Dihydronaphthyridine unsaturated alkyl ether compounds, pharmaceutical compositions and uses

Abstract

This invention belongs to the field of chemical pharmaceutical technology, and provides compounds of general formulas I, II, and III, or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof. In these formulas, R1 is selected from C1-C6 alkyl, halo- or deuterated C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, halo- or deuterated C3-C6 cycloalkyl, halo- or deuterated C3-C7 heterocycloalkyl, C3-C7 cycloalkenyl, C3-C8 cycloalkyl C1-C6 alkyl, halo- or deuterated C3-C8 cycloalkyl C1-C6 alkyl, C2-C5 alkenyl C1-C6 alkyl, C2-C5 allenyl C1-C6 alkyl, etc. This compound exhibits good affinity for mineralocorticoid receptors. This invention also relates to compositions and applications of compounds of general formulas I, II, and III, or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a dihydronaphthyl unsaturated alkyl ether compound, a pharmaceutical composition, and its application. Background Technology

[0002] The mineralocorticoid receptor (MR) is an aldosterone-activated nuclear hormone receptor that regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular disease. Increased circulating aldosterone levels raise blood pressure through its effect on urinary sodium excretion, and potentially affect the brain, heart, and vascular system. Furthermore, hyperaldosteronism is associated with many pathophysiological processes leading to renal and cardiovascular disease. Although hyperaldosteronism is usually caused by aldosterone-producing adenomas, elevated aldosterone levels are frequently observed in patients with refractory hypertension, a condition often referred to as "aldosterone escape," due to elevated serum potassium levels or residual AT1R activity.

[0003] Hyperaldosterone syndrome and aldosterone escape typically lead to increased MR activity. Drugs inhibit aldosterone-mediated damage by competitively binding to mineralocorticoid receptors, thereby blocking the binding of aldosterone to mineralocorticoid receptors and reducing the occurrence of the aforementioned diseases.

[0004] MR antagonists have been demonstrated as effective antihypertensive agents and are also effective in treating heart failure and primary aldosterone excess. Furthermore, MR antagonists have been shown to be effective in preclinical models of kidney disease and can be combined with standard therapy to reduce proteinuria in patients with kidney disease, such as chronic kidney disease, including diabetic nephropathy.

[0005] Although existing mineralocorticoid receptor antagonists have therapeutic effects on hypertension and heart failure, there are still significant unmet medical needs, and clinical practice needs to further explore new drugs with better performance to solve the treatment problems of these diseases. Summary of the Invention

[0006] To address the above problems, this invention provides a dihydronaphthidyl unsaturated alkyl ether compound, a pharmaceutical composition, and its application. This compound exhibits good affinity for MR, higher activity, and excellent performance.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a compound of general formula I, general formula II or general formula III, or a pharmaceutically usable salt, stable isotope derivative, isomer or mixture thereof:

[0008] In the formula, R1 is selected from C1-C6 alkyl, halo- or deuterated C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, halo- or deuterated C3-C7 cycloalkyl, halo- or deuterated C3-C7 heterocycloalkyl, C3-C7 cycloalkenyl, C3-C8 cycloalkyl C1-C6 alkyl, halo- or deuterated C3-C8 cycloalkyl C1-C6 alkyl, C2-C5 alkenyl C1-C6 alkyl, C2-C5 allenyl C1-C6 alkyl; or R1 is a single bond; R2, R3, and R4 are each independently selected from H, deuterium, halogen, phenyl, tolyl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl, halogenated or deuterated C1-C6 alkyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C3-C6 heterocyclic alkyl, or R2 and R3 can form C3-C8 cycloolefins or heterocyclic olefins with double bonds; R5 and R6 are independently selected from H, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, aminoacyl, aminosulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkanoyl, C1-C6 alkoxyacyl, C1-C6 acylamino, C1-C6 alkenylC3-C6 cycloalkyl, halogenated or deuterated C1-C6 alkyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C1-C6 alkoxy, C6-C 10 Aryl, heterocyclic groups consisting of 3-8 atoms, and heteroaryl groups consisting of 5-10 atoms; R9 is independently selected from H, halogen, cyano, or C1-C6 alkyl, or halogenated or deuterated C1-C6 alkyl; R7 is selected from halogens, C1-C3 alkyl groups, halogenated or deuterated C1-C3 alkyl groups, C1-C3 alkoxy groups, C1-C3 alkoxy-C1-C3 alkyl groups, and C1-C3 alkylamino-C1-C3 alkyl groups. R8 is selected from CN-, aminoacyl, aminosulfonyl, aminophosphonic acid, aminoC3-C6 cycloalkyl, aminoC3-C6 heterocycloalkyl, aminoC 1- C5 alkyl, amino halogenated C 1- C5 alkyl, C 1- C5 alkylamino, halogenated or amino-substituted C 1- A C5 alkylamino group or a heteroaryl group consisting of 5-10 atoms. , , Wherein, the amino hydrogen in the aminoacyl group, aminosulfonyl group, and aminophosphonic acid group is not substituted or is replaced by R. zSubstitution, Rz is selected from halogen, hydroxyl, amino, carbamoyl, C1-C3 alkoxy, C3-C6 cycloalkyl, heterocyclic group composed of 3-8 atoms, or amino group in which 2 hydrogens are replaced and form a 5-6 membered heterocycle with N atom; Or R7 and R8 can form a C3-C8 heterocycle; R 10 Selected from H, deuterium, halogens or C1-C3 alkyl groups, R 11 Selected from C1-C3 alkoxy, or halogenated C1-C3 alkoxy, C3-C5 cycloalkoxy; Or R 10 and R 11 Formation of C5-C8 cyclic hydrocarbons or C5-C8 heterocyclic hydrocarbons; X is either O or S; Y1 and Y2 are independently C or N, where Y1 and Y2 are not simultaneously N; Z is selected from C3-6 cycloalkyl-C1-3 alkyl, C3-C7 cycloalkenyl, bicycloalkyl-C1-C3 alkyl, and azide-C1-C3 alkyl. or The hydrogen in C3-6 cycloalkyl C1-3 alkyl and bicycloalkyl C1-C3 alkyl is either not substituted or is substituted by halogen, deuterium or C1-3 alkyl.

[0009] In one embodiment of the present invention, the compounds represented by general formulas I, II, and III, or their pharmaceutically usable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein R1 is selected from C1-C4 alkyl, halo- or deuterated C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, halo- or deuterated C3-C6 cycloalkyl, halo- or deuterated C3-C6 heterocycloalkyl, or C3-C6 cycloalkyl C1-C3 alkyl, halo- or deuterated C3-C6 cycloalkyl C1-C3 alkyl, halo- or deuterated C2-C5 alkenyl C1-C3 alkyl, C2-C5 allenyl C1-C3 alkyl, or R1 is a single bond; R2, R3, and R4 are each independently selected from H, deuterium, halogen, phenyl, tolyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl, halogenated or deuterated C1-C3 alkyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C3-C6 heterocyclic alkyl, or R2 and R3 can form C3-C8 cycloolefins or heterocyclic olefins with double bonds; R5 and R6 are independently selected from H, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, C1-C4 alkyl, or halogenated or deuterated C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkanoyl, C1-C4 alkoxyacyl, C1-C4 acylamino, C1-C3 alkenyl C3-C6 cycloalkyl, heterocyclic groups consisting of 3-6 atoms, and heteroaryl groups consisting of 5-6 atoms; The R 10 and R 11 Formation of C5-C8 cyclic hydrocarbons or C5-C8 heterocyclic hydrocarbons, wherein the C5-C8 heterocyclic hydrocarbons are or .

[0010] Further, R1 is a single bond or selected from the following groups, wherein any hydrogen on each group is not substituted, or any 1-4 hydrogens are substituted with halogen or deuterium: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, , , , , , , or .

[0011] Furthermore, R2, R3 and R4 are independently H, deuterium, F, Cl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl and epoxyethyl, respectively.

[0012] Furthermore, R5 and R6 are each independently selected from H, F, Cl, methyl, ethyl, propyl, cyclopropyl, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, methoxy, ethoxy, formyl, dimethylamino, methanesulfonyl, cycloethoxy, vinylcyclopropyl, carbamoyl, aminoacetyl, methoxyacyl, propoxyacyl, formylamino, acetylamino, etc. .

[0013] Furthermore, R9 is selected from H, F, chlorine, cyano, methyl, propyl, and ethyl.

[0014] Further, R7 is selected from F, Cl, methyl, ethyl, propyl, methoxymethyl, and methylaminomethyl; R8 is selected from CN-, , , , , , , , , , , , , , , , , , , , or Alternatively, R7 and R8 may form a C3-C8 heterocycle, wherein the C3-C8 heterocycle is... .

[0015] Furthermore, the R 10 Selected from H, deuterium, methyl, ethyl, or propyl; the R 11 Selected from ethoxy, methoxy, cyclopropoxy; or the R 10 and R 11 form or .

[0016] Furthermore, Z is selected from methyl, ethyl, , , , , , , , azide-methyl, azide-ethyl, azide- , , , , , , , , , , , , , , , , , , or .

[0017] In one embodiment of the present invention, the compounds represented by general formulas I, II, and III, or their pharmaceutically usable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein the compounds represented by general formulas I, II, and III have structural formulas as shown in formula Ia or Ib, formula IIa or IIb, formula IIIa or IIIb, preferably compounds shown in formula Ib, formula IIb, or formula IIIb.

[0018]

[0019]

[0020]

[0021] In one embodiment of the present invention, the compounds represented by general formulas I, II, and III, or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein the compounds have structural formulas as shown in formula IIc or IId:

[0022] In the formula, R1 is selected from the following unsubstituted, deuterated or halogenated groups: C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl, C1-C3 alkyl; R4 is selected from H, deuterium, halogen, methyl, halomethyl or deuterated methyl; R5, R6 and R9 are each independently selected from H, halogens, or C1-C3 alkyl groups, or halogenated or deuterated C1-C3 alkyl groups.

[0023] Furthermore, R1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, , , , , , R4 is H, deuterium, F, chlorine or methyl; R5 and R6 are independently selected from H, halogen, methyl or ethyl; R9 is selected from H, halogen or methyl.

[0024] Further, X is O; R6 is methyl or propyl; R5 is hydrogen, fluorine, or chlorine; R7 is... ;R 11 It is a methoxy group.

[0025] In one embodiment of the present invention, the compounds represented by general formulas I, II, and III, or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein the structural formula of the compound is shown as formula Ic or formula Id:

[0026] In the formula, R1 is selected from C1-C6 alkyl, C1-C6 alkenyl, halogenated or deuterated C1-C6 alkyl, halogenated or deuterated C1-C6 alkenyl, C3-C6 cycloalkyl, C3-C7 cycloalkenyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C3-C7 cycloalkenyl, or C3-C6 cycloalkyl-C1-C3 alkyl; R2, R3 and R4 are each independently selected from H, deuterium, halogen, phenyl, C1-C3 alkyl, halogenated or deuterated C1-C3 alkyl.

[0027] Further, R1 is a group selected from the following unsubstituted, halogenated, or deuterium-substituted groups: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, , , , , , , or R2 is H, deuterium, F, Cl, methyl, or ethyl; R3 and R4 are independently H, deuterium, F, Cl, methyl, ethyl, or phenyl, wherein R3 and R4 are not simultaneously phenyl; R7 is methyl, and R8 is CN-. , , or R8 preferred ;R 10 Selected from H, deuterium, halogen, methyl or ethyl; R 11 It is a methoxy group.

[0028] In one embodiment of the present invention, the compounds represented by general formulas I, II, and III, or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein the compounds have structural formulas as shown in formula IIIc or IIId:

[0029] Z is selected from azidomethyl, azidoethyl, bicyclo[1,1,1]pentylmethylene, or .

[0030] Furthermore, R7 is methyl, and R8 is CN-, , , or ;R 10 Selected from H, deuterium, halogen, methyl or ethyl, R 11 Selected from methoxy groups.

[0031] One embodiment of the present invention relates to compounds represented by general formulas I, II, and III, wherein said compounds are selected from, but not limited to:

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] Or in the form of the above-mentioned prodrug, stable isotope derivative, pharmaceutically usable salt, isomer, or mixture thereof.

[0040] The compound of this invention exhibits strong selectivity and affinity for MR. Experimental verification has shown that this compound has superior in vivo efficacy compared to fenelone; therefore, this compound can be considered a more clinically valuable and promising MR antagonist.

[0041] A second aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or combination thereof, and the aforementioned compound or its pharmaceutically acceptable salt, stable isotope derivative, isomer, or mixture thereof as an active ingredient; further comprising one or more other active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, β-receptor blockers, acetylsalicylic acid, diuretics, calcium channel blockers, statins, digitalis derivatives, calcium sensitizers, nitrates, and antithrombotic agents.

[0042] The above-mentioned pharmaceutical composition can be any dosage form, optionally such as conventional dosage forms such as tablets, granules, capsules, powders or injections, or complex dosage forms such as sustained-release, microcapsules, liposomes, etc.

[0043] Another aspect of the present invention relates to the above-mentioned compounds or their pharmaceutically usable salts, stable isotope derivatives, isomers and mixtures thereof, and the use of the above-mentioned pharmaceutical compositions in the preparation of remedies for treating, preventing or alleviating patients with the following diseases: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

[0044] Another aspect of the present invention relates to the above-described compounds or their pharmaceutically usable salts, stable isotope derivatives, isomers and mixtures thereof, and the use of the above-described pharmaceutical compositions in the preparation of a medicament, wherein the medicament is used as a mineralocorticoid receptor antagonist. Attached Figure Description

[0045] Figure 1 The cell viability versus drug concentration curves in the AR receptor selectivity study of Experiment Example 2. Figure 2 The cell viability versus drug concentration curves in the GR receptor selectivity study of Experiment Example 2. Figure 3 This is a comparative study of the effects of compound 1 in Experiment 6 on urine volume / body weight. Figure 4 This is a comparative study of the effects of compound 1 in Experiment 6 on the concentration of Na+ ions in plasma. Figure 5 This is a comparative study of the effects of compound 1 in Experiment 6 on the concentration of Ka ions in plasma. Detailed Implementation To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0046] Unless otherwise stated, all technical terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0047] In this application, "alkyl" means 1-20 carbon atoms, including saturated straight-chain or branched alkyl groups; in some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C1-C6 alkyl; in other embodiments, the alkyl group contains 1-3 carbon atoms, i.e., C1-C3 alkyl. Any one or more hydrogen atoms in the alkyl group may be substituted with halogen or deuterium.

[0048] Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl), n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0049] "Alkoxy" means that an alkyl group is attached to the rest of the molecule by an oxygen atom, wherein the alkyl group has the meaning described in this application. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy, 2-propoxy) or butoxy (including n-butoxy, isobutoxy, sec-butoxy or tert-butoxy).

[0050] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group contains 3 to 6 ring carbon atoms and is designated as C3-C6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclopentyl, etc.

[0051] In this application, when a complex group consists of two or more connected groups, the connection site follows general chemical principles, meaning the connection point is the noun group at the end of the complex group's name. For example, C 3-6 cycloalkyl C 1-6 Alkyl groups, whose connection sites with the main structural group or other groups are all "C". 1-6 "alkyl"; other similar groups are understood in accordance with this principle unless otherwise specified.

[0052] "Olefin group" refers to an unsaturated hydrocarbon group, which can be straight-chain, branched, or have a cycloalkane structure, including but not limited to vinyl, propenyl, isopropenyl, or 2-butenyl.

[0053] "Halogenated or deuterated alkyl", "halogenated or deuterated alkoxy", "halogenated" means that the alkyl or alkoxy group is replaced by one or more halogen atoms, and "deuterated" means that the alkyl or alkoxy group is replaced by one or more deuterium atoms. Such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, chloroethyl (e.g., 2-chloroethyl), trifluoroethyl (including, but not limited to, 2,2,2-trifluoroethyl), 2,2-difluoroethyl, 2-chloro-1-methylethyl, deuterated methyl, and 2,2-deuterated ethyl.

[0054] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0055] "Amino" represents the group -NH2; "carboxyl" represents the group -COOH; "hydroxyl", "cyano", "nitro", and "mercapto" represent the groups -OH, -CN, -NO2, and -SH, respectively.

[0056] "Alkylamino" indicates that the -NH2 group is replaced by one or two alkyl groups, that is, the alkylamino group includes monoalkylamino and dialkylamino groups; wherein the alkyl group has the meaning as described in this invention. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, etc.

[0057] A "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. The heterocyclic group is non-aromatic and does not contain any aromatic ring. Unless otherwise stated, the heterocyclic group can be carbocyclic or nitrogen-based, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclic groups include, but are not limited to, ethylene oxide, azirrobutyl, oxobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, etc. The heterocyclic group may consist of 3 to 8 atoms or 3 to 6 atoms, wherein the atoms are C, N, O, or S, and at least one atom is N, O, or S.

[0058] "A heteroaryl group consisting of 5-10 atoms" refers to a heteroaryl group containing 5-10 ring atoms, wherein the heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O, and S. In some embodiments, specific examples of "a heteroaryl group consisting of 5-10 atoms" as described in this invention include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, thiopheneyl, etc.

[0059] "Alkyl" and "alkoxyacyl" respectively represent the groups -C(=O)-alkyl and -C(=O)-alkoxy, wherein alkyl and alkoxy have the meanings described above in this application, and such examples include, but are not limited to, methylacyl (-C(=O)CH3), ethylacyl (-C(=O)CH2CH3), methoxyacyl (-C(=O)OCH3), ethoxyacyl (-C(=O)OCH2CH3), etc.

[0060] "Aminosulfonyl" represents the group -S(=O)2NH2; "aminoacyl" represents the group -C(=O)NH2; "aminophosphonic acid" represents -P(=O)NH 2； “C1-C6 acylamino” represents RC(=O)NH2-, where R represents C1-C6 alkyl.

[0061] The term "isomer" as used in this article refers to compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of their atoms. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers include optical isomers, geometric isomers, and conformational isomers.

[0062] The compounds of this invention can exist as optical isomers. These optical isomers are "R" or "S" configurations, depending on the configuration of the substituents surrounding the chiral carbon atom. Optical isomers include enantiomers and diastereomers. Methods for preparing and isolating optical isomers are known in the art.

[0063] The compounds of this invention may also exist as geometric isomers. This invention considers various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups, or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl or heterocyclic groups are designated as cis or trans configurations.

[0064] "Isotope" includes all isotopes of atoms appearing in the compounds of this invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds of this invention are hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, respectively, for example, but not limited to, [specific examples]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F and 36Cl. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotope-labeled reagents instead of non-isotope-labeled reagents. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0065] "Prodrug" refers to compounds of the present invention that can be administered in the form of a prodrug. A prodrug is a derivative that, under physiological conditions in vivo, is converted into the bioactive compound of the present invention through processes such as oxidation, reduction, and hydrolysis (each utilizing an enzyme or without enzyme involvement). Examples of prodrugs are compounds in which the amino group is acylated, alkylated, or phosphorylated, for example, methylacylamino, alanylamino, or neopentyloxymethylamino; or where the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate, for example, acetoxy, fumaroxy, or alanyloxy; or where the carboxyl group is esterified or amidated. These compounds can be prepared from compounds of the present invention according to known methods.

[0066] "Pharmaceutical-grade salt" or "pharmaceutically acceptable salt" refers to a salt made from a pharmaceutically acceptable base or acid, including inorganic bases or acids and organic bases or acids. In the case of compounds of the present invention containing one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically-grade salts. Thus, compounds of the present invention containing acidic groups can exist in salt form and can be used according to the present invention, for example as alkali metal salts, alkaline earth metal salts, or as ammonium salts, exemplary including sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of the present invention containing basic groups can exist in salt form and can be used according to the present invention as addition salts of themselves with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pentylamino acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes internal salts or internal ammonium salts in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0067] "Pharmaceutical composition" means a composition containing one or more of the compounds described herein or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0068] Therefore, when referring to “compound,” “compound of the present invention,” or “compound of the present invention” in this application, it includes all said compound forms, such as pharmaceutically usable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof.

[0069] This invention also provides a method for preparing the compound. The preparation of the compound of general formula (I) of this invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of this invention. The compound of this invention can also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and the methods described in this invention. The product obtained from each reaction step is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, and chromatographic separation. The starting materials and chemical reagents required for synthesis can be conventionally synthesized or purchased according to literature.

[0070] Reference Example 1 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared and designated as intermediate 1. The corresponding structural formula is intermediate 1.

[0071] The preparation route is as follows:

[0072] S1: Intermediate 1a (4-cyano-2-methoxybenzaldehyde, 3.0 g, 18.6 mmol) and acetylacetamide (2.8 mg, 27.9 mmol) were dissolved in dichloromethane (20 mL), and acetic acid (0.1 g) and piperidine (0.1 g) were added. The mixture was then heated at 40 °C. o The mixture was stirred at C until fully reacted. After cooling to room temperature, it was filtered to give intermediate 1b (2-(4-cyano-2-methoxybenzyl)-3-oxobutyramide, 3.5 g, yield 77.1%).

