ml) and water (0.44 g), and KCO (0.28 g, 0.0020 mol) was added. The reaction mixture was stirred at room temperature, and TLC indicated complete reaction. The pH of the reaction system was then adjusted to approximately 6 using 4N HCl. The mixture was concentrated under reduced pressure at 45°C and purified using silica gel column chromatography to afford compound RM-G-007M (0.08 g, 17% yield) as an oil.

[0205] RM-G-007M:ESI-MS m / z 557.12[M+Na] + .

[0206] 1 H NMR(600MHz,DMSO-d6)δ9.16(s,1H),6.96(d,J=7.7Hz,2H),6.65(d,J=7.6Hz,2H),4.70(dt,J =21.3,6.0Hz,4H),4.54(t,J=8.8Hz,1H),4.46(d,J=8.0Hz,1H),4.35(d,J=11.7Hz,1H),4.14( dd,J=12.0,6.4Hz,1H),3.81(q,J=7.7Hz,1H),3.53(q,J=8.3Hz,1H),3.46(t,J=8.0Hz,1H),3. 39(t,J=9.1Hz,1H), 3.20(t,J=9.3Hz,1H), 2.86–2.73(m,3H), 2.68–2.59(m,3H), 2.07(s,2H).

[0207] Compound TM3-2 (0.5 g, 0.87 mmol) was dissolved in a solution of methanol (10 ml) and water (0.44 g), and KCO (0.28 g, 0.0020 mol) was added to each. The reaction mixture was stirred at room temperature, and TLC indicated complete reaction of the starting materials. The pH of the reaction system was then adjusted to approximately 6 using 4N HCl. The mixture was concentrated under reduced pressure at 45°C and purified using silica gel column chromatography to afford compound RM-G-008M (0.05 g, 11% yield) as an oil.

[0208] RM-G-008M:ESI-MS m / z 557.12[M+Na] + .

[0209] 1H NMR (600MHz, DMSO-d6) δ9.16 (s, 1H), 7.03 (d, J = 8.0Hz, 2H), 6.66 (d, J = 7.8Hz, 2H) ,4.79–4.60(m,5H),4.33(d,J=7.8Hz,1H),4.15(dd,J=12.2,5.3Hz,1H),4.05(d, J=10.3Hz,1H),3.83(q,J=8.3Hz,1H),3.71–3.64(m,1H),3.60(q,J=9.1,8.6Hz,1 H), 3.41 (t, J = 9.2Hz, 1H), 3.08 (t, J = 8.4Hz, 1H), 2.89–2.63 (m, 6H), 1.24 (s, 1H).

[0210] Example 7 Synthesis of Compound RM-G-009M

[0211] Synthesis route:

[0212] Compound 3-(nitrooxy)propionic acid (4.0 g, 0.030 mol) was dissolved in DCM (12 ml), DMF (0.34 g) was added, and the reaction system was cooled to 0°C. SOCl2 (3.5 g, 0.029 mol) was added dropwise. After the addition was complete, the reaction was allowed to react at room temperature for 2 hours to prepare an acyl chloride solution for use. SM1 (3.0 g, 0.010 mol) was dissolved in DCM (45 ml), pyridine (2.9 g) and DMAP (1.2 g, 0.0098 mol) were added, and the reaction system was cooled to -5°C. The acyl chloride solution prepared above was then added dropwise, and the internal temperature was controlled to be less than 0°C during the addition. After the addition was complete, the reaction system was warmed to room temperature and reacted for 12 hours. 1N HCl (28 ml) was then added, stirred for 0.5 hours, and the layers were separated. The aqueous phase was extracted with DCM (50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography to obtain an oily product RM-G-009M (0.5 g, yield 10%).

[0213] ESI-MS m / z 557.12[M+Na] + .

[0214] 1H NMR(600MHz,DMSO-d6)δ7.32(d,J=7.6Hz,2H),7.04(d,J=7.7Hz,2H),5.21(s,1 H),5.12(s,2H),4.83(t,J=5.5Hz,2H),4.71(t,J=5.8Hz,3H),4.34(d,J=11.8H z,1H),4.24(d,J=7.3Hz,1H),4.16–4.09(m,1H),3.93–3.85(m,1H),3.69(d,J= 8.2Hz, 1H), 3.11 (t, J = 5.4Hz, 4H), 2.99 (d, J = 7.8Hz, 1H), 2.85 (d, J = 6.9Hz, 4H).

[0215] Example 8 Synthesis of Compound RM-G-010M

[0216] Synthesis route:

[0217] 8.1 Synthesis of Compound M10-2

[0218] Compound M10-1 (1000 mg, 6.28 mmol) was dissolved in dichloromethane (20 mL), and (Boc)2O (1.2 eq) and DMAP (0.5 eq) were added. The mixture was allowed to react at room temperature for 1 hour. TLC analysis showed that the reaction of the raw material M10-1 was complete. The product was washed with an appropriate amount of saturated NaCl solution, separated, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate (EA): petroleum ether (PE) = 1:49-1:9) to obtain solid compound M10-2 (1466 mg, 90% yield, 96.2% purity).

[0219] 8.2 Synthesis of Compound M10-3

[0220] Compound M10-2 (850 mg, 3.28 mmol) and NaH (1 e.q.) were dissolved in tetrahydrofuran (10 mL), tert-butyl 2-bromoacetate (959.7 mg, 1.5 eq) was added, and the mixture was reacted at room temperature for 12 hours. Ethyl acetate (10 mL) was added to the reaction system, washed with 0.1N HCl aqueous solution, separated, and the aqueous phase was extracted with EA (10 mL). The organic phase was washed with saturated NaCl, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA:PE = 1:49-1:9) to give compound M10-3 (911 mg, yield 74.3%, purity 97.1%).

[0221] 8.3 Synthesis of Compound M10-4

[0222] Compound M10-3 (900 mg, 2.41 mmol) was dissolved in a 1:1 TFA:DCM mixture (10 mL) and stirred at room temperature for 2 hours. Dichloromethane (DCM) (10 mL) and an appropriate amount of saturated sodium bicarbonate aqueous solution were added to the reaction system and stirred for 10 minutes. After separation, the DCM layer was concentrated under reduced pressure, and EA (10 mL) was added to the concentrate. The pH of the aqueous phase was adjusted to approximately 2 using 1N HCl, and the aqueous phase was extracted with EA (10 mL). The organic phase was washed with saturated NaCl. The EA organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound M10-4 (486.39 mg, 93% yield).

[0223] 8.4 Synthesis of Compound M10-5

[0224] Compound M10-4 (400 mg, 1.84 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (DIEA) (1.2 eq) and trifluoroacetic anhydride (TFAA) (1.2 eq) were added. The mixture was reacted in an ice-water bath for 1 hour. DCM (10 mL) and an appropriate amount of saturated sodium bicarbonate aqueous solution were added to the reaction system and stirred for 10 minutes. After separation, the DCM layer was concentrated under reduced pressure, and 10 mL of EA was added to the concentrate. The pH of the aqueous phase was adjusted to approximately 2 using 1N HCl, and the aqueous phase was extracted with EA (10 mL). The organic phase was washed with saturated NaCl aqueous solution. The EA organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound M10-5 (305.9 mg, yield 83.5%, purity 95.4%).

[0225] 8.5 Synthesis of Compound RM-G-010M

[0226] Compound M10-5 (200 mg, 1.0 mmol), compound M10-6 (300 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (186.3 mg, 1.2 mmol), and DMAP (122.2 mg, 1.0 mmol) were dissolved in a 1:1 dichloromethane:DMF mixed solvent (5 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was washed with an appropriate amount of saturated aqueous NaCl solution, and the aqueous phase was extracted with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound RM-G-010M (76.5 mg, yield 15.9%, purity 97.2%).