[0073] S2: Intermediate 1b (1.0 g, 4.1 mmol) and 4-amino-5-methyl-pyridine-2-ol (0.5 g, 4.1 mmol) were dissolved in isopropanol (10 mL), and the mixture was heated at 95°C. oThe mixture was stirred at C until fully reacted. The solvent was removed under vacuum to obtain the crude product, which was then purified by silica gel rapid column chromatography (eluent: 0-10% methanol in dichloromethane) to obtain compound intermediate 1 (0.9 g, yield 63.0%).

[0074] Example 1 4-(4-cyano-2-cyclopropoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 91, with the corresponding structural formula 91.

[0075] The preparation route is as follows:

[0076] S1: Sodium tert-butoxide (804.6 mg, 8.4 mmol) and cyclopropanol (389.0 mg, 6.7 mmol) were added to a 100 mL double-necked flask at room temperature. After purging with nitrogen, anhydrous tetrahydrofuran was added and stirred for 30 minutes. Compound 91a (methyl 4-cyano-2-fluorobenzoate, 800 mg, 4.47 mmol) was added, and stirring continued overnight at room temperature. The mixture was extracted with ethyl acetate (500 mL × 3), and the organic phases were combined, washed with saturated brine (500 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid, compound 91b (methyl 4-cyano-2-cyclopropoxybenzoate, 500.0 mg, yield 43.3%).

[0077] S2: Compound 91b (500.0 mg, 2.3 mmol) was dissolved in DME:H2O = 3:1 in a 100 mL single-necked flask at room temperature. Sodium hydroxide (184.1 mg, 4.6 mmol) was added, and stirring was continued for 3 hours. The mixture was extracted with ethyl acetate (500 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid, compound 91c (4-cyano-2-cyclopropoxybenzoic acid, 400.0 mg, yield 85%).

[0078] S3: Compound 91c (400.0 mg, 2.0 mmol) was dissolved in dichloromethane (50 mL) in a 100 mL single-necked flask at room temperature. Tf-DMAP (925.6 mg, 3.4 mmol), 4-dimethylaminopyridine (390.9 mg, 3.2 mmol), and pinacolborane (435.1 mg, 3.4 mmol) were added. The mixture was stirred at room temperature for 10 minutes, extracted with dichloromethane (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give solid compound 91d (4-cyano-2-cyclopropoxybenzaldehyde, 168.5 mg, yield 45.0%).

[0079] S4: Compound 91d (3.0 g, 18.6 mmol) and acetylacetamide (2.8 g, 27.9 mmol) were dissolved in isopropanol (20 mL), and acetic acid (0.1 g, 1.7 mmol) and piperidine (0.1 g, 1.2 mmol) were added. The mixture was then heated at 50 mL. o The mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 91e (2-(4-cyano-2-cyclopropoxybenzyl)-3-oxobutyramide, 3.5 g, yield 77.1%).

[0080] S5: Compound 91e (1.0 g, 4.1 mmol) and 4-amino-5-methyl-pyridin-2-ol (0.5 g, 4.1 mmol) were dissolved in sec-butanol (10 mL), and the mixture was heated in 100 mL of water. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 91f (4-(4-cyano-2-cyclopropoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 0.9 g, yield 63.0%).

[0081] S6: Compound 91f (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and bromoethane (155.4 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 91 (53.0 mg, yield 26.5%), an off-white solid.

[0082] MS (ESI) M / Z: 405.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.66 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H),7.30 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.76 (d, J= 35.3 Hz, 2H), 5.28(s, 1H), 4.08 – 3.87 (m, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 1.03 (t, J = 7.0 Hz,3H), 0.88 – 0.63 (m, 4H). Example 2 5-ethoxy-4-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-2,8-dimethyl-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 92, with the corresponding structural formula 92.

[0083] The preparation route is as follows:

[0084] S1: At room temperature, triazole (3.5 g, 51.9 mmol) and potassium carbonate (3.5 g, 26.0 mmol) dissolved in acetonitrile were added to a 100 mL single-necked flask. After stirring at room temperature for 30 minutes, compound 92a (4-fluoro-2-methoxybenzaldehyde, 2.0 g, 13.0 mmol) was added, and the temperature was raised to 80°C. o C. Continue stirring for 5 hours. After cooling, extract with ethyl acetate (500 mL × 3), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter and concentrate under reduced pressure to give a yellow oily compound 92b (2-methoxy-4-(2H-1,2,3-triazol-2-yl)benzaldehyde, 530.0 mg, yield 20.0%).

[0085] S2: Compound 92b (530.0 mg, 2.6 mmol) and acetylacetamide (263.7 mg, 2.6 mmol) were dissolved in isopropanol, and acetic acid (62.6 mg, 1.0 mmol) and piperidine (88.8 mg, 1.0 mmol) were added. The mixture was then heated at 50 °C. o The mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 92c (2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)benzylidene)-3-oxobutyramide, 700.0 mg, yield 93.7%).

[0086] S3: Compound 92c (700.0 mg, 2.4 mmol) and 4-amino-5-methyl-pyridin-2-ol (333.8 mg, 2.7 mmol) were dissolved in sec-butanol, and the mixture was heated in 100 mL of water. oThe reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 92d (4-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 785.0 mg, yield 81.8%).

[0087] S4: Compound 92d (785.0 mg, 2.0 mmol), cesium carbonate (1.0 g, 3.2 mmol), and bromoethane (326.9 mg, 3.0 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate (250 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give 92 (211.0 mg, 24.8%), an off-white solid.

[0088] MS (ESI) M / Z: 421.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.89 (s, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 35.3Hz, 2H), 5.28 (s, 1H), 4.08 – 3.87 (m, 2H), 3.81 (s, 3H), 2.13 (s, 3H), 2.11(s, 3H), 1.03 (t, J = 7.0 Hz, 3H). Example 3 5-ethoxy-4-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-2,8-dimethyl-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 93, with the corresponding structural formula 93.

[0089] The preparation route is as follows:

[0090] S1: At room temperature, triazole (3.5 g, 51.9 mmol) and potassium carbonate (3.5 g, 26.0 mmol) dissolved in acetonitrile were added to a 100 mL single-necked flask. After stirring at room temperature for 30 minutes, compound 93a (4-fluoro-2-methoxybenzaldehyde, 2.0 g, 13.0 mmol) was added, and the temperature was raised to 80°C. o C. Continue stirring for 5 hours. After cooling, extract with ethyl acetate (500 mL × 3), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter and concentrate under reduced pressure to give a yellow oily compound 93b (2-methoxy-4-(2H-1,2,3-triazol-2-yl)benzaldehyde, 530.0 mg, yield 20.0%).

[0091] S2: Compound 93b (530.0 mg, 2.6 mmol) and acetylacetamide (263.7 mg, 2.6 mmol) were dissolved in isopropanol, and acetic acid (62.6 mg, 1.0 mmol) and piperidine (88.8 mg, 1.0 mmol) were added. The mixture was then heated at 50 °C. o The mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 93c (2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)benzylidene)-3-oxobutyramide, 700.0 mg, yield 93.7%).

[0092] S3: Compound 93c (700.0 mg, 2.4 mmol) and 4-amino-5-methyl-pyridin-2-ol (333.8 mg, 2.7 mmol) were dissolved in sec-butanol, and the mixture was heated in 100 mL of water. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 93d (4-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 785.0 mg, yield 81.8%).

[0093] S4: Compound 93d (785.0 mg, 2.0 mmol), cesium carbonate (1.0 g, 3.2 mmol), and bromoethane (326.9 mg, 3.0 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate (250 mL × 2), combine the organic phases, wash with saturated brine, and dry on anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid compound 93 (211.0 mg, 24.8%).

[0094] MS (ESI) M / Z: 421.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.89 (s, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 35.3Hz, 2H), 5.28 (s, 1H), 4.08 – 3.87 (m, 2H), 3.81 (s, 3H), 2.13 (s, 3H), 2.11(s, 3H), 1.03 (t, J = 7.0 Hz, 3H). Example 4 5-(4-cyano-2-methoxyphenyl)-4-ethoxy-7-methyl-2-(methylthio)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide was prepared, denoted as compound 94, with the corresponding structural formula 94.

[0095] The preparation route is as follows:

[0096] S1: Compound 94a (4-cyano-2-methoxybenzaldehyde, 420.0 mg, 2.6 mmol) and compound 94b (acetylacetamide, 263.7 mg, 2.6 mmol) were dissolved in isopropanol, and acetic acid (62.6 mg, 1.0 mmol) and piperidine (88.8 mg, 1.0 mmol) were added. The mixture was then heated at 50 °C. o The mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 94c (2-(4-cyano-2-methoxybenzyl)-3-oxobutyramide, 586.0 mg, yield 92.0%).

[0097] S2: Compound 94c (500.0 mg, 2.0 mmol) and compound 94d (2-methylmercapto-4-amino-6-hydroxypyrimidine, 328.0 mg, 2.1 mmol) were dissolved in sec-butanol, and the mixture was heated in 100 mL of water. oThe reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 94e (5-(4-cyano-2-methoxyphenyl)-4-hydroxy-7-methyl-2-(methylthio)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide, 620.0 mg, yield 79.0%).

[0098] S3: Compound 94e (560.0 mg, 1.5 mmol), cesium carbonate (714.0 mg, 2.2 mmol), and bromoethane (254.0 mg, 2.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate (250 mL × 2), combine the organic phases, wash with saturated brine, and dry on anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give 94 (102.0 mg, 17.0%), an off-white solid.

[0099] MS (ESI) M / Z: 412.3 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 9.28 (s, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.32 (dd, J = 7.8, 1.5 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 35.0Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.81 (s, 3H), 2.42 (s, 3H), 2.06 (s, 1H), 1.07 (d, J = 7.1 Hz, 2H). Example 5 5-(4-cyano-2-methoxyphenyl)-4-hydroxy-7-methyl-2-oxo-1,2,5,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxamide was prepared, denoted as compound 95, with the corresponding structural formula 95.

[0100] The preparation route is as follows:

[0101] S1: Compound 95a (2-methylmercapto-4-amino-6-hydroxypyrimidine, 1.0 g, 6.4 mmol) and sodium tungstate dihydrate (30.0 mg, 0.1 mmol) were dissolved in 10 mL of acetic acid, and 28% hydrogen peroxide (1.5 mL, 13.2 mmol) was slowly added dropwise. The mixture was heated at 80 °C. o The mixture was stirred at C for 2 hours until fully reacted. After cooling to room temperature, the reaction solution was diluted with water, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid compound 95b (6-aminopyrimidine-2,4-diol, 261.1 mg, 31.5%).

[0102] S2: Compound 95c (4-cyano-2-methoxybenzaldehyde, 420.0 mg, 2.6 mmol) and acetylacetamide (263.7 mg, 2.6 mmol) were dissolved in isopropanol, and acetic acid (62.6 mg, 1.0 mmol) and piperidine (88.8 mg, 1.0 mmol) were added. The mixture was then heated at 50 °C. o The mixture was stirred at C and reacted thoroughly overnight. After cooling to room temperature, it was filtered to give compound 95d (2-(4-cyano-2-methoxybenzyl)-3-oxobutyramide, 586.0 mg, yield 92.0%).

[0103] S3: Compound 95d (500.0 mg, 2.0 mmol) and compound 95b (254.2 mg, 2.0 mmol) were dissolved in sec-butanol, and the mixture was heated at 100... o The mixture was stirred at C until fully reacted. The solvent was removed under vacuum to obtain the crude product, which was then purified by rapid silica gel column chromatography to give compound 95 (427.5 mg, yield 60.5%). MS (ESI) M / Z: 354.4 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 10.51 (s, 1H), 9.98 (s, 1H), 8.01 (s, 1H), 7.38 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.92 (d, J= 89.0 Hz, 2H), 5.09 (s, 1H), 3.79 (s, 3H), 1.99 (s, 3H). Example 6 Prepare 3-cyano-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-1,6-naphthidine-2-ylacetate, denoted as compound 96, with the corresponding structural formula 96.

[0104] The preparation route is as follows:

[0105] S1: Compound 96a (4-cyano-2-methoxybenzaldehyde, 1.0 g, 6.2 mmol), ethylenediamine-N,N'-diacetic acid (109.3 mg, 0.6 mmol), malononitrile (409.9 mg, 6.2 mmol), and 2,4-pyridinide (689.4 mg, 6.2 mmol) were dissolved in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give a pale yellow solid compound 96b (7-cyano-8-(4-cyano-2-methoxyphenyl)-1-hydroxy-5,8-dihydroisoquinoline-6-ylacetate, 1.0 g, 48.0%).

[0106] MS (ESI) M / Z: 362.36 [M+H] + S2: Compound 96b (560.0 mg, 1.5 mmol), cesium carbonate (714.0 mg, 2.2 mmol), and bromoethane (254.0 mg, 2.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate (250 mL × 2), combine the organic phases, wash with saturated brine, and dry on anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give 96 (102.0 mg, 17.0%) of an off-white solid.

[0107] MS (ESI) M / Z: 390.13 [M+H] + 1 H NMR (300 MHz, DMSO- d6) δ11.61 (s, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.46 – 7.36 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 6.15 (d, J = 7.2 Hz, 1H), 4.92(s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.07 (s, 3H), 1.26 (t, J =7.0 Hz, 4H). Example 7 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(prop-2-alkynyloxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 7, with the corresponding structural formula 7.

[0108] The preparation route is as follows:

[0109] S1: In a 100 mL round-bottom flask, compound 7a (4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4-dihydro-1,6-naphthidine-3-carboxamide, 300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and 3-bromopropyne (1.2 mL, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give a pale yellow solid compound 7 (18.0 mg, 5.4%).

[0110] MS (ESI) M / Z: 389.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.67 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H),7.29 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.84 (d, J= 56.1 Hz, 2H), 5.29(s, 1H), 4.66 – 4.34 (m, 2H), 3.81 (s, 3H), 3.28 (s, 1H), 2.11 (s, 3H), 2.06(s, 3H). Example 8 5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 8, with the corresponding structural formula 8.

[0111] The preparation route is as follows:

[0112] S1: Dissolve intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and 3-butynediol p-toluenesulfonate (155.4 mg, 1.3 mmol) in N,N-dimethylformamide (20 mL), and heat to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 8 (58.0 mg, yield 23.3%) as a white solid.

[0113] MS (ESI) M / Z: 403.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.76 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.74 (s, 2H), 5.37 (s, 1H), 4.16 – 3.98 (m, 2H), 3.84 (s, 3H), 2.77 (t, J = 2.6 Hz, 1H), 2.41 – 2.30 (m,2H), 2.19 (s, 3H), 2.13 (s, 3H). Example 9 5-(allyloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 9, with the corresponding structural formula 9.

[0114] The preparation route is as follows:

[0115] S1: Dissolve intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and allyl bromide (155.4 mg, 1.3 mmol) in N,N-dimethylformamide (20 mL) and heat to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 9 (75.0 mg, yield 19.2%), a yellow solid.

[0116] MS (ESI) M / Z: 391.4 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.84 (s, 1H), 7.66 (s, 1H), 7.46 (s, 1H),7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 33.3 Hz, 2H), 6.00– 5.79 (m, 1H), 5.52 (s, 1H), 5.21 – 5.02 (m, 2H), 4.75 – 4.57 (m, 2H), 3.89(s, 3H), 2.26 (s, 3H), 2.23 (s, 3H). Example 10 5-(but-3-en-2-oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 10, with the corresponding structural formula 10.

[0117] The preparation route is as follows:

[0118] S1: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), triphenylphosphine (270.0 mg, 0.9 mmol), diisopropyl azodicarbonate (208.0 mg, 1.0 mmol), and 3-buten-2-ol (0.7 mL, 1.0 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 6 hours. The mixture was quenched with water, extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 10 (25.0 mg, 7.2%) as a white solid.

[0119] MS (ESI) M / Z: 405.0 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.69 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.77 (s, 2H), 5.97 – 5.42 (m,1H), 5.39 (s, 1H), 5.29 – 5.03 (m, 1H), 4.72 – 4.37 (m, 1H), 3.81 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.27 – 0.77 (m, 3H). Example 11 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-1-en-3-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 11, with the corresponding structural formula 11.

[0120] The preparation route is as follows:

[0121] S1: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), triphenylphosphine (270.0 mg, 0.9 mmol), diisopropyl azodicarbonate (208.0 mg, 1.0 mmol), and 1-penten-3-ol (0.8 mL, 1.0 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 6 hours. The mixture was quenched with water, extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 11 (27.0 mg, 7.5%) as a white solid.

[0122] MS (ESI) M / Z: 419.3 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 7.69 (s, 1H), 7.67 – 7.62 (m, 1H), 7.36 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 34.4 Hz,2H), 5.91 – 5.74 (m, 1H), 5.41 (s, 1H), 5.34 – 5.07 (m, 2H), 4.68 – 4.21 (m,1H), 3.80 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.60 – 1.21 (m, 2H), 0.92 –0.28 (m, 3H). Example 12 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(1-vinylcyclopropoxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 12, with the corresponding structural formula 12.

[0123] The preparation route is as follows:

[0124] S1: Two drops of 12M hydrochloric acid were added to a methanol (60 mL) solution of compound 12a (1-ethoxy-1-trimethoxycyclopropane, 17.0 mL, 84.6 mmol). The mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure at low temperature to give a colorless oily compound 12b (1-ethoxy-1-cyclopropanol, 6.5 g, yield 75.0%).

[0125] S2: At room temperature, add 100.0 mL of vinyl magnesium chloride (160.0 mmol, 1.6 min THF) to a 250 mL three-necked flask. While maintaining the reaction under gentle reflux, slowly add 5 mL of a THF solution of compound 12b (8.2 g, 80.0 mmol) to the solution with vigorous stirring. After the addition is complete, heat the reaction to 80°C. o C. Reflux and stir for 30 minutes. Pour the mixture into an NH4Cl solution. Extract the mixture with ethyl acetate (75 mL × 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a brown oily compound 12c (1-vinyl-1-cyclopropanol, 5.0 g, yield 75.0%), which can be used without further purification.

[0126] S3: Crude compound 12c (5.0 g, 60.0 mmol) was dissolved in dichloromethane (30 mL) with triethylamine (8.3 mL, 60.0 mmol) and p-toluenesulfonyl chloride (11.4 g, 60.0 mmol), followed by DMAP (0.2 g, 1.6 mmol). The mixture was stirred overnight and then poured into water. The two phases were separated, and the mixture was extracted with dichloromethane (75 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 20:1) to give a colorless solid compound 12d (1-vinylcyclopropyl 4-methylbenzenesulfonic acid, 95.0 g, yield 67.0%).

[0127] S4: At room temperature, add compound intermediate 1 (295.0 mg, 0.8 mmol), compound 12d (300.0 mg, 1.3 mmol), cesium carbonate (440.0 mg, 1.4 mmol), and DMF (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 6 hours. After cooling to room temperature, the mixture was quenched with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate (v / v) = 1 / 2). This yielded a white solid, compound 12 (8.0 mg, yield 2.0%).

[0128] MS (ESI) M / Z: 417.2 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 7.74 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 34.4 Hz, 2H), 6.35– 6.24 (m, 1H), 5.43 (s, 1H), 5.02 – 4.94 (m, 2H), 3.76 (s, 3H), 2.15 (s,3H), 2.14 (s, 3H), 1.02 – 0.93 (m, 2H), 0.92 – 0.82 (m, 2H). Example 13 4-(4-cyano-2-methoxyphenyl)-5-((1,1-difluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 13, with the corresponding structural formula 13.

[0129] The preparation route is as follows:

[0130] S1: At room temperature, add intermediate 1 (200.0 mg, 0.6 mmol), compound 13a (134.0 mg, 0.9 mmol), lithium carbonate (68.0 mg, 0.9 mmol), and DMF (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 6 hours. After cooling to room temperature, the mixture was quenched with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate (v / v) = 1 / 2). This yielded a white solid, compound 13 (10.0 mg, yield 4.0%).

[0131] MS (ESI) M / Z: 427.2 [M+H] + 1 H NMR (300 MHz, DMSO- d6) δ 7.91 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 49.9 Hz, 2H), 6.01– 5.83 (m, 1H), 5.50 – 5.30 (m, 3H), 3.77 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H). Example 14 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-[(2-methacryloyloxy)]-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 14, corresponding to structural formula 14.

[0132] The preparation route is as follows:

[0133] S1: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 14a (3-bromo-2-methyl-1-propene, 0.1 mL, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 14 (22.0 mg, yield 6.4%) as a white solid.

[0134] MS (ESI) M / Z: 405.3 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.81 (d, J= 38.2 Hz, 2H), 5.44(s, 1H), 4.73 (s, 1H), 4.67 (s, 1H), 4.59 – 4.39 (m, 2H), 3.78 (s, 3H), 2.15(s, 3H), 2.14 (s, 3H), 1.53 (s, 3H). Example 15 4-(4-cyano-2-methoxyphenyl)-5-((2-fluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 15, with the corresponding structural formula 15.

[0135] The preparation route is as follows:

[0136] S1: In a 50 mL round-bottom flask, compound 15a (2-fluoro-2-propen-1-ol, 365.1 mg, 4.8 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and stirred. At 0... o NaH (230.0 mg, 5.7 mmol) was slowly added at C. After 30 minutes, p-toluenesulfonyl chloride (1.0 g, 5.3 mmol) was slowly added, and the mixture was stirred overnight. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to give a colorless, transparent liquid compound 15b (2-fluoroallyl 4-methylbenzenesulfonic acid, 426.0 mg, yield 38.6%).

[0137] S2: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 15b (0.1 mL, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 15 (17.9 mg, yield 5.1%) as a white solid.

[0138] MS (ESI) M / Z: 409.3 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.36 (s, 1H),7.27 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 31.6 Hz, 2H), 5.41(s, 1H), 4.74 – 4.32 (m, 4H), 3.78 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H). Example 16 4-(4-cyano-2-methoxyphenyl)-5-((2-chloroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 16, with the corresponding structural formula 16.

[0139] The preparation route is as follows:

[0140] S1: In a 50 mL round-bottom flask, compound 16a (2-chloro-2-propen-1-ol, 444.1 mg, 4.8 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and stirred. At 0... o NaH (230.0 mg, 5.7 mmol) was slowly added at C. After 30 minutes, p-toluenesulfonyl chloride (1.0 g, 5.3 mmol) was slowly added, and the mixture was stirred overnight. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to give a colorless, transparent liquid compound 16b (2-chloroallyl 4-methylbenzenesulfonic acid, 376.6 mg, yield 31.8%).

[0141] S2: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 16b (0.1 mL, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 16 (30.0 mg, yield 8.2%) as a white solid.

[0142] MS (ESI) M / Z: 425.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.66 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H),7.15 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 31.4 Hz, 2H), 5.32(s, 1H), 5.11 (s, 1H), 4.95 (s, 1H), 4.72 – 4.44 (m, 2H), 3.67 (s, 3H), 2.04(s, 3H), 2.01 (s, 3H). Example 17 (E)-5-(but-2-en-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 17, corresponding to structural formula 17.

[0143] The preparation route is as follows:

[0144] S1: Dissolve intermediate 1 (200.0 mg, 0.6 mmol), cesium carbonate (298.0 mg, 0.9 mmol), and 2-butenyl bromide (116.0 mg, 0.9 mmol) in N,N-dimethylformamide (10 mL) and heat to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give compound 17 (17.0 mg, yield 7.4%), an off-white solid.

[0145] MS (ESI) M / Z: 405.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.71 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H),7.27 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 27.1 Hz, 2H), 5.55– 5.26 (m, 3H), 4.59 – 4.36 (m, 2H), 3.80 (s, 3H), 2.17 (s, 3H), 2.12 (s,3H), 1.59 (s, 3H). Example 18 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((3-methylbut-2-en-1-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 18, with the corresponding structural formula 18.

[0146] The preparation route is as follows:

[0147] S1: Compound intermediate 1 (300.0 mg, 0.8 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 18a (1-bromo-3-methyl-2-butene, 191.4 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 18 (81.0 mg, 22.3%), an off-white solid.

[0148] MS (ESI) M / Z: 419.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.59 (s, 1H), 7.37 (s, 1H), 7.28 (d, J= 7.8Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 58.1 Hz, 2H), 5.27(s, 1H), 5.16 – 5.05 (m, 1H), 4.46 – 4.33 (m, 1H), 4.17 – 4.05 (m, 1H), 3.81(s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 1.68 (s, 3H), 1.65 (s, 3H). Example 19 (Z)-4-(4-cyano-2-methoxyphenyl)-5-((2-fluorobut-2-en-1-yl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 19, with the corresponding structural formula 19.

[0149] The preparation route is as follows:

[0150] S1: Under nitrogen atmosphere, a 6 mL solution of THF containing compound 19b (triethyl 2-fluoro-2-phosphorylacetate, 2.4 g, 10.0 mmol) was added to a 250 mL Schlenk tube fitted with a stir bar and a rubber diaphragm. The solution was cooled to -78°C. o C, add BuLi (2.5M in hexane, 4.0 ml, 10.0 mmol) dropwise over approximately 10 minutes. At -78°C o Stirring at C for 10 minutes, then compound 19a (acetaldehyde, 5 M in hexane, 2.0 ml, 10.0 mmol) was added to the reaction mixture. The mixture was then stirred at -78°C. o Stir at C for 1 hour, then remove from the cooling tank and stir to room temperature (approximately 45 minutes). Pour the mixture into an NH4Cl solution. Extract the mixture with dichloromethane (75 mL × 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a yellow oily compound 19c ((Z)-2-fluoro-2-butenoic acid ethyl ester, 990.0 mg, yield 75.0%).

[0151] S2: Add DIBAL-H (1M in hexane, 26.7 ml, 10.0 mmol) to a 100 mL single-necked flask, and cool the solution to 0 °C. o C, add a solution of compound 19c (1.7 mg, 28.9 mmol) in dichloromethane (35 mL) dropwise over 10 minutes. After the addition is complete, 0o Stir at C for 1 hour. Then stir at 0. o The mixture was quenched at room temperature by adding methanol (5 mL) at C to bring it to ambient temperature. After adding saturated NaCl solution (30 mL) and Et2O (30 mL), the mixture was filtered through diatomaceous earth. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily compound 19d ((Z)-2-fluoro-2-buten-1-ol, 1.1 g, yield 95.0%).

[0152] S3: In a dry Schlenk flask, add sodium hydroxide (132.0 mg, 3.3 mmol), compound 19d (200.0 mg, 2.2 mmol), and Et₂O (5 mL) under a nitrogen atmosphere. Cool to 0°C. o C. Add a solution of p-toluenesulfonyl chloride (464.0 mg, 2.4 mmol) in Et2O (5 mL) dropwise with stirring, and react at room temperature for 3 hours after the addition is complete. Slowly add saturated NH4Cl solution, separate the two phases, and extract the mixture with Et2O (3 × 75 mL). Dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a pale yellow oily compound 19e ((Z)-2-fluorobut-2-en-1-yl-4-methylbenzenesulfonate, 483.0 mg, yield 90%).

[0153] S4: At room temperature, add intermediate 1 (192.0 mg, 0.6 mmol), compound 19e (200.0 mg, 0.8 mmol), lithium carbonate (65.0 mg, 0.9 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 1 hour. The mixture was cooled to room temperature and quenched with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate (v / v) = 1 / 2). This yielded a white solid, compound 19 (12.0 mg, yield 5.0%).

[0154] MS (ESI) M / Z: 423.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.59 (s, 1H), 7.34 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.13 (d,J = 7.8 Hz, 1H), 6.73 (s, 2H), 5.38 (s, 1H), 5.38 – 5.17 (m, 1H), 4.81 – 4.46 (m, 2H), 3.79 (s, 3H), 2.19 (s, 3H), 2.14(s, 3H), 1.57 – 1.43 (m, 3H). Example 20 5-(cinnamoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 20, with the corresponding structural formula 20.

[0155] The preparation route is as follows:

[0156] S1: Compound intermediate 1 (200.0 mg, 0.6 mmol), cesium carbonate (298.0 mg, 0.9 mmol), and compound 20a ((E)-(3-bromoprop-1-en-1-yl)benzene, 169.0 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give compound 20 (20.0 mg, yield 7.5%), an off-white solid.

[0157] MS (ESI) M / Z: 467.3 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.59 (s, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.32 – 7.24 (m, 5H), 7.16 (d, J = 7.9 Hz, 1H), 6.76 (d, J= 48.4Hz, 2H), 6.30 – 6.24 (m, 1H), 6.24 – 6.14 (m, 1H), 5.47 (s, 1H), 4.90 – 4.63(m, 2H), 3.76 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H). Example 21 4-(4-cyano-2-methoxyphenyl)-5-((2,3-dimethylbut-2-en-1-yl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 21, with the corresponding structural formula 21.

[0158] The preparation route is as follows:

[0159] S1: In a 100 mL round-bottom flask, compound 21a (2,3-dimethyl-1,3-butadiene, 500.0 mg, 6.1 mmol) was dissolved in dichloromethane (10 mL), followed by slow dropwise addition of 48% hydrobromic acid solution (1.0 mL, 6.1 mmol) under an ice-water bath, with stirring at room temperature overnight. The solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a colorless liquid compound 21b (1-bromo-2,3-dimethylbut-2-ene, 575.8 mg, yield 58.1%).

[0160] S2: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 21b (211.9 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. o C. Stir for 4 hours. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 21 (37.8 mg, 9.7%) as a white solid.

[0161] MS (ESI) M / Z: 433.1 [M+H] + 1H NMR (300 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 31.1 Hz,2H), 5.35 (s, 1H), 4.55 – 4.45 (m, 2H), 3.74 (s, 3H), 2.15 (s, 3H), 2.12 (s,3H), 1.62 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H). Example 22 Preparation of 5-(allyloxy)-4-(4-cyano-2-(methoxy- d 3) Phenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 22, corresponding to structural formula 22.

[0162] The preparation route is as follows:

[0163] S1: Compound 22a (4-formyl-3-hydroxybenzonitrile, 1.0 g, 6.8 mmol) and potassium carbonate (1.4 g, 10.3 mmol) were dissolved in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature for 30 minutes, and deuterated iodomethane (1.2 g, 8.2 mmol) was slowly added. The mixture was stirred at 60 °C. o Stir overnight at C. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluting solvent: petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a white solid compound 22b (4-formyl-3-(methoxy- d 3) Benzenenitrile, 1.0 g, yield 89.3%.

[0164] S2: Compound 22b (1.0 g, 6.1 mmol) and compound acetylacetamide (616.0 mg, 6.1 mmol) were dissolved in isopropanol (20 mL), and the mixture was heated at 50 mL. oGlacial acetic acid (35.0 μL, 0.6 mmol) and piperidine (52.0 mg, 0.6 mmol) were slowly added at C, and the mixture was stirred overnight. The mixture was filtered, and the filter cake was washed with dichloromethane to give a white solid compound 22c((E)-2-(4-cyano-2-(methoxy-) d 3) (benzyl)-3-oxobutyramide, 1.1 g, yield 69.5%.

[0165] S3: Compound 22c (1.0 g, 4.0 mmol) and compound 4-amino-5-methyl-pyridine-2-ol (510.0 mg, 4.0 mmol) were dissolved in sec-butanol (10 mL), and the mixture was stirred at 100 mL. o Stir overnight at C. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a white solid compound 22d(4-(4-cyano-2-(methoxy- d 3) Phenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 380.0 mg, yield 26.6%.

[0166] S4: Compound 22d (260.0 mg, 0.7 mmol), cesium carbonate (384.0 mg, 1.2 mmol), and 3-bromo-1-propene (134.0 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give compound 22 (17.0 mg, yield 5.9%), an off-white solid.

[0167] MS (ESI) M / Z: 394.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.84 (s, 1H), 7.66 (s, 1H), 7.46 (s, 1H),7.38 (d, J= 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 33.3 Hz, 2H), 6.00– 5.79 (m, 1H), 5.52 (s, 1H), 5.21 – 5.02 (m, 2H), 4.75 – 4.57 (m, 2H), 2.26 (s, 3H), 2.23 (s, 3H). Example 23 5-(allyloxy)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 23, with the corresponding structural formula 23.

[0168] The preparation route is as follows:

[0169] S1: Compound 23a (4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid, 10.0 g, 46.9 mmol) and methanol (200 mL) were added to a 500 mL single-necked flask at room temperature. Thionyl chloride (8.4 g, 61.9 mmol) was then slowly added dropwise under an ice-water bath. The mixture was heated to 70°C. o The reaction was carried out at C for 1.5 hours. The mixture was cooled to room temperature. The reaction was quenched with saturated sodium bicarbonate aqueous solution (300 mL). The mixture was extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid, compound 23b (methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 10.5 g, yield 98.5%).

[0170] S2: At room temperature, add compound 23b (10.5 g, 46.2 mmol), 10% palladium on carbon (5.4 g, 5.0 mmol), sodium hydroxide (3.2 g, 78.8 mmol), and methanol (200 mL) to a 500 mL sealed inner tube. Heat to 30°C under hydrogen pressure at 3 atmospheres. o React at C overnight. Cool to room temperature. Filter through diatomaceous earth and wash the filter cake with ethyl acetate (500 mL). Combine the filtrates, wash with saturated brine (500 mL), and dry to anhydrous sodium sulfate. Filter under reduced pressure and concentrate to give a yellow solid, compound 23c (methyl 4-amino-2,3-dihydrobenzofuran-7-carboxylate, 4.8 g, yield 53.6%).

[0171] S3: At room temperature, add compound 23c (4.2 g, 21.8 mmol), tert-butyl nitrite (3.2 g, 30.7 mmol), cuprous bromide (4.2 g, 29.4 mmol), and acetonitrile (20 mL) to a 50 mL single-necked flask. Purge with nitrogen and heat to 70°C. o React at C for half an hour. Cool to room temperature. Concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a yellow solid compound 23d (methyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate, 3.5 g, yield 62.8%).

[0172] S4: At room temperature, add compound 23d (3.2 g, 12.5 mmol), zinc cyanide (9.5 g, 81.6 mmol), tris(dibenzylacetone)dipalladium (1.1 g, 1.3 mmol), DPPF (1.4 g, 2.5 mmol), and N-methylpyrrolidone (20 mL) to a 50 mL single-necked flask. Purge with nitrogen and heat to 120 °C. o React at C for 2 hours. Cool to room temperature. Quench with aqueous solution (100 mL). Extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (100 mL), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 6 / 1) to give a white solid compound 23e (methyl 4-cyano-2,3-dihydrobenzofuran-7-carboxylate, 2.2 g, yield 86.6%).

[0173] S5: At room temperature, add compound 23e (1.8 g, 8.9 mmol), tetrahydrofuran (20 mL), and a solution of lithium borohydride in tetrahydrofuran (2.0 M, 6.5 mL, 13.3 mmol) to a 50 mL single-necked flask. Purge with nitrogen and heat to 60°C. o React at C for 20 minutes. Cool to room temperature. Quench with water (50 mL). Extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a white solid compound 23F (7-(hydroxymethyl)-2,3-dihydrobenzofuran-4-nitrile, 960.0 mg, yield 61.9%).

[0174] S6: Compound 23f (920.0 mg, 6.6 mmol), dichloromethane (10 mL), and Desmartin reagent (3.2 g, 7.0 mmol) were added to a 25 mL single-necked flask at room temperature. Nitrogen was purged, and the reaction was carried out at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6 / 1) to give a yellow solid, compound 23 g (7-formyl-2,3-dihydrobenzofuran-4-onitrile, 800.0 mg, yield 70.2%).

[0175] S7: 23 g (3.0 g, 18.6 mmol) of compound and acetylacetamide (2.8 mg, 27.9 mmol) were dissolved in isopropanol (20 mL), and acetic acid (0.1 g) and piperidine (0.1 g) were added. The mixture was then heated at 50 mL. o The mixture was stirred at C and reacted thoroughly overnight. After cooling to room temperature, it was filtered to give compound 23h (2-((4-cyano-2,3-dihydrobenzofuran-7-yl)methylene)-3-oxobutyramide, 3.5 g, yield 77.1%).

[0176] S8: Compound 23h (1.0 g, 4.1 mmol) and 4-amino-5-methyl-pyridin-2-ol (0.51 g, 4.1 mmol) were dissolved in sec-butanol (10 mL), and the mixture was heated in 100 mL of water. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 23i (4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 0.9 g, yield 63.0%).

[0177] S9: Compound 23i (300 mg, 0.86 mmol), cesium carbonate (557 mg, 1.71 mmol), and bromopropylene (155.37 mg, 1.28 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 23 (61.0 mg, yield 17.7%) as a white solid.

[0178] MS (ESI) M / Z: 403.1 [M+H] + 1H NMR (300 MHz, DMSO- d 6) δ 7.65 (s, 1H), 7.17 (s, 1H), 7.10 (d, J = 8.1Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 42.7 Hz, 2H), 5.91 – 5.70 (m,1H), 5.13 – 4.89 (m, 3H), 4.65 – 4.08 (m, 4H), 3.29 – 2.90 (m, 2H), 2.13 (s,3H), 2.01 (s, 3H). Example 24 5-(allyloxy)-4-(7-cyanobenzo[d][1,3]dioxo-4-yl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 24, with the corresponding structural formula 24.

[0179] The preparation route is as follows:

[0180] S1: Compound 24a (2,3-dihydroxy-1,4-phthalic acid, 2.6 g, 13.1 mmol) and ethanol (50 mL) were added to a 250 mL three-necked flask at room temperature. o After slowly adding thionyl chloride (9.1 g, 76.3 mmol) dropwise at C, 70 o The reaction was carried out overnight at C. The mixture was cooled to room temperature, and the reaction solution was slowly added dropwise to quench the reaction with saturated sodium bicarbonate aqueous solution (52 mL). Extraction was performed with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a grayish-white solid, compound 24b (diethyl 2,3-dihydroxyterephthalate, 3.1 g, yield 93.5%).

[0181] S2: Compound 24b (3.1 g, 12.3 mmol), bromochloromethane (175.0 g, 13.5 mmol), potassium carbonate (3.4 g, 24.6 mmol), and DMSO (50 mL) were added to a 250 mL three-necked flask at room temperature. After purging with nitrogen, 90 mL of the solution was added. oThe reaction was carried out overnight at C. The mixture was cooled to room temperature and quenched with saturated brine (40 mL). Extraction was performed with ethyl acetate (42 mL × 3). The combined organic phases were washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a grayish-white solid compound 24c (benzo[d|[1,3]dioxane-4,7-dicarboxylic acid diethyl ester, 2.9 g, yield 88.4%).

[0182] S3: Compound 24c (2.9 g, 10.9 mmol), tetrahydrofuran (50 mL), and lithium borohydride (2 M in THF, 5.4 mL, 10.9 mmol) were added to a 250 mL three-necked flask at room temperature. After purging with nitrogen, the mixture was heated to 60 °C. o React at C for 2 hours. Cool to 0°C. o C. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (60 mL) for quenching. Extraction was performed with ethyl acetate (45 mL × 3). The organic phases were combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 7 / 3) to give a white solid compound 24d (ethyl 7-hydroxymethylbenzo[d][1,3]dioxane-4-carboxylate, 1.7 g, yield 69.0%).

[0183] S4: Compound 24d (1.7 g, 7.5 mmol), dichloromethane (40 mL), and Desmartin reagent (4.0 g, 9.4 mmol) were added to a 250 mL three-necked flask at room temperature. Nitrogen was purged and the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a yellow solid, compound 24e (ethyl 7-formylbenzo[d][1,3]dioxane-4-carboxylate, 1.6 g, 99.1% yield).

[0184] S5: At room temperature, add compound 24e (1.6 g, 7.6 mmol), hydroxylamine hydrochloride (1.6 g, 22.7 mmol), and DMSO (60 mL) to a 250 mL three-necked flask. Purge with nitrogen and heat to 90°C. o The reaction was carried out at C for 1 hour. After cooling to room temperature, the mixture was quenched with saturated brine (30 mL). The mixture was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined, washed with saturated brine (60 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give a yellow solid compound 24f (ethyl 7-cyanobenzo[d][1,3]dioxane-4-carboxylate, 1.2 g, yield 73.7%).

[0185] S6: At room temperature, add compound 24f (1.2 g, 5.5 mmol), tetrahydrofuran (40 mL), and a 2M lithium borohydride solution in tetrahydrofuran (4.1 mL, 8.2 mmol) to a 250 mL three-necked flask. After purging with nitrogen, add 60 mL of the solution. o React at C for 2 hours. Cool to 0°C. o C. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (32 mL) for quenching. Extraction was performed with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give 24 g of a white solid compound (7-hydroxymethylbenzo[d][1,3]dioxane-4-carboxynitrile, 0.8 g, yield 77.3%).

[0186] S7: 24 g (0.8 g, 4.2 mmol) of the compound, 20 mL of dichloromethane, and Desmartin reagent (2.7 g, 6.4 mmol) were added to a 250 mL three-necked flask at room temperature. After purging with nitrogen, the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a yellow solid, compound 24h (7-formylbenzo[1,3]dioxacyclopentene-4-carboxynitrile, 0.7 g, yield 90.4%).

[0187] S8: Compound 24h (3.2 g, 18.6 mmol) and acetylacetamide (2.8 mg, 27.9 mmol) were dissolved in isopropanol (20 mL), and acetic acid (0.1 g) and piperidine (0.1 g) were added. The mixture was then heated at 50 mL. o The mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 24i (2-((7-cyanobenzo[d][1,3]dioxo-4-yl)methylene)-3-oxobutyramide, 3.4 g, yield 71.1%).

[0188] S9: Compound 24i (1.0 g, 4.1 mmol) and 4-amino-5-methyl-pyridin-2-ol (0.5 g, 4.1 mmol) were dissolved in sec-butanol (10 mL), and the mixture was heated in 100 mL of water. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 24j (4-(7-cyanobenzo[d][1,3]dioxo-4-yl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 0.8 g, yield 53.1%).

[0189] S10: Compound 24j (313.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and bromopropylene (155.4 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 24 (24.0 mg, 7.1%) as a white solid.