[0227] ESI-MS m / z 482.14[M+H] + .

[0228] 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), δ7.03 (dt, J=8.5, 1.0Hz, 2H), 6.75–6.69 (m, 2H ),5.00(d,J=6.1Hz,1H),4.76-4.68(m,2H),4.63(d,J=1.1Hz,2H),4.34(dd,J=11.8, 4.9Hz,1H),4.27-4,20(m,3H),3.90(d,J=6.6Hz,1H),3.81(dt,J=11.7,6.4Hz,1H),3 .75–3.58(m,3H),3.47-3.42(m,1H),3.35-3.31(m,1H),2.88(tt,J=6.3,0.9Hz,2H).

[0229] Example 9 Synthesis of Compound RM-G-011M

[0230] Synthesis route:

[0231] 9.1 Synthesis of Compound M11-2

[0232] Tetrahydropyrrole (10 g, 140.8 mmol) was dissolved in diethyl ether (100 mL), and sodium hydroxide (1.0 eq) was added. After complete dissolution, the mixture was transferred to a stainless steel autoclave. The air was replaced with nitrogen, and NO gas was introduced at a pressure of 15 psi. The reaction was allowed to proceed at room temperature for 3 days. After completion of the reaction, the reaction solution was filtered and washed with diethyl ether to obtain compound M11-2 (21.5 g, 87% yield, 98.7% purity).

[0233] 9.2 Synthesis of Compound M11-4

[0234] Compound M11-2 (10 g, 65.3 mmol) and methyl bromoacetate (1.2 eq) were dissolved in methanol (100 mL) and stirred at room temperature for 4 hours. Lithium hydroxide (1 mol / L aqueous solution, 130 mL) was then slowly added and reacted at room temperature for 12 hours. The reaction system was concentrated under reduced pressure, and the remaining aqueous solution was washed twice with ether (100 mL), and the ether organic phase was extracted with water twice. After combining the aqueous phases, the pH value was adjusted to about 2 with 1N HCl, extracted three times with EA (150 mL), and the combined EA organic phases were dried over anhydrous sodium sulfate and concentrated to give compound M11-4 (8.51 g, 41.9 mmol, yield 64.2%, purity 98.0%).

[0235] 9.3 Synthesis of Compound RM-G-011M

[0236] Compound M11-4 (1 g, 5.3 mmol), compound M11-5 (1.59 g, 5.3 mmol), EDCI (1.2 eq), and DMAP (1.0 eq) were dissolved in a 1:1 DCM:DMF mixed solvent (10 mL) for reaction. After completion of the reaction, the mixture was washed with an appropriate amount of saturated aqueous NaCl solution, and the aqueous phase was extracted with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound RM-G-011M (443.2 mg, 0.94 mmol, 17.7% yield, 98.21% purity).

[0237] ESI-MS m / z 472.19[M+H] + .

[0238] 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), δ7.03 (dt, J=8.5, 1.0Hz, 2H), 6.79–6.66 (m, 2H), 5.00 (d,J=6.2Hz,1H),4.81–4.63(m,4H),4.34(dd,J=11.9,4.9Hz,1H),4.24(dd,J=11.7,4.9Hz ,1H),3.90(d,J=6.6Hz,1H),3.81(dt,J=11.7,6.4Hz,1H),3.75-3.70(m,1H),3.66-3.58(m ,6H),3.47-3.42(m,1H),3.35-3.33(m,1H),2.88(tt,J=6.3,0.9Hz,2H),2.00–1.82(m,4H).

[0239] Example 10 Synthesis of Compound RM-G-027M

[0240] Synthesis route:

[0241] 10.1 Synthesis of Compound M27-2

[0242] Compound M27-1 (5 g, 26.43 mmol) was dissolved in acetonitrile (25 mL), excess triphosgene (1.2 eq) was added, and the mixture was refluxed for 4 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to dryness to obtain compound M27-2 (5.88 g).

[0243] 10.2 Synthesis of Compound M27-4

[0244] Compound M27-3 (3.00 g, 10 mmol) and sodium carbonate (1.06 g, 10 mmol) were added to an aqueous solution (20 ml) containing tetrabutylammonium bromide (TBAB) (48.4 mg, 0.15 mmol), and the mixture was stirred under ice-water bath conditions, and the temperature of the mixture was cooled to 5 ° C to obtain a solution to be reacted. Acetyl chloride (10 mmol) was dissolved in ethyl acetate (10 ml), and the temperature of the reaction system was maintained at about 5 ° C under ice-water bath and stirring conditions. The ethyl acetate solution of acetyl chloride was slowly added to the above-mentioned solution to be reacted, and the reaction was stirred under ice-water bath conditions for 1 hour. After the reaction was completed, it was extracted with ethyl acetate (15 mL x 3), the combined organic phases were washed with dilute hydrochloric acid and separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound M27-4 (2.94 g, 8.6 mmol, yield 86%, purity 98.1%).

[0245] 10.3 Synthesis of Compound M27-5

[0246] Compound M27-2 (1.98 g, 8 mmol) and compound M27-4 (2.74 g, 8 mmol) were dissolved in dichloromethane (25 mL), 2,4,6-trimethylpyridine (0.97 g, 1 e.q.) was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was washed with saturated aqueous sodium bicarbonate solution (12 mL x 3), the dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and then purified by column chromatography to obtain compound M27-5 (1.61 g, 2.89 mmol, yield 36.1%, purity 97.8%).

[0247] 10.4 Synthesis of Compound RM-G-027M

[0248] Compound M27-5 (1.0 g, 1.8 mmol) was dissolved in 10 ml of methanol, potassium carbonate (0.25 g) was added, and the reaction was stirred at room temperature for 16 h. After completion of the reaction, the mixture was filtered, and the filtrate was purified by column chromatography to obtain compound RM-G-027M (0.73 g, 1.62 mmol, 87.3% yield, 98.3% purity).

[0249] ESI-MS m / z 518.15[M+H] + .

[0250] 1H NMR(400MHz, DMSO-d6)δ9.18(s,1H),7.03(dt,J=8.5,1.0Hz,2H),6.75–6.69(m,2H),5.35-5.33(m,1H),5.18-5.16 (m,1H),5.00(d,J=6.2Hz,1H),4.75–4.66(m,3H),4.65-4.63(m,1H),4.46(dd,J=11.9,4.9Hz,1H),4.40(dd,J=11.9 ,4.9Hz,1H),4.08(dd,J=12.4,2.5Hz,1H),4.00(dd,J=12.3,4.2Hz,1H),3.90(d,J=6.6Hz,1H),3.87–3.76(m,3H), 3.75–3.67(m,2H),3.62(dt,J=11.7,6.3Hz,1H),3.47-3.42(m,1H),3.35-3.30(m,1H),2.88(tt,J=6.2,1.0Hz,2H).

[0251] Biological Examples

[0252] Biological Example 1 Study on the regulatory mechanism of the compound of formula (I) on glaucoma-related factors and trabecular meshwork extracellular matrix secretion

[0253] 1.1 Cell plating: Human normal trabecular meshwork cells (NTM) (BNCC / Beina Biotech) were cultured in F12 medium containing 10% fetal bovine serum (FBS) (GIBCO, USA). When the well-grown normal trabecular meshwork cells reached 75%-80% confluence, the cells were digested with 0.25% trypsin and plated at 10 cells per well. 5 The cells were seeded into 6-well plates and cultured in a 37°C 5% CO2 incubator for 2 days.