[0190] MS (ESI) M / Z: 405.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.76 (s, 1H), 7.57 (s, 1H), 7.05 (d, J = 8.2Hz, 1H), 7.02 – 6.74 (m, 2H), 6.70 (d, J = 8.3 Hz, 1H), 6.22 – 6.07 (m, 2H), 5.93 – 5.77 (m, 1H), 5.23 (s, 1H), 5.13 – 5.02 (m, 2H), 4.68 – 4.53 (m, 2H), 2.15 (s, 3H), 2.10 (s, 3H). Example 25 5-(but-3-en-1-oxy)-4(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 25, with the corresponding structural formula 25.

[0191] The preparation route is as follows:

[0192] S1: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and 4-bromobutene (173.0 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. oC. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 25 (30.0 mg, 8.7%) as a white solid.

[0193] MS (ESI) M / Z: 405.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.59 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 7.7Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 57.4 Hz, 2H), 5.78– 5.62 (m, 1H), 5.28 (s, 1H), 5.00 – 4.96 (m, 1H), 4.96 – 4.91 (m, 1H), 3.93– 3.83 (m, 1H), 3.81 (s, 3H), 3.61 – 3.48 (m, 1H), 2.33 – 2.18 (m, 2H), 2.11 (s, 3H), 2.02 (s, 3H). Example 26 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-4-en-2-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 26, with the corresponding structural formula 26.

[0194] The preparation route is as follows:

[0195]

[0196] S1: In a 50 mL round-bottom flask, compound 26a (4-penten-2-ol, 300.0 mg, 3.5 mmol), pyridine (827.0 mg, 10.5 mmol), and DMAP (42.6 mg, 0.4 mmol) were dissolved in dichloromethane (10 mL). Then, a dichloromethane solution of p-toluenesulfonyl chloride (797.0 mg, 4.2 mmol dissolved in 5 mL dichloromethane) was slowly added dropwise under an ice-water bath, and the mixture was stirred overnight at room temperature. The solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a colorless liquid compound 26b (penten-4-yl 4-methylbenzenesulfonate, 350.0 mg, yield 41.8%).

[0197] S2: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 26b (amyl 4-methyl-4-en-2-ylbenzenesulfonate, 309.0 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. o C. Stir for 4 hours. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 26 (18.0 mg, 5.0%) as a white solid.

[0198] MS (ESI) M / Z: 419.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.68 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H),7.29 (d, J = 7.9 Hz, 1H), 7.17 – 7.11 (m, 1H), 6.73 (s, 2H), 5.92 – 5.68 (m,1H), 5.09 – 4.91 (m, 2H), 4.80 – 4.68 (m, 1H), 3.82 (s, 3H), 2.38 – 2.20 (m,1H), 2.20 – 2.15 (m, 3H), 2.12 (s, 3H), 2.00 – 1.91 (m, 1H), 1.19 – 0.64 (m,3H). Example 27 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-[(3-methylpent-4-en-2-yl)oxy]-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 27, with the corresponding structural formula 27.

[0199] The preparation route is as follows:

[0200]

[0201] S1: In a 50 mL round-bottom flask, compound 27a (3-methyl-4-en-2-pentanol, 300.0 mg, 3.0 mmol), pyridine (710.0 mg, 9.0 mmol), and DMAP (36.6 mg, 0.3 mmol) were dissolved in dichloromethane (10 mL). Then, a dichloromethane solution of p-toluenesulfonyl chloride (685.0 mg, 3.6 mmol dissolved in 5 mL dichloromethane) was slowly added dropwise under an ice-water bath, and the mixture was stirred overnight at room temperature. The solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a colorless liquid compound 27b (3-methylpent-4-en-2-yl-4-methylbenzenesulfonate, 320.0 mg, 42.0%).

[0202] S2: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 27b (330.0 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 27 (12.0 mg, 3.2%), an off-white solid.

[0203] MS (ESI) M / Z: 433.1 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 7.83 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.08 (d,J = 7.8 Hz, 1H), 6.87 (d, J = 60.0 Hz, 2H), 5.62– 5.50 (m, 1H), 5.37 (s, 1H), 4.96 – 4.79 (m, 4H), 3.79 (s, 3H), 2.15 (s,3H), 2.10 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.48 (d, J = 6.8 Hz, 3H). Example 28 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((2-methylbut-3-en-1-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 28, with the corresponding structural formula 28.

[0204] The preparation route is as follows:

[0205]

[0206] S1: Compound 28a (2-methyl-3-buten-1-ol, 100.0 mg, 1.2 mmol) was dissolved in triethylamine (352.0 mg, 3.5 mmol), diluted with dichloromethane (6 mL), and then dissolved in triethylamine. o p-Toluenesulfonic anhydride (568.0 mg, 1.7 mmol) was slowly added at C, and the mixture was stirred overnight. The reaction solution was diluted with water (30 mL), extracted with dichloromethane (20 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a colorless, transparent liquid compound 28b (2-methylbut-3-en-1-yl-4-methylbenzenesulfonate, 147.0 mg, yield 52.7%).

[0207] S2: Compound intermediate 1 (143.0 mg, 0.4 mmol), cesium carbonate (213.0 mg, 0.6 mmol), and compound 28b (147.0 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 60 °C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product. Purify by reversed-phase preparative chromatography (eluent: 10-60% methanol-water) to give a white solid compound 28C (4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((2-methylbut-3-en-1-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide, 14.0 mg, yield 8.2%).

[0208] S3: Compound 28c (14.0 mg, 0.03 mmol) was resolved chirally under the following conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C). o C; Injection volume: 5 uL). The enantiomer monomer compound 28 was obtained: a white solid (6.3 mg, yield 45.0%).

[0209] MS (ESI) M / Z: 419.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.71 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 29.9 Hz, 2H), 5.76– 5.56 (m, 1H), 5.40 (s, 1H), 5.01 – 4.85 (m, 2H), 4.07 – 3.84 (m, 2H), 3.80(s, 3H), 2.44 – 2.32 (m, 1H), 2.16 (s, 3H), 2.13 (s, 3H), 0.89 – 0.77 (m, 3H). Example 29 4-(4-cyano-2-methoxyphenyl)-5-((2-fluorobut-3-en-1-yl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 29, with the corresponding structural formula 29.

[0210] The preparation route is as follows:

[0211]

[0212] S1: Rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (250.0 mg, 0.6 mmol) was placed in a three-necked flask, purged three times with nitrogen, and triethylamine trifluoroate (5.9 g, 36.9 mmol) and 5 mL of anhydrous diethyl ether were added and stirred. Compound 29a (2-vinyl ethylene oxide, 863.0 mg, 12.3 mmol) and trifluorotoluene (594.0 mg, 4.1 mmol) were separately mixed with 5 mL of anhydrous diethyl ether and then added to the three-necked flask in one go. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (8 mL) was added for extraction, and the resulting organic phase 20 was obtained. o After vacuum distillation to a small amount of solvent remaining, compound 29b (2-fluoro-3-buten-1-ol) was obtained and used directly in the next reaction.

[0213] S2: Dissolve compound 29b from the previous step in triethylamine (3.7 g, 36.9 mmol), dilute with dichloromethane (20 mL), -20 o p-Toluenesulfonic anhydride (4.8 g, 14.8 mmol) was slowly added at C, and the mixture was stirred overnight. The reaction solution was diluted with water (30 mL), extracted with dichloromethane (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a colorless, transparent liquid compound 29c (2-fluoro-3-buten-1-yl-4-methylbenzenesulfonate, 1.3 g, combined yield 43.6%).

[0214] S3: Intermediate 1 (244.0 mg, 0.70 mmol), cesium carbonate (453.0 mg, 1.4 mmol), and compound 29c (170.0 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to 60°C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give compound 29 (15.0 mg, yield 5.1%), an off-white solid.

[0215] MS (ESI) M / Z: 423.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.76 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H),7.31 – 7.25 (m, 1H), 7.18 – 7.07 (m, 1H), 6.77 (s, 2H), 6.03 – 5.62 (m, 1H),5.41 (s, 1H), 5.36 – 4.87 (m, 3H), 4.29 – 4.04 (m, 2H), 3.81 (s, 3H), 2.23 –2.15 (m, 3H), 2.14 (s, 3H). Example 30 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((1,1,2,2-tetrafluorobuten-3-en-1-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 30, with the corresponding structural formula 30.

[0216] The preparation route is as follows:

[0217] S1: Intermediate 1 (200.0 mg, 0.6 mmol), cesium carbonate (298.0 mg, 0.9 mmol), and compound 30a (4-bromo-3,3,4,4-tetrafluorobutene, 177.0 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 60°C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give a white solid compound 30 (18.0 mg, yield 6.6%).

[0218] MS (ESI) M / Z: 477.4 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.96 – 7.79 (m, 1H), 7.78 – 7.66 (m, 1H), 7.39 – 7.35 (m, 1H), 7.31 – 7.25 (m, 1H), 7.19 – 7.08 (m, 1H), 6.90 (d, J =57.0 Hz, 2H), 6.23 – 5.54 (m, 2H), 5.28 (s, 1H), 4.69 – 4.30 (m, 1H), 3.80 (s, 3H), 2.17 – 2.00 (m, 6H). Example 31 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((3-methylbut-3-en-1-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 31, with the corresponding structural formula 31.

[0219] The preparation route is as follows:

[0220]

[0221] S1: Compound 31a (3-methyl-3-buten-1-ol, 200.0 mg, 2.3 mmol) was dissolved in triethylamine (705.0 mg, 7.0 mmol), diluted with dichloromethane (10 mL), and then dissolved at -20°C. op-Toluenesulfonic anhydride (1.1 g, 3.5 mmol) was slowly added at C, and the mixture was stirred overnight. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a colorless, transparent liquid compound 31b (3-methylbut-3-en-1-yl-4-methylbenzenesulfonate, 210.0 mg, yield 37.6%).

[0222] S2: Compound intermediate 1 (205.0 mg, 0.6 mmol), cesium carbonate (305.0 mg, 0.9 mmol), and compound 31b (210.0 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol-water) to give a white solid compound 31c (4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((3-methylbut-3-en-1-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide, 16.0 mg, yield 6.7%).

[0223] S3: Compound 31c (16.0 mg, 0.04 mmol) was resolved chirally under the following conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C). o C; Injection volume: 5 uL). The enantiomer monomer compound 31 was obtained: white solid (6.1 mg, yield 38.1%).

[0224] MS (ESI) M / Z: 404.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.74 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.28 (d, J= 7.8 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.76 (s, 2H), 5.36 (s, 1H), 4.69 – 4.59 (m, 1H), 4.57 – 4.50 (m, 1H), 4.12 (t, J = 6.9 Hz, 2H), 3.81 (s,3H), 2.26 – 2.07 (m, 8H), 1.61 (s, 3H). Example 32 (E)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-3-en-1-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 32, with the corresponding structural formula 32.

[0225] The preparation route is as follows:

[0226]

[0227] S1: In a 50 mL round-bottom flask, compound 32a ((E)-pent-3-en-1-ol, 300.0 mg, 3.5 mmol), pyridine (827.0 mg, 10.5 mmol), and DMAP (42.6 mg, 0.4 mmol) were dissolved in dichloromethane (10 mL). Then, a dichloromethane solution of p-toluenesulfonyl chloride (797.0 mg, 4.2 mmol dissolved in 5 mL dichloromethane) was slowly added dropwise under an ice-water bath, and the mixture was stirred overnight at room temperature. The solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a colorless liquid compound 32b ((E)-pent-3-en-1-yl 4-methylbenzenesulfonate, 320.0 mg, yield 38.2%).

[0228] S2: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and compound 32b (309.0 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. oC. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 32 (20.0 mg, 5.6%) as a white solid.

[0229] MS (ESI) M / Z: 418.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.72 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H),7.29 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 29.1 Hz, 2H), 5.39(s, 1H), 5.38 – 5.28 (m, 1H), 5.23 – 5.11 (m, 1H), 4.09 – 3.88 (m, 2H), 3.81(s, 3H), 2.17 (s, 3H), 2.16 – 2.13 (m, 2H), 2.13 (s, 3H), 1.54 (d, J = 6.3 Hz, 3H). Example 33 4-(4-cyano-2-methoxyphenyl)-5-((4-methylpent-3-en-1-yl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 33, with the corresponding structural formula 33.

[0230] The preparation route is as follows:

[0231] S1: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and 5-bromo-2-methyl-2-pentene (209.0 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. oC. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 33 (19.0 mg, 5.1%) as a white solid.

[0232] MS (ESI) M / Z: 432.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.72 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 30.4 Hz, 2H), 5.38(s, 1H), 4.94 – 4.78 (m, 1H), 4.06 – 3.88 (m, 2H), 3.81 (s, 3H), 2.17 (s,3H), 2.13 (s, 3H), 2.12 – 2.02 (m, 2H), 1.59 (s, 3H), 1.51 (s, 3H). Example 34 4-(4-cyano-2-methoxyphenyl)-5-((4,4-difluorobut-3-en-1-yl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 34, with the corresponding structural formula 34.

[0233] The preparation route is as follows:

[0234] S1: In a 100 mL round-bottom flask, intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and 4-bromo-1,1-difluorobutene (220.0 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 50 °C. oC. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 34 (28.0 mg, 7.4%) as a white solid.

[0235] MS (ESI) M / Z: 441.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.72 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 38.2 Hz, 2H), 5.39(s, 1H), 4.33 – 4.14 (m, 1H), 4.19 – 4.00 (m, 2H), 3.80 (s, 3H), 2.26 – 2.05(m, 8H). Example 35 Preparation of 5-((but-3-en-1-yl-1,2-) d 2) (oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 35, corresponding to structural formula 35.

[0236] The preparation route is as follows:

[0237] S1: At room temperature, add stannous chloride (15.3 g, 80.7 mmol), potassium iodide (18.5 g, 111.0 mmol), compound 35a (3-bromopropene, 9.0 mL, 43.3 mmol), and 150 mL of water to a 250 mL single-necked flask. Heat the mixture to 35°C. o C, add a 35 mL solution of glyoxal (3.3 mL, 40% w / w solution, 28.9 mmol) in water over 10 minutes. oStirred and heated at C for 1 hour. Concentrated hydrochloric acid (30 mL) was added and the mixture was extracted with ethyl acetate (75 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) gave a pale yellow oily compound 35b (octyl-1,7-diene-4,5-diol, 3.9 g, yield 95.0%).

[0238] S2: Compound 35b (1.5 g, 10.2 mmol) was dissolved in dichloromethane (5 mL), water (5 mL) was added, and the mixture was stirred and cooled to 0 °C. o C. Add sodium periodate (2.2 g, 10.2 mmol) in proportion, stir for 2 hours, and then add water (5 mL). Take the supernatant, and separate the aqueous phase with dichloromethane (1 mL × 2). Wash the combined organic phases with brine (5 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a yellow solution of compound 35c (but-3-enal, 1.1 g, yield 74.4%).

[0239] S3: Dissolve lithium aluminum deuteride (300.0 mg, 7.1 mmol) in anhydrous Et2O (20 mL) and cool to 0°C under nitrogen. o C. Add dropwise a solution of anhydrous Et₂O (10 mL) and dichloromethane (7 mL) of compound 35c (approximately 20.0 mmol), stir for 30 minutes, heat to room temperature and stir for 1 hour, then heat the mixture under reflux for 10 minutes, and finally cool to 0°C. o C. Add water (0.3 mL), 15% aq NaOH (0.9 mL), and water (0.3 mL) dropwise. After stirring for 10 minutes, filter the mixture through diatomaceous earth, dry the filtrate with anhydrous sodium sulfate, filter under vacuum, and concentrate under reduced pressure to obtain a pale yellow oily compound 35d (but-3-ene-1,2- d 2-1 alcohol, 938.0 mg, yield 48.0%.

[0240] S4: Dissolve p-toluenesulfonyl chloride (470.0 mg, 2.5 mmol) in anhydrous dichloromethane (5 mL), add pyridine (195.0 mg, 2.5 mmol) under ice bath conditions, and then add dropwise a solution of compound 35d (120.0 mg, 1.6 mmol) in anhydrous dichloromethane (3 mL). React overnight. Add water and extract the mixture with dichloromethane (25 mL × 3). Dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a brown oil. Purify by silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 40 / 1) to give a pale yellow oil, compound 35e (but-3-en-1-yl-1,2- d2,4-Methylbenzenesulfonate, 60.0 mg, yield 16.0% S5: At room temperature, add compound intermediate 1 (160.0 mg, 0.5 mmol), compound 35e (156.0 mg, 0.7 mmol), cesium carbonate (158.0 mg, 0.7 mmol), and DMF (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 2 hours. The mixture was cooled to room temperature and quenched with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate (v / v) = 1 / 2). The result was a white solid, 35 (16.0 mg, yield 9.0%).

[0241] MS (ESI) M / Z: 407.1 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 33.7 Hz, 2H), 5.69– 5.54 (m, 1H), 5.37 (s, 1H), 5.07 – 4.81 (m, 2H), 4.13 – 3.89 (m, 1H), 3.81(s, 3H), 2.24 – 2.18 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H). Example 36 (S)-5-((but-3-en-1-yl-1,1-d2)oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 36, with the corresponding structural formula 36.

[0242] The preparation route is as follows:

[0243] S1: In a 50 mL double-necked flask, lithium deuterated aluminum (107.3 mg, 2.6 mmol) was suspended in dry diethyl ether under ice bath conditions. Nitrogen was applied, and compound 36a (vinylacetic acid, 200.0 mg, 2.3 mmol) was added dropwise. The mixture was stirred for 20 minutes, refluxed for 2 hours, cooled to room temperature, and stirred for another 40 hours. Water (0.3 mL), 15% aq NaOH (0.9 mL), and water (0.3 mL) were added dropwise. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily compound 36b (but-3-ene-1,1- d 2-1 alcohol, 73.2 mg, yield 42.5%.

[0244] S2: Toluenesulfonyl chloride (470.0 mg, 2.5 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (195.0 mg, 2.5 mmol) was added under ice bath conditions. Then, a solution of compound 36b (120.0 mg, 1.6 mmol) in anhydrous dichloromethane (3 mL) was added dropwise, and the reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification was performed by silica gel chromatography (petroleum ether / ethyl acetate = 40:1) to give a pale yellow oil, compound 36c (but-3-en-1-yl-1,1-yl-ethyl ... d 2,4-Methylbenzenesulfonate, 60.0 mg, yield 16.0%.

[0245] S3: At room temperature, add intermediate 1 (160.0 mg, 0.5 mmol), compound 36c (78.0 mg, 0.35 mmol), cesium carbonate (79.0 mg, 0.35 mmol), and DMF (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 2 hours. The mixture was cooled to room temperature and quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 2). The result was a white solid compound 36d(5-((but-3-en-1-yl-1,1-d2)oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 13.0 mg, yield 24.0%).

[0246] S4: Compound 36d (13.0 mg, 0.03 mmol) was resolved chirally under the following conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C). o C; Injection volume: 5 uL). The enantiomer monomer compound 36 was obtained: white solid (5.8 mg, yield 44.6%).

[0247] MS (ESI) M / Z: 407.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.71 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H),7.28 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 22.1 Hz, 2H), 5.77– 5.53 (m, 1H), 5.38 (s, 1H), 5.10 – 4.80 (m, 2H), 3.81 (s, 3H), 2.30 – 2.03(m, 8H). Example 37 Preparation of (S)-5-(but-3-en-1-yloxy)-4-(4-cyano-2-(methoxy- d 3) Phenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, designated as compound 37, corresponding to structural formula 37.

[0248] The preparation route is as follows:

[0249] S1: Compound 37a (4-formyl-3-hydroxybenzonitrile, 1.0 g, 6.8 mmol) and potassium carbonate (1.4 g, 10.3 mmol) were dissolved in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature for 30 minutes, and deuterated iodomethane (1.2 g, 8.2 mmol) was slowly added. The mixture was stirred at 60 °C. oStir overnight at C. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluting solvent: petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a white solid compound 37b (4-formyl-3-(methoxy- d 3) Benzenenitrile, 1.0 g, yield 89.3%.

[0250] S2: Compound 37b (1.0 g, 6.1 mmol) and compound acetylacetamide (616.0 mg, 6.1 mmol) were dissolved in isopropanol (20 mL), and the mixture was heated at 50 mL. o Glacial acetic acid (35.0 μL, 0.6 mmol) and piperidine (52.0 mg, 0.6 mmol) were slowly added at C, and the mixture was stirred overnight. The mixture was filtered, and the filter cake was washed with dichloromethane to give a white solid compound 37c((E)-2-(4-cyano-2-(methoxy-) d 3) (benzylidene)-3-oxobutyramide, 1.1 g, yield 69.5%.

[0251] S3: Compound 37c (1.0 g, 4.0 mmol) and 4-amino-5-methyl-pyridine-2-ol (510.0 mg, 4.0 mmol) were dissolved in sec-butanol (10 mL), and the mixture was stirred at 100 mL. o Stirred overnight at C. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a white solid compound 37d(4-(4-cyano-2-(methoxy- d 3) Phenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 380.0 mg, yield 26.6%.

[0252] S4: Compound 37d (120.0 mg, 0.3 mmol), cesium carbonate (177.0 mg, 0.5 mmol), and bromobutene (69.0 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the solution was heated to 60 °C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (30 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol-water) to give the off-white solid compound 37e(5-(but-3-en-1-yloxy)-4-(4-cyano-2-(methoxy-) d 3) Phenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 13.0 mg, yield 9.4%.

[0253] S5: Compound 37e (13.0 mg, 0.03 mmol) was resolved chirally under the following conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C). o C; Injection volume: 5 uL). The enantiomer monomer compound 37 was obtained: white solid (5.2 mg, yield 40.1%).

[0254] MS (ESI) M / Z: 408.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.59 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 7.7Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 57.4 Hz, 2H), 5.78– 5.62 (m, 1H), 5.28 (s, 1H), 5.00 – 4.96 (m, 1H), 4.96 – 4.91 (m, 1H), 3.93– 3.83 (m, 1H), 3.61 – 3.48 (m, 1H), 2.33 – 2.18 (m, 2H), 2.11 (s, 3H), 2.02(s, 3H). Example 38 5-(but-3-en-1-yloxy)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 38, with the corresponding structural formula 38.

[0255] The preparation route is as follows:

[0256] S1: Compound 38a (4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid, 10.0 g, 46.9 mmol) and methanol (thionyl chloride 8.4 g, 61.9 mmol) were added dropwise to a 500 mL single-necked flask at room temperature. The mixture was heated to 70°C. o The reaction was carried out at C for 1.5 hours. The mixture was cooled to room temperature. The reaction was quenched with saturated sodium bicarbonate aqueous solution (300 mL). The mixture was extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid, compound 38b (methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 10.5 g, yield 98.5%).

[0257] S2: At room temperature, add compound 38b (10.5 g, 46.2 mmol), 10% palladium on carbon (5.4 g, 5.0 mmol), sodium hydroxide (3.2 g, 78.8 mmol), and methanol (200 mL) to a 500 mL sealed inner tube. Heat to 30°C under hydrogen pressure at 3 atmospheres. o React at C overnight. Cool to room temperature. Filter through diatomaceous earth and wash the filter cake with ethyl acetate (500 mL). Combine the filtrates, wash with saturated brine (500 mL), and dry to anhydrous sodium sulfate. Filter under reduced pressure and concentrate to give a yellow solid, compound 38c (methyl 4-amino-2,3-dihydrobenzofuran-7-carboxylate, 4.8 g, yield 53.6%).

[0258] S3: At room temperature, add compound 38c (4.2 g, 21.8 mmol), tert-butyl nitrite (3.2 g, 30.7 mmol), cuprous bromide (4.2 g, 29.4 mmol), and acetonitrile (20 mL) to a 50 mL single-necked flask. Purge with nitrogen and heat to 70°C. o React at C for half an hour. Cool to room temperature. Concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give a yellow solid compound 38d (methyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate, 3.5 g, yield 62.8%).

[0259] S4: Compound 38d (3.2 g, 12.5 mmol), zinc cyanide (9.5 g, 81.6 mmol), tris(dibenzylacetone)palladium (1.1 g, 1.3 mmol), DPPF (1.4 g, 2.5 mmol) and [other compounds] were added to a 50 mL single-necked flask at room temperature. N 20 mL of methylpyrrolidone was purged with nitrogen and heated to 120°C. o React at C for 2 hours. Cool to room temperature. Quench with aqueous solution (100 mL). Extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (100 mL), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a white solid compound 38e (methyl 4-cyano-2,3-dihydrobenzofuran-7-carboxylate, 2.2 g, yield 86.6%).

[0260] S5: At room temperature, add compound 38e (1.8 g, 8.9 mmol), tetrahydrofuran (20 mL), and a solution of lithium borohydride in tetrahydrofuran (6.5 mL, 2.0 M, 13.3 mmol) to a 50 mL single-necked flask. Purge with nitrogen and heat to 60°C. o React at C for 20 minutes. Cool to room temperature. Quench with water (50 mL). Extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate. Filter under vacuum, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to give a white solid compound 38F (7-(hydroxymethyl)-2,3-dihydrobenzofuran-4-nitrile, 960.0 mg, yield 61.9%).

[0261] S6: Compound 38f (920.0 mg, 6.6 mmol), dichloromethane (10 mL), and Desmartin reagent (3.2 g, 7.0 mmol) were added to a 25 mL single-necked flask at room temperature. The atmosphere was purged with nitrogen, and the reaction was carried out at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a yellow solid, compound 38 g (7-formyl-2,3-dihydrobenzofuran-4-onitrile, 800.0 mg, yield 70.2%).

[0262] S7: 38 g (3.0 g, 18.6 mmol) of compound and acetylacetamide (2.8 g, 27.9 mmol) of compound were dissolved in isopropanol (20 mL), and acetic acid (0.1 g) and piperidine (0.1 g) were added. The mixture was then heated at 50 mL. oThe mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 38h (2-((4-cyano-2,3-dihydrobenzofuran-7-yl)methylene)-3-oxobutyramide, 3.5 g, yield 77.1%).

[0263] S8: Compound 38h (1.0 g, 4.1 mmol) and compound 4-amino-5-methyl-pyridine-2-ol (0.5 g, 4.1 mmol) were dissolved in sec-butanol (10 mL), and the mixture was stirred at 100 mL. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 38i (4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 0.9 g, yield 63.0%).

[0264] S9: Compound 38i (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and bromobutene (155.4 mg, 1.3 mmol) were dissolved in... N,N In dimethylformamide (20 mL), heat to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 38 (61.0 mg, yield 17.7%) as a white solid.

[0265] MS (ESI) M / Z: 417.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.56 (s, 1H), 7.12 (d, J = 8.0Hz, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.76 (s, 2H), 5.78 – 5.57 (m, 1H), 5.18 (s,1H), 5.06 – 4.88 (m, 2H), 4.69 – 4.53 (m, 2H), 4.18 – 3.95 (m, 2H), 3.35 –3.30 (m, 2H), 2.32 – 2.21 (m, 2H), 2.19 (s, 3H), 2.12 (s, 3H). Example 39 5-(but-3-en-1-yloxy)-4-(7-cyanobenzo[d][1,3]dioxo-4-yl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 39, with the corresponding structural formula 39.

[0266] The preparation route is as follows:

[0267] S1: Compound 39a (2,3-dihydroxyterephthalic acid, 2.6 g, 13.1 mmol) and ethanol (50 mL) were added to a 250 mL three-necked flask at room temperature. o After slowly adding thionyl chloride (9.1 g, 76.3 mmol) dropwise at C, 70 o The reaction was carried out overnight. After cooling to room temperature, the reaction solution was quenched by slowly adding dropwise to a saturated sodium bicarbonate aqueous solution (52 mL). Extraction was performed with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a grayish-white solid, compound 39b (diethyl 2,3-dihydroxyterephthalate, 3.1 g, yield 93.5%).

[0268] S2: Compound 39b (3.1 g, 12.3 mmol), bromochloromethane (175.0 g, 13.5 mmol), potassium carbonate (3.4 g, 24.6 mmol), and DMSO (50 mL) were added to a 250 mL three-necked flask at room temperature. After purging with nitrogen, 90 mL of the solution was added. o The reaction was carried out overnight at C. The mixture was cooled to room temperature and quenched with saturated brine (40 mL). Extraction was performed with ethyl acetate (42 mL × 3). The combined organic phases were washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a grayish-white solid compound 39c (benzo[d|[1,3]dioxane-4,7-dicarboxylic acid diethyl ester, 2.9 g, yield 88.4%).

[0269] S3: At room temperature, add compound 39c (2.9 g, 10.9 mmol), tetrahydrofuran (50 mL), and a 2M lithium borohydride solution in tetrahydrofuran (5.4 mL, 10.9 mmol) to a 250 mL three-necked flask. After purging with nitrogen, add 60 mL of the solution. o React at C for 2 hours. Cool to 0°C. o C. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (60 mL) for quenching. Extraction was performed with ethyl acetate (45 mL × 3). The organic phases were combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 7:3) to give a white solid compound 39d (ethyl 7-hydroxymethylbenzo[d][1,3]dioxane-4-carboxylate, 1.7 g, yield 69.0%).

[0270] S4: Compound 39d (1.7 g, 7.5 mmol), dichloromethane (40 mL), and Desmartin reagent (4.0 g, 9.4 mmol) were added to a 250 mL three-necked flask at room temperature. Nitrogen was purged and the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to give a yellow solid, compound 39e (ethyl 7-formylbenzo[d][1,3]dioxane-4-carboxylate, 1.7 g, 99.1% yield).

[0271] S5: At room temperature, add compound 39e (1.7 g, 7.6 mmol), hydroxylamine hydrochloride (1.6 g, 22.7 mmol), and DMSO (60 mL) to a 250 mL three-necked flask. Purge with nitrogen and heat to 90°C. o The reaction was carried out at C for 1 hour. After cooling to room temperature, the mixture was quenched with saturated brine (30 mL). The mixture was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined, washed with saturated brine (60 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give a yellow solid compound 39f (ethyl 7-cyanobenzo[d][1,3]dioxane-4-carboxylate, 1.2 g, yield 73.7%).

[0272] S6: At room temperature, add compound 39f (1.2 g, 5.5 mmol), tetrahydrofuran (40 mL), and a 2M lithium borohydride solution in tetrahydrofuran (4.1 mL, 8.2 mmol) to a 250 mL three-necked flask. After purging with nitrogen, add 60 mL of the solution. o React at C for 2 hours. Cool to 0°C. oC. The reaction solution was slowly added to a saturated ammonium chloride aqueous solution (32 mL) for quenching. Extraction was performed with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give 39 g of a white solid compound (7-hydroxymethylbenzo[d][1,3]dioxane-4-carboxynitrile, 0.8 g, yield 77.3%).

[0273] S7: 39 g (0.8 g, 4.2 mmol) of the compound, 20 mL of dichloromethane, and Desmartin reagent (2.7 g, 6.4 mmol) were added to a 250 mL three-necked flask at room temperature. After purging with nitrogen, the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to give a yellow solid, compound 39h (7-formylbenzo[1,3]dioxane-4-carboxynitrile, 0.7 g, yield 90.4%).

[0274] S8: Compound 39h (3.2 g, 18.6 mmol) and compound acetylacetamide (2.8 mg, 27.9 mmol) were dissolved in isopropanol (20 mL), and acetic acid (0.1 g) and piperidine (0.1 g) were added. The mixture was then heated at 50 mL. o The mixture was stirred at C and reacted overnight. After cooling to room temperature, it was filtered to give compound 39i (2-((7-cyanobenzo[d][1,3]dioxo-4-yl)methylene)-3-oxobutyramide, 3.4 g, yield 71.1%).

[0275] S9: Compound 39i (1.0 g, 4.1 mmol) and compound 4-amino-5-methyl-pyridine-2-ol (0.5 g, 4.1 mmol) were dissolved in sec-butanol (10 mL), and the mixture was stirred at 100 mL. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 39j (4-(7-cyanobenzo[d][1,3]dioxo-4-yl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxamide, 0.8 g, yield 53.1%).

[0276] S10: Compound 39j (313.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and bromobutene (172.8 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 39 (19.8 mg, 5.5%) as a white solid.

[0277] MS (ESI) M / Z: 419.1 [M+H] + 1 H NMR (400 MHz, DMSO- d 6) δ 7.60 (s, 1H), 7.25 (s, 1H), 7.04 (d, J = 8.4Hz, 1H), 7.02 – 6.75 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.18 (s, 1H), 6.09 (s,1H), 5.80 – 5.65 (m, 1H), 5.11 (s, 1H), 5.01 – 4.91 (m, 2H), 3.95 – 3.81 (m,1H), 3.62 – 3.51 (m, 1H), 2.36 – 2.20 (m, 2H), 2.11 (s, 3H), 2.00 (s, 3H). Example 40 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-4-en-1-yloxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 40, with the corresponding structural formula 40.

[0278] The preparation route is as follows:

[0279] S1: Compound intermediate 1 (300.0 mg, 0.9 mmol), cesium carbonate (557.0 mg, 1.7 mmol), and bromopentene (191.4 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60°C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give 40 (85.0 mg, yield 23.7%), a yellow solid.

[0280] MS (ESI) M / Z: 419.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 33.4 Hz, 2H), 5.83– 5.61 (m, 1H), 5.39 (s, 1H), 4.94 – 4.79 (m, 2H), 4.10 – 3.87 (m, 2H), 3.80(s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 1.89 – 1.77 (m, 2H), 1.60 – 1.46 (m, 2H). Example 41 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methoxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 41, with the corresponding structural formula 41.

[0281] The preparation route is as follows:

[0282] S1: Compound 41a (perillyl alcohol, 500.0 mg, 3.3 mmol) and triphenylphosphine (1.2 g, 4.6 mmol) were dissolved in dichloromethane. NBS (841.8 mg, 4.7 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a transparent oily compound 41b (1-(bromomethyl)-4-(prop-1-en-2-yl)cyclohexyl-1-ene, 300 mg, yield 51.5%).

[0283] S2: Compound intermediate 1 (215.0 mg, 0.6 mmol), cesium carbonate (319.9 mg, 1.0 mmol), and compound 41b (198.4 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 41 (63.0 mg, yield 21.7%), an off-white solid.

[0284] MS (ESI) M / Z: 485.3 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.94 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.1Hz, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.13 (d, J = 59.3 Hz, 2H), 5.72 – 5.46 (m,2H), 5.09 – 4.90 (m, 2H), 4.79 – 4.63 (m, 1H), 4.37 – 4.22 (m, 1H), 4.13 (s,3H), 2.83 (s, 3H), 2.44 (s, 3H), 2.25 – 1.84 (m, 9H), 1.72 – 1.49 (m, 1H). Example 42 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((3-methylenecyclobutyl)methoxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 42, with the corresponding structural formula 42.

[0285] The preparation route is as follows:

[0286] S1: Compound 42a (3-methylenecyclobutane-methanol, 227.0 mg, 2.3 mmol) was dissolved in triethylamine (705.0 mg, 7.0 mmol), diluted with dichloromethane (10 mL), and then dissolved in -20 mL of triethylamine. o p-Toluenesulfonic anhydride (1.1 g, 3.5 mmol) was slowly added at C, and the mixture was stirred overnight. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a colorless, transparent liquid compound 42b (methyl 4-methylbenzenesulfonic acid (3-methylenecyclobutyl) methyl ester, 219.0 mg, yield 37.2%).

[0287] S2: Compound intermediate 1 (205.0 mg, 0.6 mmol), cesium carbonate (305.0 mg, 0.9 mmol), and compound 42b (219.0 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 60°C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give a white solid compound 42 (19.0 mg, yield 7.6%).

[0288] MS (ESI) M / Z: 431.0 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H),7.28 (d, J= 7.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 34.2 Hz, 2H), 5.36(s, 1H), 4.71 (s, 2H), 4.12 – 3.92 (m, 2H), 3.80 (s, 3H), 2.69 – 2.55 (m,2H), 2.31 – 2.17 (m, 2H), 2.15 (s, 3H), 2.13 (s, 3H). Example 43 4-(4-cyano-2-methoxyphenyl)-5-((3-fluorobicyclo[1.1.1]pent-1-yl)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 43, with the corresponding structural formula 43.

[0289] The preparation route is as follows:

[0290] S1: Compound 43a ((3-fluorobicyclo[1.1.1]pent-1-yl)methanol, 101.0 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL), and DMAP (212.0 mg, 1.7 mmol) was added. o p-Toluenesulfonic acid chloride (250.0 mg, 1.3 mmol) was slowly added at C, and the mixture was stirred overnight. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a colorless, transparent liquid compound 43b (4-methylbenzenesulfonic acid (3-fluorobicyclo[1.1.1]pent-1-yl) methyl ester, 235.0 mg, yield 93.9%).

[0291] S2: Compound intermediate 1 (205.0 mg, 0.6 mmol), cesium carbonate (305.0 mg, 0.9 mmol), and compound 43b (235.0 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 60°C. oC. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and the residue is subjected to silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give a white solid compound 43 (8.0 mg, yield 3.5%).

[0292] MS (ESI) M / Z: 449.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 55.5 Hz, 2H), 5.36(s, 1H), 4.47 (d, J = 11.7 Hz, 1H), 4.14 (d, J = 11.8 Hz, 1H), 3.78 (s, 3H), 2.12(s, 3H), 2.10 (s, 3H), 1.75 – 1.69 (m, 6H). Example 44 O-(3-carbamoyl-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthid-5-yl)dimethylcarbamosulfate was prepared, denoted as compound 44, with the corresponding structural formula 44.

[0293] The preparation route is as follows:

[0294] S1: In a 25 mL round-bottom flask, intermediate 1 (50.0 mg, 0.1 mmol), potassium carbonate (39.4 mg, 0.3 mmol), and dimethylaminothiocarbamate chloride (22.0 μL, 0.2 mmol) were dissolved in tetrahydrofuran (5 mL). oStirring at C for 6 hours. Quenching with water, extraction with ethyl acetate (10 mL × 2), combining the organic phases, washing with saturated brine (20 mL × 2), and drying over anhydrous sodium sulfate. Filtering, removing the solvent under reduced pressure, and purifying the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 44 (26.0 mg, yield 41.6%) as a white solid.

[0295] MS (ESI) M / Z: 438.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.96 (s, 1H), 7.75 (s, 1H), 7.40 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.73 (s, 2H), 5.36 (s, 1H), 3.79 (s, 3H), 3.34 (s, 3H), 3.04 (s, 3H), 2.26 – 2.19 (m, 6H). Example 45 3-Carbamoyl-4-[(4-cyano-2-methoxyphenyl)methyl]-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-5-carboxamide was prepared, denoted as compound 45, with the corresponding structural formula 45.

[0296] The preparation route is as follows:

[0297] S1: In a 25 mL round-bottom flask, intermediate 1 (50.0 mg, 0.1 mmol), potassium carbonate (39.4 mg, 0.3 mmol), and dimethylcarbamoyl chloride (20.0 μL, 0.2 mmol) were dissolved in tetrahydrofuran (5 mL). o Stirring at C for 6 hours. Quenching with water, extraction with ethyl acetate (10 mL × 2), combining the organic phases, washing with saturated brine (20 mL × 2), and drying over anhydrous sodium sulfate. Filtering, removing the solvent under reduced pressure, and purifying the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give a white solid compound 45 (20.0 mg, yield 33.3%).

[0298] MS (ESI) M / Z: 422.1 [M+H] + 1 H NMR (300 MHz, DMSO-d 6) δ 7.90 (s, 1H), 7.70 (s, 1H), 7.38 (s, 1H),7.31 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.79 (s, 2H), 5.34 (s, 1H), 3.76 (s, 3H), 2.83 (s, 3H), 2.82 (s, 3H), 2.24 – 2.14 (m, 6H). Example 46 (S)-5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 46, with the corresponding structural formula 46.

[0299]

[0300] Preparation method: 5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.25 mmol) (compound 8) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 46 (40.3 mg, yield 40.3%) was obtained.

[0301] MS (ESI) M / Z: 403.2 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.74 (s, 2H), 5.37 (s,1H), 4.16 – 3.98 (m, 2H), 3.84 (s, 3H), 2.77 (t, J = 2.6 Hz, 1H), 2.41 – 2.30(m, 2H), 2.19 (s, 3H), 2.13 (s, 3H). Example 47 (S)-5-(allyloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 47, with the corresponding structural formula 47.

[0302]

[0303] Preparation method: 5-(allyloxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.26 mmol) (compound 9) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 47 (43.3 mg, yield 43.3%) was obtained.

[0304] MS (ESI) M / Z: 391.4 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.66 (s, 1H), 7.46 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 33.3 Hz,2H), 6.00 – 5.79 (m, 1H), 5.52 (s, 1H), 5.21 – 5.02 (m, 2H), 4.75 – 4.57 (m,2H), 3.89 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H). Example 48 (S)-5-(but-3-en-2-oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 48, with the corresponding structural formula 48.

[0305]

[0306] Preparation method: 5-(but-3-en-2-oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.25 mmol) (compound 10) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 48 (47.1 mg, yield 47.1%) was obtained.

[0307] MS (ESI) M / Z: 405.0 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.77 (s, 2H), 5.97 – 5.42(m, 1H), 5.39 (s, 1H), 5.29 – 5.03 (m, 1H), 4.72 – 4.37 (m, 1H), 3.81 (s,3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.27 – 0.77 (m, 3H). Example 49 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-1-en-3-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 49, with the corresponding structural formula 49.

[0308]

[0309] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-1-en-3-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 11) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) oC; Injection volume: 5 uL). A white solid compound 49 (38.6 mg, yield 38.6%) was obtained.

[0310] MS (ESI) M / Z: 419.3 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.67 – 7.62 (m, 1H), 7.36(s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.76 (d, J =34.4 Hz, 2H), 5.91 – 5.74 (m, 1H), 5.41 (s, 1H), 5.34 – 5.07 (m, 2H), 4.68 –4.21 (m, 1H), 3.80 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.60 – 1.21 (m, 2H), 0.92 – 0.28 (m, 3H). Example 50 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(1-vinylcyclopropoxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 50, with the corresponding structural formula 50.

[0311]

[0312] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(1-vinylcyclopropoxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 12) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). 50 (41.8 mg, yield 41.8%) of white solid compound were obtained.