[0254] 1.2 Experimental grouping: The original culture medium was discarded, and DMEM / F12 culture medium was added for culture and grouping according to the following scheme: normal human trabecular meshwork cells were cultured normally as the blank control group, normal human trabecular meshwork cells were added with dexamethasone (Dr. E) as the experimental control group, and normal human trabecular meshwork cells were added with dexamethasone and different concentrations of the compounds of the present invention (RM-G-002M to RM-G-009M, RM-G-010M, RM-G-011M, RM-G-027M) as the experimental group (the dexamethasone concentration in the culture medium of the experimental control group and the experimental group was 10 -7mol / L, 3 parallel wells in each group, the concentrations of the compound of the present invention were 0.1 μM, 1 μM, and 10 μM, respectively), and the trabecular meshwork cells were cultured in a 37° C. 5% CO 2 incubator for 24 h.

[0255] 1.3 Trabecular meshwork extracellular matrix protein gene detection:

[0256] 1.3.1 Total RNA extraction

[0257] First, remove the culture medium with a pipette, then wash twice with PBS, discard the supernatant, and add 1 ml of Trizol. After 5 minutes, allow the cells to lyse, then pipette repeatedly and transfer to a 1.5 ml Eppendorf tube. Add 400 μl of chloroform to each Eppendorf tube, shake vigorously, and place the tube on ice for 5 minutes. Centrifuge the tube at 4°C, 12,000 rpm for 25 minutes. Remove the tube, aspirate 400 μl of the supernatant, transfer it to a new Eppendorf tube, add an equal volume of pre-chilled isopropanol, gently invert the tube to mix, and place in a -20°C refrigerator for 4 hours. Remove the tube and place it in a high-speed centrifuge at 4°C, 12,000 rpm for 15 minutes. Discard the supernatant, then add 1 ml of pre-chilled ethanol diluted in 75% DEPC water to each Eppendorf tube, gently shake to wash the pellet, and centrifuge at 4°C, 8,000 rpm for 5 minutes. Discard the supernatant, air-dry the EP tube in a fume hood, and then add an appropriate amount of DEPC water to dissolve the precipitate.

[0258] 1.3.2 RNA concentration determination

[0259] Use DEPC water to adjust the RNA concentration to 1 μg / μl, so that the OD260 (nucleic acid absorption wavelength) / OD280 (protein absorption wavelength) value is between 1.8-2.0, then store the RNA in a refrigerator at -80°C and reverse transcribe it into cDNA as soon as possible.

[0260] 1.3.3 Reverse transcription

[0261] Reverse transcription was performed using a PrimeScript™ reverse transcription kit (Takara) in a PCR instrument according to the following reaction parameters: 37°C for 15 minutes; 85°C for 5 seconds (to inactivate reverse transcriptase), centrifuged to mix, and then placed on ice.

[0262] 1.3.4 Quantitative PCR reaction

[0263] qPCR reactions were performed using cDNA obtained by reverse transcription of RNA as template. A 10-μl volume was loaded with the following: 1 μl of 10-fold diluted cDNA template, 1 μl of primers (0.5 μl forward primer and 0.5 μl reverse primer), 5 μl of SYBR Green PCR Master Mix (Takara), and 3 μl of ddH2O. The plates were loaded on ice and protected from light. After loading, the 384-well plate was centrifuged at 2000 rpm and 4°C for 2 minutes before being placed in a qPCR instrument. The reaction conditions were: 95°C, 30-second hot start; 95°C, 20 seconds; 60°C, 34 seconds; and 72°C, 40 seconds. After 40 cycles of 95°C, 15 seconds; 60°C, 40 seconds; and 95°C, 15 seconds, a melting curve was generated. The results were analyzed using Delta Delta CT Relative Quantitation software.