[0313] MS (ESI) M / Z: 417.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1), 7.27 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 34.4 Hz,2H), 6.35 – 6.24 (m, 1H), 5.43 (s, 1H), 5.02 – 4.94 (m, 2H), 3.76 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 1.02 – 0.93 (m, 2H), 0.92 – 0.82 (m, 2H). Example 51 (S)-4-(4-cyano-2-methoxyphenyl)-5-((1,1-difluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 51, with the corresponding structural formula 51.

[0314]

[0315] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-((1,1-difluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 13) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 51 (43.2 mg, yield 43.2%) was obtained.

[0316] MS (ESI) M / Z: 427.2 [M+H] + 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 49.9 Hz,2H), 6.01 – 5.83 (m, 1H), 5.50 – 5.30 (m, 3H), 3.77 (s, 3H), 2.17 (s, 3H),2.15 (s, 3H). Example 52 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-[(2-methacryloyloxy)]-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 52, with the corresponding structural formula 52.

[0317]

[0318] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-[(2-methacryloyloxy)]-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.25 mmol) (compound 14) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 52 (45.5 mg, yield 45.5%) was obtained.

[0319] MS (ESI) M / Z: 405.3 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 38.2 Hz,2H), 5.44 (s, 1H), 4.73 (s, 1H), 4.67 (s, 1H), 4.59 – 4.39 (m, 2H), 3.78 (s,3H), 2.15 (s, 3H), 2.14 (s, 3H), 1.53 (s, 3H). Example 53 (S)-4-(4-cyano-2-methoxyphenyl)-5-((2-fluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 53, with the corresponding structural formula 53.

[0320]

[0321] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-((2-fluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 15) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 53 (34.4 mg, yield 34.4%) was obtained.

[0322] MS (ESI) M / Z: 409.3 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 31.6 Hz,2H), 5.41 (s, 1H), 4.74 – 4.32 (m, 4H), 3.78 (s, 3H), 2.17 (s, 3H), 2.13 (s,3H). Example 54 (S)-4-(4-cyano-2-methoxyphenyl)-5-((2-chloroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 54, with the corresponding structural formula 54.

[0323]

[0324] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-((2-chloroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 16) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). White solid compound 54 (41.9 mg, yield 41.9%) was obtained.

[0325] MS (ESI) M / Z: 425.1 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 31.4 Hz,2H), 5.32 (s, 1H), 5.11 (s, 1H), 4.95 (s, 1H), 4.72 – 4.44 (m, 2H), 3.67 (s,3H), 2.04 (s, 3H), 2.01 (s, 3H). Example 55 (S)-5-(but-3-en-1-oxy)-4(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 55, with the corresponding structural formula 55.

[0326]

[0327] Preparation method: 5-(but-3-en-1-oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (123 mg, 0.3 mmol) (compound 25) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 55 (51 mg, yield 41.5%) was obtained.

[0328] MS (ESI) M / Z: 405.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.59 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 7.7Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 57.4 Hz, 2H), 5.78– 5.62 (m, 1H), 5.28 (s, 1H), 5.00 – 4.96 (m, 1H), 4.96 – 4.91 (m, 1H), 3.93– 3.83 (m, 1H), 3.81 (s, 3H), 3.61 – 3.48 (m, 1H), 2.33 – 2.18 (m, 2H), 2.11 (s, 3H), 2.02 (s, 3H). Example 56 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-4-en-2-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 56, with the corresponding structural formula 56.

[0329]

[0330] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-4-en-2-oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 26) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 56 (40.8 mg, yield 40.8%) was obtained.

[0331] MS (ESI) M / Z: 419.1 [M+H] + 1H NMR (300 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.17 – 7.11 (m, 1H), 6.73 (s, 2H), 5.92 – 5.68 (m,1H), 5.09 – 4.91 (m, 2H), 4.80 – 4.68 (m, 1H), 3.82 (s, 3H), 2.38 – 2.20 (m,1H), 2.20 – 2.15 (m, 3H), 2.12 (s, 3H), 2.00 – 1.91 (m, 1H), 1.19 – 0.64 (m,3H). Example 57 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-[(3-methylpent-4-en-2-yl)oxy]-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 57, with the corresponding structural formula 57.

[0332]

[0333] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-[(3-methylpent-4-en-2-yl)oxy]-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 27) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 57 (42.2 mg, yield 42.2%) was obtained.

[0334] MS (ESI) M / Z: 433.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 60.0 Hz,2H), 5.62 – 5.50 (m, 1H), 5.37 (s, 1H), 4.96 – 4.79 (m, 4H), 3.79 (s, 3H),2.15 (s, 3H), 2.10 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.48 (d, J = 6.8 Hz, 3H). Example 58 Preparation of (S)-5-((but-3-en-1-yl-1,2-) d 2) (oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 58, corresponding to structural formula 58.

[0335]

[0336] Preparation method: 5-((but-3-en-1-yl-1,2-) d 2) 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.25 mmol) (compound 35) was resolved chirally under the following conditions: (chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 58 (42.8 mg, yield 42.8%) was obtained.

[0337] MS (ESI) M / Z: 407.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 33.7 Hz,2H), 5.69 – 5.54 (m, 1H), 5.37 (s, 1H), 5.07 – 4.81 (m, 2H), 4.13 – 3.89 (m,1H), 3.81 (s, 3H), 2.24 – 2.18 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H). Example 59 (S)-5-(2-azidoethoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 59, with the corresponding structural formula 59.

[0338] The preparation route is as follows:

[0339]

[0340] S1: Compound 59a (2-azidoethanol, 500 mg, 5.74 mmol) was dissolved in tetrahydrofuran (10 mL), and NaOH (690 mg, 17.25 mmol) was added. o p-Toluenesulfonyl chloride (2.19 g, 11.48 mmol) was slowly added to the mixture under C conditions. The mixture was stirred for 1 hour, then the ice bath was removed, and stirring was continued at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 30 / 1) to give a colorless, transparent liquid compound 59b (4-methylbenzenesulfonic acid-2-azidoethyl ester, 330.0 mg, yield 91.9%).

[0341] S2: Intermediate 1 (300 mg, 0.86 mmol), compound 59b (247.89 mg, 1.03 mmol), and lithium carbonate (94.9 mg, 1.28 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 90°C. oC. Stir for 4 hours. Cool to room temperature, dilute the reaction solution with water (10 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 60 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-60% methanol and water) to give compound 59 (28.0 mg, yield 7.8%), an off-white solid.

[0342] MS (ESI) M / Z: 420.1 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.72 (s, 2H), 5.39 (s,1H), 4.33 – 4.07 (m, 2H), 3.85 (s, 3H), 3.46 (d, J = 5.2 Hz, 2H), 2.21 (s,3H), 2.14 (s, 3H). Example 60 5-((3-chlorobut-3-en-1-yl)oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 60, with the corresponding structural formula 60.

[0343] The preparation route is as follows:

[0344] S1: In a 50 mL round-bottom flask, compound 60a (3-butynediol p-toluenesulfonic acid, 200.0 mg, 0.89 mmol) was dissolved in 10 mL of anhydrous dichloromethane and stirred. At 0... o Hydrogen chloride gas (65.0 mg, 1.78 mmol) was slowly introduced at C, and the mixture was stirred for 4 hours. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was purified by rapid silica gel column chromatography to give a colorless and transparent liquid compound 60b (3-chloro-3-buten-1-yl-4-methylbenzenesulfonate, 125.0 mg, yield 53.8%).

[0345] S2: In a 100 mL round-bottom flask, intermediate 1 (150.0 mg, 0.43 mmol), cesium carbonate (223.2 mg, 0.69 mmol), and compound 60b (0.167 mg, 0.69 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and the mixture was heated to 50 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 60 (16.0 mg, yield 8.52%) as a white solid.

[0346] MS (ESI) M / Z: 439.1 [M+H] + 1H NMR (300 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 34.8 Hz,2H), 5.36 (s, 1H), 5.08 (s, 2H), 4.30 – 4.09 (m, 2H), 3.82 (s, 3H), 2.61 –2.52 (m, 2H), 2.17 (s, 3H), 2.14 (s, 3H). Example 61 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-3-yn-1-yloxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 61, with the corresponding structural formula 61.

[0347] The preparation route is as follows:

[0348]

[0349] S1: Compound 61a (pentan-3-yn-1-ol, 500 mg, 5.94 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (662 mg, 6.54 mmol) was added under a nitrogen atmosphere. op-Toluenesulfonyl chloride (1.25 g, 6.54 mmol) was slowly added to the mixture under C conditions. The ice bath was removed, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 25 / 1) to give a colorless, transparent liquid compound 61b (pentyl-3-yne-1-ester of 4-methylbenzenesulfonate, 750.0 mg, yield 52.8%).

[0350] S2: Intermediate 1 (441.1 mg, 1.26 mmol), compound 61b (449.9 mg, 1.89 mmol), and lithium carbonate (148.83 mg, 2.01 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the solution was heated to 90°C. o C. Stir for 4 hours. Cool to room temperature, dilute the reaction solution with water (10 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 60 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-70% methanol and water) to give compound 61 (35.0 mg, yield 6.7%), an off-white solid.

[0351] MS (ESI) M / Z: 417.1 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.74 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.74 (s, 2H), 5.39 (s,1H), 4.10 – 3.99 (m, 2H), 3.86 (s, 3H), 2.36 – 2.26 (m, 2H), 2.20 (s, 3H),2.14 (s, 3H), 1.70 (t, J = 2.5 Hz, 3H). Example 62 The preparation of 5-(but-3-en-1-yloxy)-8-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 62, with corresponding structural formula 62.

[0352] The preparation route is as follows:

[0353] S1: Compound 62a (2,5-dichloro-4-aminopyridine, 10.0 g, 61.3 mmol), sodium ethoxide (23.8 g, 349.7 mmol), and potassium fluoride (7.1 g, 122.7 mmol) were added to a 500 mL pressure-resistant bottle, followed by 55 mL of ethanol. The mixture was then heated to 150 mL. o The mixture was stirred at C until fully reacted. After the reaction was complete, it was cooled to room temperature, and 200 mL of ethyl acetate was added. The mixture was stirred at room temperature for 30 min and then filtered. The solvent was removed from the filtrate under vacuum to obtain a yellow solid intermediate 62b (5-chloro-2-ethoxypyridine-4-amine, 10.1 g, yield 95.5%).

[0354] S2: Compound 62b (10.1 g, 58.6 mmol) and aluminum trichloride (26.6 g, 175.5 mmol) were dissolved in toluene (300 mL), and the mixture was stirred under reflux until fully reacted. After the reaction was complete, the mixture was cooled to room temperature and poured into 500 mL of ice water. The pH was adjusted to 9 with 1N NaOH solution. 200 mL of ethyl acetate was added, and the aqueous phase was separated. The solvent was removed from the aqueous phase under vacuum to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give a white solid compound 62c (4-amino-5-chloropyridin-2-ol, 4.3 g, yield 50.9%).

[0355] S3: Compound 62c (4.3 g, 29.7 mmol) and intermediate 1b (2-(4-cyano-2-methoxybenzyl)-3-oxobutyramide, 7.3 g, 29.7 mmol) were dissolved in glacial acetic acid (50 mL), and the mixture was heated at 110 °C. o The mixture was stirred at C until fully reacted. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel rapid column chromatography (eluent: 0-10% methanol in dichloromethane) to give a white solid compound 62d (8-chloro-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 2.5 g, yield 23.0%).

[0356] S1: Compound 62d (2.5 g, 6.7 mmol), cesium carbonate (3.5 g, 10.7 mmol), and 4-bromobutene (1.4 g, 10.1 mmol) were dissolved in N,N-dimethylformamide (50 mL), and the solution was heated to 50°C. oC. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (100 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine (60 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 62 (99.4 mg, yield 3.5%) as a white solid.

[0357] MS (ESI) M / Z: 425.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 8.03 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 49.5 Hz, 2H), 5.69– 5.52 (m, 1H), 5.38 (s, 1H), 5.03 – 4.87 (m, 2H), 4.15 – 3.99 (m, 2H), 3.78(s, 3H), 2.27 – 2.16 (m, 2H), 2.13 (s, 3H). Example 63 Prepare ethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methylimino acid, denoted as compound 63, with the corresponding structural formula 63.

[0358] The preparation route is as follows:

[0359] S1: In a 100 mL round-bottom flask, compound 1a ((S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxynitrile, 300.0 mg, 0.79 mmol) and onium triethoxytetrafluoroborate (150.61 mg, 0.79 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at room temperature for 6 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 63 (65.0 mg, yield 20.89%) as a white solid.

[0360] MS (ESI) M / Z: 407.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.74 (s, 1H), 7.56 (d, J = 0.9 Hz, 1H), 7.45(s, 1H), 7.35 (s, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 5.35(s, 1H), 4.04 – 3.97 (m, 2H), 3.97 – 3.87 (m, 2H), 3.84 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). Example 64 (Z)-N-acetyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methylimino ethyl ester was prepared, designated as compound 64, with the corresponding structural formula 64.

[0361] The preparation route is as follows:

[0362] S1: In a 100 mL round-bottom flask, compound 63 (ethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methyliminoate, 300.0 mg, 0.74 mmol) and ammonium acetate (56.89 mg, 0.74 mmol) were dissolved in anhydrous ethanol (20 mL). The mixture was stirred at room temperature for 6 hours, and the solvent was removed by vacuum distillation. The residue was purified by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give compound 64 (120.0 mg, yield 36.25%), an off-white solid.

[0363] MS (ESI) M / Z: 449.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.79 (s, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 5.35 (s, 1H), 4.02 – 3.97 (m,2H), 3.96 – 3.90 (m, 2H), 3.83 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 1.90 (s,3H), 1.12 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H). Example 65 4-(8-((2-chloroallyl)oxy)-3-hydroxy-5-methyl-1-oxo-1,3,4,9-tetrahydrofurano[3,4-b][1,6]naphthid-9-yl)-3-methoxybenzonitrile was prepared, denoted as compound 65, with the corresponding structural formula 65.

[0364] The preparation route is as follows:

[0365] S1: Compound 65a (4-cyano-2-methoxybenzaldehyde, 1 g, 6.21 mmol) and compound ethyl 4,4-difluoroacetoacetate (1.03 g, 6.21 mmol) were dissolved in isopropanol (20 ml), and acetic acid (37.26 mg, 0.62 mmol) and piperidine (52.84 mg, 0.62 mmol) were added. The mixture was then heated at 50 mL. oThe mixture was stirred at C and reacted overnight. After cooling to room temperature, it was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a yellow solid compound 65b (ethyl 2-(4-cyano-2-methoxybenzyl)-4,4-difluoro-3-oxobutyrate, 1.5 g, yield 78%).

[0366] S2: Compound 65b (1.0 g, 3.23 mmol) and compound 4-amino-5-methyl-pyridinol (0.4 g, 3.23 mmol) were dissolved in sec-butanol (10 mL), and the mixture was stirred at 100 mL. o The reaction was stirred at C until complete. The solvent was removed under vacuum to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 65c (ethyl 4-(4-cyano-2-methoxyphenyl)-2-(difluoromethyl)-8-methyl-5-oxo-1,5-dihydro-4H-6l2-1,6-naphthidine-3-carboxylate, 0.7 g, yield 52.2%).

[0367] S3: Compound 65c (577.0 mg, 1.39 mmol), lithium carbonate (164.2 mg, 2.2 mmol), and 2-chloroallyl 4-methylbenzenesulfonate (514.0 mg, 2.08 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (30 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid compound 65d (ethyl 5-((2-chloroallyl)oxy)-4-(4-cyano-2-methoxyphenyl)-2-(difluoromethyl)-8-methyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid, 40 mg, yield 5.8%).

[0368] S4: Compound 65d (200.0 mg, 0.41 mmol) was dissolved in a mixture of 6 mL methanol and 1 mL water. Potassium hydroxide (45.8 mg, 0.82 mmol) was added, and the mixture was heated under reflux for 4 h. The pH was adjusted to 7 with 1 M hydrochloric acid, and the reaction mixture was diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to give compound 65 (40 mg, yield 5.8%) as a white solid.

[0369] MS (ESI) M / Z: 440.09 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 9.84 (s, 1H), 7.71 (s, 1H), 7.39 (m, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.07 (s, 1H), 5.35 (s, 1H), 5.24 (d, J = 1.7 Hz,1H), 5.04 (q, J = 1.4 Hz, 1H), 4.78–4.62 (m, 2H), 3.80 (s, 3H), 2.19 (s, 3H). Example 66 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((4-methylhept-1,2,6-trien-4-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 66, with the corresponding structural formula 66.

[0370] The preparation route is as follows:

[0371] S1: Under nitrogen atmosphere, add a solution of 6 mL of ether containing acetaldehyde (5 M in THF, 2 mL, 10 mmol) to a 250 mL three-necked flask. Cool the solution to -40°C. o C. Compound 66a (propargyl magnesium bromide, 1 M in Et₂O, 12.5 mL, 12.5 mmol) was added dropwise over approximately 10 minutes. The mixture was stirred for 30 minutes, then removed from the cooling bath and stirred for 1 hour at room temperature. The mixture was poured into an ammonium chloride solution. The mixture was extracted with diethyl ether (3 × 75 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily compound 66b (pentane-4-yn-2-ol, 214 mg, 25.0% yield).

[0372] S2: Toluenesulfonyl chloride (680 mg, 3.57 mmol) was dissolved in anhydrous dichloromethane (5 mL). Pyridine (282 mg, 3.57 mmol) was added under ice bath conditions, followed by dropwise addition of a solution of compound 66b (200 mg, 2.38 mmol) in anhydrous dichloromethane (3 mL). The reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification was performed by silica gel chromatography (petroleum ether / ethyl acetate = 40:1) to give a pale yellow oily compound 66c (pent-4-yn-2-yl 4-methylbenzenesulfonate, 180 mg, yield 32.0%). S3: At room temperature, add intermediate 1 (176 mg, 0.50 mmol), compound 66c (180 mg, 0.75 mmol), cesium carbonate (263 mg, 0.80 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 6 hours. After cooling to room temperature, the mixture was quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate = 1 / 2). The result was a white solid, compound 66 (2 mg, yield 1.0%).

[0373] Example 67 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylonitrile was prepared and designated as compound 67, corresponding to structural formula 67.

[0374] The preparation route is as follows:

[0375] S1: Compound 1a (200.0 mg, 0.35 mmol), triethylamine (160.4 mg, 1.59 mmol), and triphenylphosphine oxide (1.47 mg, 0.0053 mmol) were dissolved in anhydrous acetonitrile (20 mL), and oxalyl chloride (134.2 mg, 1.06 mmol) was slowly added dropwise. The reaction was allowed to proceed for 30 minutes. The mixture was quenched with water, extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 60 / 1) to give a pale yellow solid 67 (37.5 mg, yield 16.9%).

[0376] MS (ESI) M / Z: 361.2 [M+H]+ 1 H NMR (300 MHz, DMSO- d 6) δ 8.70 (s, 1H), 7.68 (s, 1H), 7.47 (s, 1H),7.34 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 5.19 (s, 1H), 4.09 – 3.90 (m,2H), 3.85 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 0.96 (t, J = 7.0 Hz, 3H). Example 68 5-(but-3-yn-1-yloxy)-8-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 68, with the corresponding structural formula 68.

[0377] The preparation route is as follows:

[0378] S1: Compound 68a (2,5-dichloro-4-aminopyridine, 10.0 g, 61.3 mmol), sodium ethoxide (23.8 g, 349.7 mmol), and potassium fluoride (7.1 g, 122.7 mmol) were added to a 500 mL pressure-resistant bottle, followed by 55 mL of ethanol. The mixture was then heated to 150 mL. o The mixture was stirred at C until fully reacted. After the reaction was complete, it was cooled to room temperature, and 200 mL of ethyl acetate was added. The mixture was stirred at room temperature for 30 min and then filtered. The solvent was removed from the filtrate under vacuum to obtain a yellow solid intermediate 68b (5-chloro-2-ethoxypyridine-4-amine, 10.1 g, yield 95.5%).

[0379] S2: Compound 68b (10.1 g, 58.6 mmol) and aluminum trichloride (26.6 g, 175.5 mmol) were dissolved in toluene (300 mL), and the mixture was stirred under reflux until fully reacted. After the reaction was complete, the mixture was cooled to room temperature and poured into 500 mL of ice water. The pH was adjusted to 9 with 1N NaOH solution. 200 mL of ethyl acetate was added, and the aqueous phase was separated. The solvent was removed from the aqueous phase under vacuum to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to give a white solid compound 68c (4-amino-5-chloropyridin-2-ol, 4.3 g, yield 50.9%).

[0380] S3: Compound 68c (4.3 g, 29.7 mmol) and intermediate 1b (2-(4-cyano-2-methoxybenzyl)-3-oxobutyramide, 7.3 g, 29.7 mmol) were dissolved in glacial acetic acid (50 mL), and the mixture was heated at 110 °C. o The mixture was stirred at C until fully reacted. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel rapid column chromatography (eluent: 0-10% methanol in dichloromethane) to obtain a white solid compound 68d (8-chloro-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 2.5 g, yield 23.0%).

[0381] S4: Compound 68d (2.5 g, 6.7 mmol), cesium carbonate (3.5 g, 10.7 mmol), and 3-butynediol p-toluenesulfonate (2.3 g, 10.1 mmol) were dissolved in N,N-dimethylformamide (50 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (100 mL), extract with ethyl acetate (150 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 68 (150.0 mg, yield 5.3%) as a white solid.

[0382] MS (ESI) M / Z: 423.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 8.06 (s, 1H), 7.86 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 29.7 Hz, 2H), 5.37 (s, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.79 (s, 4H), 2.81 – 2.69 (m,1H), 2.42 – 2.30 (m, 3H), 2.14 (s, 4H). Example 69 5-(but-3-yn-1-yloxy)-7-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 69, with the corresponding structural formula 69.

[0383] The preparation route is as follows:

[0384] S1: Intermediate 1a (850 mg, 5.27 mmol) and acetylacetamide (533.25 mg, 5.27 mmol) were dissolved in isopropanol (20 mL), and the mixture was heated at 50 mL. o At temperature C, glacial acetic acid (31.6 mg, 0.53 mmol) and piperidine (44.1 mg, 0.53 mmol) were slowly added and stirred overnight. The mixture was filtered, and the filter cake was washed with dichloromethane to give intermediate 1b (870.0 mg, yield 67.4%).

[0385] S2: Intermediate 1b (870.0 mg, 3.56 mmol) and 4-amino-6-chloropyridin-2(1H)-one (514.9 mg, 3.56 mmol) were dissolved in isopropanol (15 mL), and the mixture was heated in 100 mL of water. o Stirred overnight at C. Cool to room temperature, dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluent: dichloromethane / methanol (v / v) = 40 / 1) to give a white solid compound 69a (600.0 mg, yield 45.5%).

[0386] S3: Compound 69a (600.0 mg, 1.62 mmol), 3-butynediol p-toluenesulfonate (544.4 mg, 2.43 mmol), and cesium carbonate (843.56 mg, 2.59 mmol) were dissolved in N,N-dimethylformamide (15 mL) and heated to 50°C. o C. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-70% methanol and water) to give compound 69 (110.0 mg, yield 16.1%), an off-white solid.

[0387] MS (ESI) M / Z: 423.1 [M+H] + 1H NMR (300 MHz, DMSO) δ 9.04 (s, 1H), 7.37 (s, 1H), 7.29 (d, J = 7.8Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 18.5 Hz, 2H), 6.48 (s, 1H), 5.33 (s, 1H), 4.14 – 3.99 (m, 2H), 3.82 (s, 3H), 2.81 – 2.75 (m, 1H), 2.42 –2.33 (m, 2H), 2.09 (s, 3H). Example 70 5-(bicyclo[1.1.1]pentan-1-ylmethoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 70, with the corresponding structural formula 70.

[0388] The preparation route is as follows:

[0389]

[0390] S1: In 0 o Under a nitrogen atmosphere, a solution of compound 70a (bicyclo[1.1.1]pentane-1-carboxylic acid, 200.0 mg, 1.78 mmol) in diethyl ether (8 mL) was slowly added to lithium aluminum hydride (74.47 mg, 1.96 mmol), and the mixture was stirred at room temperature for 3 hours. A 10% sodium hydroxide solution was added to the reaction mixture until it became alkaline. The solid was removed by filtration, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a colorless, transparent liquid compound 70b (bicyclo[1.1.1]pentane-1-ylmethanol, 120.0 mg, yield 68.6%).

[0391] S2: Compound 70b (50.0 mg, 0.51 mmol) was dissolved in dichloromethane (6 mL) and heated at 0°C. oAdd 4-dimethylaminopyridine (249.0 mg, 2.04 mmol), N,N-diisopropylethylamine (131.69 mg, 1.02 mmol), and p-toluenesulfonyl chloride (106.83 mg, 0.56 mmol) to C. Remove the ice bath and continue stirring at room temperature for 16 hours. Dilute the reaction solution with water (10 mL), extract with ethyl acetate (10 mL × 2), combine the organic phases, wash with saturated brine (10 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluting agent: petroleum ether / ethyl acetate (v / v) = 40 / 1) to give a colorless transparent liquid compound 70c (bicyclo[1.1.1]pent-1-ylmethyl-4-methylbenzenesulfonate, 94.0 mg, yield 53.7%).

[0392] S3: Intermediate 1 (79.4 mg, 0.23 mmol), compound 70c (80.0 mg, 0.32 mmol), and cesium carbonate (110.68 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (6 mL), and the solution was heated to 50°C. o C. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (10 mL), extract with ethyl acetate (10 mL × 2), combine the organic phases, wash with saturated brine (10 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 60 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-70% methanol and water) to give a white solid compound 70 (25.0 mg, yield 25.6%).

[0393] MS (ESI) M / Z: 431.2 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.69 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 1.0Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.29 (dd, J = 7.8, 1.5 Hz, 1H), 7.09 (d, J= 7.8 Hz, 1H), 6.82 (d, J = 48.9 Hz, 2H), 5.38 (s, 1H), 4.26 – 4.10 (m, 2H), 3.79 (s, 3H), 2.38 (s, 1H), 2.20 – 2.05 (m, 6H), 1.52 – 1.47 (m, 3H), 1.47 –1.41 (m, 3H). Example 71 Preparation of 5-((but-3-yn-1-yl-1,1-) d 2) (oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 71, corresponding to structural formula 71.

[0394] The preparation route is as follows:

[0395] S1: In a 50 mL double-necked flask, lithium deuterated aluminum (107.3 mg, 2.6 mmol) was suspended in dry diethyl ether under ice bath. Nitrogen was applied, and compound 71a (3-butynedic acid, 200.0 mg, 2.3 mmol) was added dropwise. After stirring for 20 minutes, the mixture was refluxed for 2 hours and cooled to room temperature with continued stirring for 40 hours. Water (0.3 mL), 15% aq NaOH (0.9 mL), and water (0.3 mL) were added dropwise. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate was dried over anhydrous sodium sulfate, filtered under vacuum, and concentrated under reduced pressure to obtain a pale yellow oily compound 71b (but-3-yne-1,1- d 2-1 alcohol, 48.8 mg, yield 28.3%.

[0396] S2: Toluenesulfonyl chloride (470.0 mg, 2.5 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (195.0 mg, 2.5 mmol) was added under ice bath conditions. Then, a solution of compound 71b (120.0 mg, 1.6 mmol) in anhydrous dichloromethane (3 mL) was added dropwise, and the reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification was performed by silica gel chromatography (petroleum ether / ethyl acetate = 40:1) to give a pale yellow oil, compound 71c (but-3-yn-1-yl-1,1-yl-yl-2 ... d 2,4-Methylbenzenesulfonate, 60.0 mg, yield 16.0%.

[0397] S3: At room temperature, add intermediate 1 (160.0 mg, 0.45 mmol), compound 71c (169 mg, 0.68 mmol), cesium carbonate (238 mg, 0.73 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. oThe reaction was carried out at C for 2 hours. The mixture was cooled to room temperature and quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 2). This yielded a white solid, compound 71 (10.0 mg, yield 18.4%).

[0398] MS (ESI) M / Z: 405.18 [M+H] + 1 H NMR (300 MHz, DMSO- d 6)δ7.76 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.73 (s, 2H), 5.37 (s,1H), 3.84 (s, 3H), 2.75 (m, 1H), 2.34 (d, J = 2.7 Hz, 2H), 2.19 (s, 3H), 2.13(s, 3H). Example 72 4-(4-cyano-2-methoxyphenyl)-5-((3,3-difluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared and designated as compound 72, corresponding to structural formula 72.

[0399] The preparation route is as follows:

[0400] S1: At room temperature, add intermediate 1 (200 mg, 0.57 mmol), compound 72a (3-bromo-1,1-difluoropropene, 134 mg, 0.86 mmol), lithium carbonate (68 mg, 0.91 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 2 hours. The mixture was cooled to room temperature and quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 1 / 2). 72 mg (0.8%) of a white solid compound was given.

[0401] MS (ESI) M / Z: 427.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.37(d, J = 1.5 Hz, 1H), 7.28 (dd, J = 7.8, 1.5 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.74(s, 2H), 5.37 (s, 1H), 4.79 – 4.42 (m, 3H), 3.81 (s, 3H), 2.18 (s, 2H), 2.14(s, 2H). Example 73 4-(4-cyano-2-methoxyphenyl)-5-(hex-5-yn-3-yloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 73, with the corresponding structural formula 73.

[0402] The preparation route is as follows:

[0403] S1: Add zinc powder (394 mg, 6.06 mmol) to a 250 mL three-necked flask and cool to 0 °C under a nitrogen atmosphere. o C. Slowly add 6 mL of anhydrous tetrahydrofuran, followed by dropwise addition of a 6 mL solution of 73a (3-bromopropyne, 600 mg, 5.04 mmol) of tetrahydrofuran and propionaldehyde (352 mg, 6.06 mmol). o Stir at C for 1 hour, then at room temperature for 4 hours. Pour the mixture into the chlorination tank. ammonium In solution. The mixture was extracted with diethyl ether (3 × 75 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily compound 73b (hexane-5-yn-3-ol, 440 mg, yield 88.9%).

[0404] S2: p-Toluenesulfonyl chloride (1203 mg, 6.31 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (499 mg, 6.31 mmol) was added under ice bath conditions. Then, a solution of compound 73b (563 mg, 5.74 mmol) in anhydrous dichloromethane (3 mL) was added dropwise, and the reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification was achieved by silica gel chromatography (petroleum ether / ethyl acetate = 40:1) to give a pale yellow oil (hexyl-5-yn-3-methylbenzenesulfonate, 354 mg, yield 24%). S3: At room temperature, add intermediate 1 (278 mg, 0.79 mmol), compound 73c (300 mg, 1.19 mmol), cesium carbonate (413 mg, 1.27 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 6 hours. After cooling to room temperature, the mixture was quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by pre-TLC (petroleum ether / ethyl acetate = 1 / 2). A white solid compound 73 (9 mg, yield 3%) was given.

[0405] MS (ESI) M / Z: 431.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.55 (s, 1H), 7.34 (d, J = 5.9Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.72 (s, 2H), 5.34 (s, 1H), 4.85 (s, 1H), 3.80 (s, 2H), 2.84 (s, 0H), 2.17 (s, 3H), 2.12 (s, 3H), 1.76 –1.46 (m, 0H), 0.60 (dt, J = 189.4, 7.4 Hz, 3H). Example 74 4-(4-cyano-2-methoxyphenyl)-5-((1-ethynylcyclopropyl)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 74, with the corresponding structural formula 74.

[0406] The preparation route is as follows:

[0407] S1: In a 50 mL double-necked flask, compound 74a (1-ethynylcyclopropylcarboxylic acid, 283.0 mg, 2.57 mmol) was dissolved in dry diethyl ether under ice bath conditions. Nitrogen was applied, and lithium aluminum hydride (107.3 mg, 2.83 mmol) was added dropwise. The mixture was stirred for 20 minutes, refluxed for 2 hours, cooled to room temperature, and stirred for another 3 hours. Water (0.3 mL), 15% aq NaOH (0.9 mL), and water (0.3 mL) were added dropwise. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily compound 74b ((1-ethynylcyclopropyl)methanol, 47.8 mg, yield 19.3%).

[0408] S2: p-Toluenesulfonyl chloride (470.0 mg, 2.5 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (195.0 mg, 2.5 mmol) was added under ice bath conditions. Then, a solution of compound 74b (154.3 mg, 1.6 mmol) in anhydrous dichloromethane (3 mL) was added dropwise, and the reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification was achieved by silica gel chromatography (petroleum ether / ethyl acetate = 40:1) to give a pale yellow oil, compound 74c (methyl 4-methylbenzenesulfonic acid (1-ethynylcyclopropyl) ester, 72.0 mg, yield 19.3%). S3: At room temperature, add intermediate 1 (160.0 mg, 0.45 mmol), compound c (171.4 mg, 0.68 mmol), cesium carbonate (238.4 mg, 0.73 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 2 hours. The mixture was cooled to room temperature and quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by pre-TLC (petroleum ether / ethyl acetate = 1 / 2). The result was a white solid, compound 74 (20.3 mg, yield 18.4%).

[0409] MS (ESI) M / Z: 429.18 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.58 – 7.53 (m, 1H), 7.36 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.77 (s, 2H), 5.39(s, 1H), 4.03 (d, J = 11.1 Hz, 2H), 3.83 (s, 3H), 2.66 (s, 1H), 2.17 (s, 3H), 2.15 – 2.10 (m, 3H), 0.85 – 0.54 (m, 4H). Example 75 4-(4-cyano-2-methoxyphenyl)-5-((2,2-dimethylcyclopropylene)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 75, with the corresponding structural formula 75.

[0410] The preparation route is as follows:

[0411] S1: In a 50 mL double-necked flask, compound 75a (2,2-dimethyl-but-3-ynyleneic acid, 281.0 mg, 2.57 mmol) was dissolved in dry diethyl ether under ice bath conditions. Nitrogen was applied, and lithium aluminum hydride (107.3 mg, 2.83 mmol) was added dropwise. The mixture was stirred for 20 minutes, refluxed for 2 hours, cooled to room temperature, and stirred for another 3 hours. Water (0.3 mL), 15% aq NaOH (0.9 mL), and water (0.3 mL) were added dropwise. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily compound 75b (2,2-dimethyl-but-3-ynylene-1-ol, 99.8 mg, 41% yield).

[0412] S2: p-Toluenesulfonyl chloride (470.0 mg, 2.5 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (195.0 mg, 2.5 mmol) was added under ice bath conditions. Then, a solution of compound 75b (151.4 mg, 1.6 mmol) in anhydrous dichloromethane (3 mL) was added dropwise, and the reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification was performed by silica gel chromatography (petroleum ether / ethyl acetate = 40:1) to give a pale yellow oil, compound 75c (2,2-dimethylbut-3-yn-1-yl-4-methylbenzenesulfonate, 145.3 mg, yield 43%). S3: At room temperature, add intermediate 1 (160.0 mg, 0.45 mmol), compound c (169.4 mg, 0.68 mmol), cesium carbonate (238.4 mg, 0.73 mmol), and N,N-dimethylformamide (5 mL) to a 100 mL single-necked flask. o The reaction was carried out at C for 2 hours. After cooling to room temperature, the mixture was quenched with water (10 mL). Extraction was performed with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate = 1 / 2). 75 μL of a white solid (20.3 mg, yield 18.4%) was given.

[0413] MS (ESI) M / Z: 431.20 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.82 (s, 1H), 7.60 (s, 1H), 7.54 (m, 1H), 7.39 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 49.8Hz, 2H), 5.46 (s, 1H), 3.81 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.33 (d, J =16.0 Hz, 2H), 1.18 (s, 3H), 1.12 (s, 3H). Example 76 (E)-4-(3-cyano-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthid-4-yl)-N'-hydroxy-3-methoxybenzimidamine was prepared, designated as compound 76, with the corresponding structural formula 76.

[0414] The preparation route is as follows:

[0415] S1: In a 100 mL round-bottom flask, compound 67 ((S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxynitrile, 300.0 mg, 0.79 mmol), hydroxylamine hydrochloride (110.02 mg, 1.59 mmol), and triethylamine (102.46 mg, 0.79 mmol) were dissolved in methanol (20 mL), and the mixture was heated to 50 °C. o C. Stir for 3 hours, remove solvent by vacuum distillation, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give white solid compound 76 (68.0 mg, yield 20.85%).

[0416] MS (ESI) M / Z: 394.2 [M+H] + 1 H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.63 (s, 1H), 7.66 (s, 1H), 7.24 (s, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.80 (s,2H), 5.11 (s, 1H), 4.11 – 3.91 (m, 2H), 3.81 (s, 3H), 2.16 (s, 3H), 2.14 (s,3H), 1.00 (t, J = 7.0 Hz, 3H). Example 77 (Z)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-N'-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-formamidinium was prepared, designated as compound 77, with the corresponding structural formula 77.

[0417] The preparation route is as follows:

[0418] S1: In a 100 mL round-bottom flask, compound 67 ((S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxynitrile, 300.0 mg, 0.79 mmol), hydroxylamine hydrochloride (110.02 mg, 1.59 mmol), and triethylamine (102.46 mg, 0.79 mmol) were dissolved in methanol (20 mL), and the mixture was heated to 50 °C. o C. Stir for 3 hours, remove solvent by vacuum distillation, and purify the residue by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give white solid compound 77 (8.0 mg, yield 2.45%).

[0419] MS (ESI) M / Z: 394.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.27 (s, 1H), 8.05 (s, 1H), 7.31 (s, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 11.7 Hz, 1H), 5.88 (s, 2H),5.27 (s, 1H), 4.07 – 3.85 (m, 3H), 3.62 (s, 3H), 2.92 (s, 3H), 2.68 (s, 3H),0.69 (t, J = 6.5 Hz, 3H). Example 78 5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2-methyl-8-propyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared and designated as compound 78, corresponding to structural formula 78.

[0420] The preparation route is as follows:

[0421] S1: Compound 78a (2,5-dichloro-4-aminopyridine, 10.0 g, 61.3 mmol), sodium ethoxide (23.8 g, 349.7 mmol), and potassium fluoride (7.1 g, 122.7 mmol) were added to a 500 mL pressure-resistant bottle, followed by 55 mL of ethanol. The mixture was then heated to 150 mL. oThe mixture was stirred at C until fully reacted. After the reaction was complete, it was cooled to room temperature, and 200 mL of ethyl acetate was added. After stirring at room temperature for 30 min, the mixture was filtered. The solvent was removed from the filtrate under vacuum to obtain a yellow solid intermediate 78b (5-chloro-2-ethoxypyridine-4-amine, 10.1 g, yield 95.5%).

[0422] S2: Compound 78b (10.1 g, 58.6 mmol), cyclopropylboronic acid (7.5 g, 87.9 mmol), palladium acetate (1.3 g, 5.9 mmol), S-Phos (4.8 g, 11.7 mmol), and potassium phosphate (37.3 g, 175.8 mmol) were placed under a N2 atmosphere and suspended in toluene (220 mL) and water (22 mL). The reaction mixture was then placed under a N2 atmosphere and 95%... o The mixture was stirred at C for 16 h. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with brine (150 mL), and the solvent was removed under vacuum to obtain a crude product, which was purified by silica gel rapid column chromatography (eluent: 0-10% methanol in dichloromethane) to give a yellow solid compound 78c (5-cyclopropyl-2-ethoxypyridine-4-amine, 4.2 g, yield 40.3%).

[0423] S3: Dissolve compound intermediate 78c (4.2 g, 23.6 mmol) and aluminum trichloride (10.7 g, 70.8 mmol) in toluene (40 mL), and dissolve the mixture in a 150 mL pressure vessel at 150 °C. o Stir the mixture thoroughly until the reaction is complete. After the reaction is complete, cool to room temperature and pour into 100 mL of ice water. Adjust the pH to 9 with 1N NaOH solution. Add 40 mL of ethyl acetate, separate the aqueous phase, and remove the solvent under vacuum to obtain the crude product. Purify by reversed-phase preparative chromatography (eluent: 10-60% methanol in water) to obtain a white solid compound 78d (4-amino-5-propylpyridine-2-ol, 2.2 g, yield 61.5%).

[0424] S4: Compound 78d (2.2 g, 14.5 mmol) and intermediate 1b (2-(4-cyano-2-methoxybenzyl)-3-oxobutyramide, 3.5 g, 14.5 mmol) were dissolved in isopropanol (50 mL), and the mixture was placed in a pressure-resistant bottle at 130 °C. oThe mixture was stirred at C until fully reacted. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel rapid column chromatography (eluting agent: 0-10% methanol in dichloromethane) to give a white solid compound 78e (4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl-8-propyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 1.2 g, yield 21.7%).

[0425] S5: Compound 78e (1.2 g, 3.1 mmol), cesium carbonate (1.6 g, 5.0 mmol), and 3-butynediol p-toluenesulfonate (1.1 g, 4.7 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the solution was heated to 60 °C. o C. Stir overnight. Cool to room temperature, dilute the reaction solution with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter under vacuum, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give compound 78 (30.6 mg, yield 2.3%) as a white solid.

[0426] MS (ESI) M / Z: 431.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H),7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 29.7 Hz, 2H), 5.35(s, 1H), 4.14 – 4.02 (m, 2H), 3.82 (s, 3H), 2.80 – 2.76 (m, 1H), 2.60 – 2.52(m, 2H), 2.42 – 2.34 (m, 2H), 2.19 (s, 3H), 1.62 – 1.45 (m, 2H), 0.93 (t, J =7.3 Hz, 3H). Example 79 5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxy-5-methylphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 79, with the corresponding structural formula 79.

[0427] The preparation route is as follows:

[0428] S1: Compound 79a (3-bromo-4-methylphenol, 5 g, 26.73 mmol), paraformaldehyde (6.42 g, 213.86 mmol), magnesium chloride (3.82 g, 40.10 mmol), and triethylamine (9.47 g, 93.56 mmol) were dissolved in acetonitrile (50 mL), and the mixture was heated at 80 °C. o Stir at C for 4 hours. Cool to room temperature, dilute the reaction solution with water (30 mL), adjust the pH to 2-3 with 1M hydrochloric acid, extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine (50 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and precipitate the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 45 / 1) to give crude pale yellow liquid compound 79b (4-bromo-2-hydroxy-5-methylbenzaldehyde, 2.63 g, yield 45.7%).