[0264] Quantitative PCR Primer Table

[0265] 1.4 Data Analysis

[0266] Real-time PCR was used to examine the effects of the compounds of the present invention on dexamethasone-induced extracellular matrix in human trabecular meshwork. The experimental results are shown in Figures 1-11. The results showed that dexamethasone increased the mRNA expression levels of fibronectin (FN), type IV collagen (COL-IV), and laminin (LN) in normal human trabecular meshwork cells, while the addition of the compounds of the present invention decreased the mRNA expression levels of FN, COL-IV, and LN in trabecular meshwork cells. In the figures, "*" indicates P < 0.05, and "**" indicates P < 0.01.

[0267] Biological Example 2 Effects of the Compounds of the Present Invention on Intraocular Pressure in Beagle Dogs

[0268] 2.1 The compounds of the present invention (RM-G-002M to RM-G-009M) were dissolved in physiological saline to prepare a 0.25% solution. The compounds of the present invention (RM-G-010M, RM-G-011M, RM-G-027M) were dissolved in physiological saline to prepare a 0.25% solution.

[0269] 2.2 Beagle dogs weighing approximately 10-14 kg and aged approximately 9-21 months (Jiangsu Yadong Experimental Animal Research Institute Co., Ltd.) were selected (3 per group).

[0270] 2.3 All animals underwent a physical examination before the start of the study, and no obvious abnormalities were found in the anterior segment and fundus of the eye to confirm that the animals were healthy and suitable for use in this study. Animals that failed the physical examination would be excluded or replaced before the start of the study.

[0271] 2.4 At least 4 weeks of behavioral and conscious IOP training are required before the trial until a stable IOP value is obtained.

[0272] 2.5 During the experimental dosing phase, the subjects were divided into the following groups: normal control group (normal saline group), positive drug group (timolol maleate eye drops (Bausch + Lomb), specification: 0.5%), compound group I of the present invention (0.2% RM-G-002M to RM-G-009M solution), and compound group II of the present invention (0.25% RM-G-010M solution, 0.25% RM-G-011M solution, 0.25% RM-G-027M solution). The route of administration was intra-conjunctival sac eye drops, with a dosing volume of 50 μL / eye / time, twice a day at 10:00 am and 17:00 pm for 15 consecutive days. The first day of administration was recorded as the first day. During administration, the eyelids were gently opened to avoid touching the surface of the eyeball. 50 μL of the vehicle or test sample was pipetted and gently dropped into the conjunctival sac, and the eyelids were gently closed several times.

[0273] 2.6 Intraocular pressure measurement: Intraocular pressure measurement was performed before the first dose on day 1, 2 hours and 4 hours after the first dose on day 1, before the first dose on day 2, before the first dose on day 4, before the first dose on day 7, before the first dose on day 13, before the first dose on day 15, and once on day 16. Detailed test data are shown in Tables 1 and 2, Figures 12 and 13.

[0274] Table 1 Summary of IOP data for beagle dogs in compound group I of the present invention

[0275] *** indicates p ≤ 0.001 compared with the vehicle group.

[0276] Table 2 Summary of IOP data for beagle dogs in compound group II of the present invention

[0277] *** indicates p ≤ 0.001 compared with the vehicle group.

[0278] As shown in Table 1, Table 2, Figure 12, and Figure 13, there was no significant change in intraocular pressure in the normal control group throughout the experiment. The mean intraocular pressure in the positive drug group and the compound of the present invention groups (Groups I and II) were significantly different from that in the normal control group. The compounds of the compound of the present invention groups (Groups I and II) at concentrations of 0.2% and 0.25% achieved superior intraocular pressure-lowering effects compared to the positive drug group at a concentration of 0.5% timolol maleate.

[0279] Effects of the compound in Biological Example 3 on intraocular pressure in rats

[0280] 3.1 Compounds RM-G-004M, RM-G-010M, RM-G-011M, and RM-G-027M were dissolved in a solvent (0.5% Tween 80 and 0.02% benzalkonium chloride in a 10 mM sodium hydrogen phosphate buffer solution (pH = 7.0)) to prepare a 0.25% solution.

[0281] 3.2 One hundred SD rats weighing approximately 160-180 g and aged approximately 35 days (Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected for modeling experiments and randomly divided into a blank control group of 16 rats, a dexamethasone group of 68 rats, and a vehicle group of 16 rats using a random number table.

[0282] 3.3 All animals underwent a physical examination before the start of the study, and no obvious abnormalities were found in the anterior segment and fundus of the eye to confirm that the animals were healthy and suitable for use in this study. Animals that failed the physical examination would be excluded or replaced before the start of the study.

[0283] 3.4 7 days, 3 days and 1 day before rats started modeling, the normal interval of right eye intraocular pressure value was measured as the baseline intraocular pressure value of rats. After the intraocular pressure of SD rats stabilized, dexamethasone sodium phosphate eye drops (Xinxiang Huaqing Pharmaceutical Co., Ltd.) were quantitatively instilled into the right eyes of dexamethasone group rats at 8:30 and 13:30 twice a day for 5 hours, and solvent (0.02 ml) was instilled into the right eyes of vehicle group rats. The blank control group was simply used as a control. IOP was measured every 2 days, and the rat systemic and eye local reactions were observed. The modeling was successful for about 7-10 days with the rat right eye intraocular pressure value increased to more than 20 mmHg.

[0284] 3.5 In the experimental dosing phase, rats with successful modeling (60) were selected and divided into groups according to the following scheme, namely, a negative control group (high intraocular pressure vehicle group), a positive control group (administered with timolol maleate eye drops (Bausch and Lomb), specification: 0.5%), and a test group of compounds RM-G-004M, RM-G-010M, RM-G-011M, and RM-G-027M (administered with 0.25% compound solution). In addition, 10 rats were randomly selected from the vehicle group of the modeling test described in 3.4 above as a non-model blank control group in the efficacy test phase in the same manner. The route of administration was intraocular drops in the conjunctival sac of the right eye of the rat, with a dosing volume of 20 μL / eye / time, and twice a day at 10:00 am and 17:00 pm for 15 consecutive days. The first day of administration was recorded as Day 1. When administering the drug, gently pull the eyelids apart to avoid touching the surface of the eyeball. Use a pipette to draw 20 μL of the vehicle or test sample and gently drop it into the conjunctival sac, and gently close the eyelids several times. In this experiment, dexamethasone sodium phosphate eye drops will continue to be used at a fixed time every day during modeling to treat the right eyes of the negative control group (high intraocular pressure vehicle group), the positive control group (administered with timolol maleate eye drops (Bausch and Lomb), specification: 0.5%), and the compound RM-G-004M, RM-G-010M, RM-G-011M, and RM-G-027M test groups (administered with 0.25% compound solution) twice to maintain the intraocular pressure of the rats' right eyes.

[0285] 3.6 Intraocular Pressure Measurement: Intraocular pressure measurements were performed before the first dose on Day 1, before the first dose on Day 2, before the first dose on Day 4, before the first dose on Day 6, before the first dose on Day 8, before the first dose on Day 10, before the first dose on Day 13, before the first dose on Day 15, and on Day 16. Detailed test data from the efficacy trial phase are shown in Table 3 and Figures 14 and 15.

[0286] Table 3 Effects of compounds on intraocular pressure in rats

[0287] T.Test: Compared with the negative control group, *** indicates p≤0.001.

[0288] According to the results in Table 3, Figures 14 and 15, there was no significant change in intraocular pressure in the blank control group and the negative control group throughout the experiment. The average intraocular pressure of the positive control group and the test groups with compounds RM-G-004M, RM-G-010M, RM-G-011M, and RM-G-027M was significantly different from that of the negative control group. The compounds in the test groups with compounds RM-G-004M, RM-G-010M, RM-G-011M, and RM-G-027M at a concentration of 0.25% achieved a superior IOP-lowering effect compared to the positive control group at a concentration of 0.5% timolol maleate.

[0289] The above description is only a specific embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent transformation made by using the present invention, or directly or indirectly applied in other related technical fields, is also included in the protection scope of the present invention.

Claims

1. A compound having the structure of the following formula (I): or a pharmaceutically acceptable salt thereof, wherein, R 1 、R 2 、R 3 、R 4 and R 5 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, acyl, -NO2 and -L-R', where each alkyl, alkenyl, alkynyl is unsubstituted or substituted by at least one substituent independently selected from R X ; -L- is -(CH2) o -, where each -(CH2)- is independently and optionally replaced by a carbonyl group or -O-; R’ is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO2, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heterocycloalkyl, heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X ; Among them, the R 1 , R 2 , R 3 , R 4 , R 5 and at least one of R' is NO2; R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl-SC 1-6 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted; Each R 10 、R 11 、R 12 and R 13 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1- 6alkyl-S-C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted by at least one substituent independently selected from R X ; R X Selected from hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and 5- to 10-membered heteroaryl, wherein each hydroxy, alkyl, alkoxy, alkenyl, alkynyl, heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R Y ; R Y Selected from hydroxyl, halogen, cyano, NO2, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; 1* C, 2* C, 3* C, 4* C and 5* C respectively represent the carbon atoms that may be chiral in the compound of formula (I) structure; o, m, and n are each independently selected from the integers 0 - 6.

2. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from -NO2 and -L-R'; Preferably, R 1 is -NO2; or R 1 is -L-R', where -L- is -(CH2) o -, where o is 4, and -(CH2) o - has one end replaced by a carbonyl group, and -(CH2) o - has the other end replaced by -O-, R' is -NO2 and is connected to -O-; or R 1 For or R 1 For or R 1 For 3. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 2 selected from hydrogen and acyl; Preferably, R 2 is hydrogen; or R 2 is an acetyl group.

4. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 3 selected from hydrogen, acyl and -L-R'; Preferably, R 3 is hydrogen; R 3 is an acetyl group; or R 3 is -L-R', where -L- is -(CH2) o -, where o is 4, and -(CH2) o - has one end replaced by a carbonyl group, and -(CH2) o - has the other end replaced by -O-, R' is -NO2 and is connected to -O-.

5. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 4 selected from hydrogen, acyl, and -L-R'; Preferably, R 4 is hydrogen; R 4 is an acetyl group; or R 4 is -L-R', -L- is -(CH2) o -, where o is 4, and -(CH2) o - has one end replaced by a carbonyl group, -(CH2) o - has the other end replaced by -O-, R' is -NO2 and is connected to -O-.

6. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 5 selected from hydrogen and acyl; Preferably, R 5 is hydrogen; or R 5 is an acetyl group.

7. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently hydrogen.

8. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, m is 2.

9. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, n is 1.

10. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, o is an integer from 2 - 4.

11. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Chiral carbon atom 1* C is in the R configuration.

12. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Chiral carbon atom 2* C is in the R or S configuration.

13. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Chiral carbon atom 3* C has the S configuration.

14. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Chiral carbon atom 4* C is in the R configuration.

15. The compound of the formula (I) structure according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Chiral carbon atom 5* C has the R configuration.

16. The compound of the formula (I) structure according to claim 1, which is selected from the following structures: or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound of the formula (I) structure according to any one of claims 1 - 16 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

18. Use of the compound of the formula (I) structure according to any one of claims 1 - 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17 in the preparation of a drug for treating, ameliorating or preventing extracellular matrix protein abnormal diseases or diseases associated with ocular hypertension.

19. Use of the compound of the formula (I) structure according to any one of claims 1 - 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17 in the preparation of a drug for preventing or treating glaucoma, subretinal fibrosis in age - related macular degeneration, diabetic retinopathy, ocular hypertension caused by posterior capsular cataract and tissue fibrosis, trabecular meshwork cell and ganglion cell damage, or oxidative damage of corneal epithelial cells caused by dry eye.

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