[0429] S2: Compound 79b (2.63 g, 12.23 mmol), iodomethane (2.08 g, 14.68 mmol), and potassium carbonate (3.38 g, 24.46 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 45 / 1) to give crude pale yellow liquid compound 79c (4-bromo-2-methoxy-5-methylbenzaldehyde, 2.19 g, yield 78.2%).

[0430] S3: Under a nitrogen atmosphere, compound 79c (2.19 g, 9.56 mmol), potassium ferricyanide (4.72 g, 14.34 mmol), palladium acetate (429.27 mg, 1.91 mmol), and sodium carbonate (2.03 g, 19.12 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the mixture was heated at 120 °C. oThe mixture was stirred overnight at C. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 45 / 1) to give a white solid compound 79d (4-formyl-5-methoxy-2-methylbenzonitrile, 540 mg, yield 32.3%).

[0431] S4: Compound 79d (540 mg, 3.08 mmol) and acetylacetamide (311.65 mg, 3.08 mmol) were dissolved in isopropanol (10 mL), and the mixture was heated at 50 mL. o Glacial acetic acid (18.51 mg, 0.31 mmol) and piperidine (26.25 mg, 0.31 mmol) were slowly added at C, and the mixture was stirred overnight. The mixture was filtered, and the filter cake was washed with dichloromethane to give compound 79e (2-(4-cyano-2-methoxy-5-methylbenzyl)-3-oxobutyramide, 750.0 mg, yield 94.2%).

[0432] S5: Compound 79e (750.0 mg, 2.90 mmol) was dissolved in sec-butanol (15 mL), and the mixture was heated in 100 mL of water. o Stirred overnight at C. Cool to room temperature, dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel rapid column chromatography (eluting agent: dichloromethane / methanol (v / v) = 40 / 1) to give a white solid compound 79f (4-(4-cyano-2-methoxy-5-methylphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, 340.0 mg, yield 30.7%).

[0433] S6: Compound 79f (340.0 mg, 0.93 mmol), 3-butynediol p-toluenesulfonate (313.88 mg, 1.40 mmol), and cesium carbonate (486.40 mg, 1.49 mmol) were dissolved in N,N-dimethylformamide (15 mL) and heated to 50°C. oC. Stir for 5 hours. Cool to room temperature, dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), and dry with anhydrous sodium sulfate. Filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol (v / v) = 45 / 1) to obtain the crude product, which is purified by reversed-phase preparative chromatography (eluent: 10-70% methanol and water) to give compound 79 (4.0 mg, yield 1.0%), an off-white solid.

[0434] MS (ESI) M / Z: 417.1 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.73 (s, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 7.03 (s, 1H), 6.71 (d, J = 12.6 Hz, 2H), 5.32 (s, 1H), 4.10 – 4.01 (m, 2H), 3.79 (s, 3H), 2.79 – 2.75 (m, 1H), 2.40 – 2.32 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H). Example 80 (S)-5-(2-azidoethoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 80, with the corresponding structural formula 80.

[0435]

[0436] Preparation method: 5-(2-azidoethoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 59) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 80 (45.7 mg, yield 45.7%) was obtained.

[0437] MS (ESI) M / Z: 420.1 [M+H] + 1H NMR (300 MHz, DMSO) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.72 (s, 2H), 5.39 (s,1H), 4.33 – 4.07 (m, 2H), 3.85 (s, 3H), 3.46 (d, J = 5.2 Hz, 2H), 2.21 (s,3H), 2.14 (s, 3H). Example 81 (S)-5-((3-chlorobut-3-en-1-yl)oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 81, with the corresponding structural formula 81.

[0438]

[0439] Preparation method: 5-((3-chlorobut-3-en-1-yl)oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 60) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 81 was obtained (40.8 mg, yield 40.8%).

[0440] MS (ESI) M / Z: 439.1 [M+H] + 1H NMR (300 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 34.8 Hz,2H), 5.36 (s, 1H), 5.08 (s, 2H), 4.30 – 4.09 (m, 2H), 3.82 (s, 3H), 2.61 –2.52 (m, 2H), 2.17 (s, 3H), 2.14 (s, 3H). Example 82 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pent-3-yn-1-yloxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 82, with the corresponding structural formula 82.

[0441]

[0442] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-(pentan-3-yn-1-yloxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 61) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 82 (45.8 mg, yield 45.8%) was obtained.

[0443] MS (ESI) M / Z: 417.1 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.74 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.74 (s, 2H), 5.39 (s,1H), 4.10 – 3.99 (m, 2H), 3.86 (s, 3H), 2.36 – 2.26 (m, 2H), 2.20 (s, 3H),2.14 (s, 3H), 1.70 (t, J = 2.5 Hz, 3H). Example 83 (S)-5-(but-3-en-1-yloxy)-8-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 82, with the corresponding structural formula 82.

[0444]

[0445] Preparation method: 5-(but-3-en-1-yloxy)-8-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 62) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 83 (41.8 mg, yield 41.8%) was obtained.

[0446] MS (ESI) M / Z: 425.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 8.03 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 49.5 Hz, 2H), 5.69– 5.52 (m, 1H), 5.38 (s, 1H), 5.03 – 4.87 (m, 2H), 4.15 – 3.99 (m, 2H), 3.78(s, 3H), 2.27 – 2.16 (m, 2H), 2.13 (s, 3H). Example 84 (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methylimino ethyl ester was prepared, designated as compound 82, with the corresponding structural formula 82.

[0447]

[0448] Preparation method: Ethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methyliminoate (100 mg, 0.25 mmol) (compound 63) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) oC; Injection volume: 5 uL). White solid compound 84 (39.6 mg, yield 39.6%) was obtained.

[0449] MS (ESI) M / Z: 407.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.74 (s, 1H), 7.56 (d, J = 0.9 Hz, 1H), 7.45(s, 1H), 7.35 (s, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 5.35(s, 1H), 4.04 – 3.97 (m, 2H), 3.97 – 3.87 (m, 2H), 3.84 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). Example 85 Prepare (S)-(Z)-N-acetyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methylimino acid ethyl ester, denoted as compound 85, with corresponding structural formula 85.

[0450]

[0451] Preparation method: (Z)-N-acetyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-methyliminoethyl ester (100 mg, 0.22 mmol) (compound 64) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 85 (48.6 mg, yield 48.6%) was obtained.

[0452] MS (ESI) M / Z: 449.2 [M+H] + 1H NMR (300 MHz, DMSO- d 6) δ 7.79 (s, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 5.35 (s, 1H), 4.02 – 3.97 (m,2H), 3.96 – 3.90 (m, 2H), 3.83 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 1.90 (s,3H), 1.12 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H). Example 86 (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((4-methylhept-1,2,6-trien-4-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 86, with the corresponding structural formula 86.

[0453]

[0454] Preparation method: 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-((4-methylhept-1,2,6-trien-4-yl)oxy)-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.22 mmol) (compound 66) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 86 (47.6 mg, yield 47.6%) was obtained.

[0455] MS (ESI) M / Z: 455.2 [M+H] + 1 H NMR (300 MHz, DMSO- d6) δ 8.07 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 41.5 Hz, 2H), 6.10 – 5.91 (m, 1H), 5.37 – 5.10 (m, 2H), 4.39 – 4.21 (m, 1H), 4.16 (s,3H), 2.88 (d, J = 1.9 Hz, 3H), 2.38 – 2.18 (m, 1H), 2.16 – 1.98 (m, 2H), 1.10(s, 1H). Example 87 (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxynitrile was prepared, designated as compound 87, with the corresponding structural formula 87.

[0456]

[0457] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxynitrile (100 mg, 0.27 mmol) (compound 67) was resolved by chirality. Resolution conditions: (Chiral column: ChiralpakIA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). Two white solid compounds, 87 (43.6 mg, yield 43.6%), were obtained.

[0458] MS (ESI) M / Z: 361.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 8.70 (s, 1H), 7.68 (s, 1H), 7.47 (s, 1H),7.34 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 5.19 (s, 1H), 4.09 – 3.90 (m,2H), 3.85 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 0.96 (t,J = 7.0 Hz, 3H). Example 88 (S)-5-(but-3-yn-1-yloxy)-8-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 88, with the corresponding structural formula 88.

[0459]

[0460] Preparation method: 5-(but-3-yn-1-yloxy)-8-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 68) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 88 (43.1 mg, yield 43.1%) was obtained.

[0461] MS (ESI) M / Z: 423.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 8.06 (s, 1H), 7.86 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 29.7 Hz, 2H), 5.37 (s, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.79 (s, 4H), 2.81 – 2.69 (m,1H), 2.42 – 2.30 (m, 3H), 2.14 (s, 4H). Example 89 (S)-5-(but-3-yn-1-yloxy)-7-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 89, with the corresponding structural formula 89.

[0462]

[0463] Preparation method: 5-(but-3-yn-1-yloxy)-7-chloro-4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 69) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 89 (43.3 mg, yield 43.3%) was obtained.

[0464] MS (ESI) M / Z: 423.1 [M+H] + 1 H NMR (300 MHz, DMSO) δ 9.04 (s, 1H), 7.37 (s, 1H), 7.29 (d, J = 7.8Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 18.5 Hz, 2H), 6.48 (s, 1H), 5.33 (s, 1H), 4.14 – 3.99 (m, 2H), 3.82 (s, 3H), 2.81 – 2.75 (m, 1H), 2.42 –2.33 (m, 2H), 2.09 (s, 3H). Example 90 Prepare (S)-5-(bicyclo[1.1.1]pentan-1-ylmethoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 90, corresponding to structural formula 90.

[0465]

[0466] Preparation method: 5-(bicyclo[1.1.1]pentan-1-ylmethoxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 70) was resolved by chirality under the following conditions: (chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 90 (43.9 mg, yield 43.9%) was obtained.

[0467] MS (ESI) M / Z: 431.1 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.69 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 1.0Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.29 (dd, J = 7.8, 1.5 Hz, 1H), 7.09 (d, J= 7.8 Hz, 1H), 6.82 (d, J = 48.9 Hz, 2H), 5.38 (s, 1H), 4.26 – 4.10 (m, 2H), 3.79 (s, 3H), 2.38 (s, 1H), 2.20 – 2.05 (m, 6H), 1.52 – 1.47 (m, 3H), 1.47 –1.41 (m, 3H). Example 91 Preparation of (S)-5-((but-3-yn-1-yl-1,1-) d 2) (oxy)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, denoted as compound 1, corresponding to structural formula 1.

[0468]

[0469] Preparation method: 5-((but-3-yn-1-yl-1,1-) d 2) 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.25 mmol) (compound 71) was resolved by chirality under the following conditions: (chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). White solid compound 1 was obtained (42.1 mg, yield 42.1%).

[0470] MS (ESI) M / Z: 405.1 [M+H] + 1 H NMR (300 MHz, DMSO- d6) δ 7.76 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.73 (s, 2H), 5.37 (s,1H), 3.84 (s, 3H), 2.75 (m, 1H), 2.34 (d, J = 2.7 Hz, 2H), 2.19 (s, 3H), 2.13(s, 3H). Example 92 (S)-4-(4-cyano-2-methoxyphenyl)-5-((3,3-difluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 2, with the corresponding structural formula 2.

[0471]

[0472] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-((3,3-difluoroallyl)oxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 72) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). White solid compound 2 was obtained (42.3 mg, yield 42.3%).

[0473] MS (ESI) M / Z: 427.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.28 (dd, J = 7.8, 1.5 Hz, 1H), 7.13 (d, J = 7.9Hz, 1H), 6.74 (s, 2H), 5.37 (s, 1H), 4.79 – 4.42 (m, 3H), 3.81 (s, 3H), 2.18(s, 2H), 2.14 (s, 2H) Example 93 (S)-4-(4-cyano-2-methoxyphenyl)-5-(hex-5-yn-3-yloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 3, with the corresponding structural formula 3.

[0474]

[0475] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-(hex-5-yn-3-yloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 73) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 3 (42.7 mg, yield 42.7%) was obtained.

[0476] MS (ESI) M / Z: 431.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.55 (s, 1H), 7.34 (d, J =5.9 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.72 (s, 2H), 5.34 (s,1H), 4.85 (s, 1H), 3.80 (s, 2H), 2.84 (s, 0H), 2.17 (s, 3H), 2.12 (s, 3H), 1.76 – 1.46 (m, 0H), 0.60 (dt, J = 189.4, 7.4 Hz, 3H). Example 94 (S)-4-(4-cyano-2-methoxyphenyl)-5-((1-ethynylcyclopropyl)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 4, with the corresponding structural formula 4.

[0477]

[0478] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-((1-ethynylcyclopropyl)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 74) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 4 (42.8 mg, yield 42.8%) was obtained.

[0479] MS (ESI) M / Z: 429.18 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.58 – 7.53 (m, 1H), 7.36 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.77 (s, 2H), 5.39 (s, 1H), 4.03 (d, J = 11.1 Hz, 2H), 3.83 (s, 3H), 2.66 (s, 1H), 2.17 (s,3H), 2.15 – 2.10 (m, 3H), 0.85 – 0.54 (m, 4H). Example 95 (S)-4-(4-cyano-2-methoxyphenyl)-5-((2,2-dimethylcyclopropylene)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 5, corresponding to structural formula 5.

[0480]

[0481] Preparation method: 4-(4-cyano-2-methoxyphenyl)-5-((2,2-dimethylcyclopropylene)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 75) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) oC; Injection volume: 5 uL). A white solid compound 5 (42.1 mg, yield 42.1%) was obtained.

[0482] MS (ESI) M / Z: 431.2 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.82 (s, 1H), 7.60 (s, 1H), 7.54 (m, 1H),7.39 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.82 (d, J= 49.8 Hz, 2H), 5.46 (s, 1H), 3.81 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.33(d, J = 16.0 Hz, 2H), 1.18 (s, 3H), 1.12 (s, 3H). Example 96 (S)-5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2-methyl-8-propyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, denoted as compound 6, with the corresponding structural formula 6.

[0483]

[0484] Preparation method: 5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxyphenyl)-2-methyl-8-propyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.23 mmol) (compound 78) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 6 (45.8 mg, yield 45.8%) was obtained.

[0485] MS (ESI) M / Z: 431.1 [M+H] + 1 H NMR (300 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H),7.28 (d,J = 7.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 29.7 Hz, 2H), 5.35(s, 1H), 4.14 – 4.02 (m, 2H), 3.82 (s, 3H), 2.80 – 2.76 (m, 1H), 2.60 – 2.52(m, 2H), 2.42 – 2.34 (m, 2H), 2.19 (s, 3H), 1.62 – 1.45 (m, 2H), 0.93 (t, J =7.3 Hz, 3H). Example 97 (S)-5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxy-5-methylphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide was prepared, designated as compound 97, with the corresponding structural formula 97.

[0486]

[0487] Preparation method: 5-(but-3-yn-1-yloxy)-4-(4-cyano-2-methoxy-5-methylphenyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (100 mg, 0.24 mmol) (compound 79) was resolved by chirality. Resolution conditions: (Chiral column: Chiralpak IA chiral separation column; mobile phase: methyl tert-butyl ether-acetonitrile (10:90); flow rate: 0.8 mL / min; detection wavelength: 255 nm; column temperature: 40 °C) o C; Injection volume: 5 uL). A white solid compound 97 (45.5 mg, yield 45.5%) was obtained.

[0488] MS (ESI) M / Z: 417.1 [M+H] + 1H NMR (300 MHz, DMSO) δ 7.73 (s, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 7.03 (s, 1H), 6.71 (d, J = 12.6 Hz, 2H), 5.32 (s, 1H), 4.10 – 4.01 (m, 2H), 3.79 (s, 3H), 2.79 – 2.75 (m, 1H), 2.40 – 2.32 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H). Experimental Example I. Compound Activity Testing Experiment Single luciferase reporter gene assay Experimental procedure: S1: Cell Culture HEK293T cells were cultured at 5% CO2 and 37°C. o C. Cultured under humid conditions in DMEM medium (brand name Gibco), which contains 10% fetal bovine serum (Gibco), 100 units / mL penicillin G and 100 μg / mL streptomycin sulfate (Keygen) to obtain complete DMEM medium.

[0489] S2: HEK293T cells were transiently transfected with hMR / pcDNA3.1(+) and CRE / pGL3-basic plasmids. HEK293T cells were seeded in 6-well plates (6 × 10⁵ cells / well) one day before transfection, with 2 mL of DMEM complete medium per well, and cultured for 12–24 hours to 80%–90% cell density. The plasmid (hMR / pcDNA3.1(+):CRE / pGL3-basic = 1:5) and Lipofectamine® 2000 (Invitrogen) were dissolved separately in serum-depleted medium (Opti-MEM, Gibco) at a 1:1 volume ratio to form a DNA-liposome complex. The mixture was incubated at room temperature for 5 minutes. The original HEK293T cell culture medium was then replaced with Opti-MEM medium. Subsequently, 250 μL of the DNA-liposome complex was added dropwise to each well, resulting in a final plasmid volume of 2500 ng / well and a final Lipofectamine® 2000 volume of 9 μL / well. After 6 hours, the original culture medium was replaced with DMEM complete medium, and the cells were cultured for another 12–24 hours.

[0490] S3: Detection of the compound's activity against cellular MR transcriptional repression HEK293T cells transiently expressing hMR (human mineralocorticoid receptor) and luciferase reporter gene were collected and resuspended in DMEM complete medium at 5 × 10⁵ cells / mL. 20 μL of the cell suspension and 20 μL of 2× assay compound were seeded into 384-well white-background cell culture plates. After incubation for 30 minutes, aldosterone ligand (0.5 nM) was added, and the plates were incubated at 37°C with 5% CO₂. o C. Incubate under humid conditions for 24 hours, then remove the 384-well cell culture plate with a white background and allow it to equilibrate to room temperature for 30 minutes. Add 40 μL of the One-Lite assay reagent from the One-Lite Luciferase Assay System (Vazyme) to each well. Allow the cells to lyse fully at room temperature for at least 3 minutes. Then, read the full-wavelength fluorescence signal using SpectraMax i3X. Calculate the IC50 of the test compound by fitting the inhibitor dose-response curve using a 4-parameter nonlinear regression program in GraphPad Prism 8. 50 value.

[0491] Using fenelazol (batch number: Fin-20230724) as a positive control, the IC50 values ​​of compounds 1-97 and fenelazol were determined. 50 The experimental results are shown in Table 1.

[0492] Table 1 IC 50 Test data

[0493]

[0494] Experimental conclusion: The above results indicate that compounds 1-2, 6, 8-11, 13-17, 19, 22, 25, 26, 28, 31, 35-38, 40, 43, 46-49, 51-56, 58, 60, 62-63, 71-72, 78, 81, 83-84, and 87-90 all exhibit activity against MR receptors. They exhibit good activity; among them, compounds 16, 36, 46, 52, 53, 60, 62-63, 71-72, and 78 have activity against MR receptors comparable to the positive control drug phenelzine; while compounds 1-2, 6, 28, 31, 37, 54-55, 58, 81, 83-84, and 90 have significantly better activity against MR receptors than the positive control drug phenelzine.

[0495] The chemical structural formula of the active ingredient fenelone is shown in Formula IV:

[0496] Formula IV Its chemical name is: (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide.

[0497] II. Compound Receptor Selectivity Test Experiment (1) Single-luciferase reporter gene assay targeting AR receptor Experimental procedure: S1: Cell Culture HEK293T cells were cultured at 5% CO2 and 37°C. o C. Cultured under humid conditions in DMEM medium (brand: Gibco), which contains 10% fetal bovine serum (brand: Gibco), 100 units / mL penicillin G, and 100 μg / mL streptomycin sulfate (brand: Keygen) to obtain complete DMEM medium.

[0498] S2: HEK293T cells were transiently transfected with hAR / pcDNA3.1(+) and ARE / pGL3-basic plasmids. HEK293T cells were seeded in 6-well plates (6 × 10⁵ cells / well) one day before transfection, with 2 mL of DMEM complete medium per well, and cultured for 12–24 hours to 80%–90% cell density. The plasmid (hAR / pcDNA3.1(+):ARE / pGL3-basic = 1:5) and Lipofectamine® 2000 (Invitrogen) were dissolved separately in serum-depleted medium (Opti-MEM, Gibco) at a 1:1 volume ratio to form a DNA-liposome complex. The mixture was incubated at room temperature for 5 minutes. The original HEK293T cell culture medium was then replaced with Opti-MEM medium. Subsequently, 250 μL of the DNA-liposome complex was added dropwise to each well, resulting in a final plasmid volume of 2500 ng / well and a final Lipofectamine® 2000 volume of 9 μL / well. After 6 hours, the original culture medium was replaced with DMEM complete medium, and the cells were cultured for another 12–24 hours.

[0499] S3: Detection of the compound's activity against cellular AR transcriptional repression HEK293T cells transiently expressing hAR (human androgen receptor gene) and luciferase reporter gene were collected and resuspended in DMEM complete medium at 5 × 10⁵ cells / mL. 20 μL of the cell suspension and 20 μL of 2× the test compound were seeded into 384-well white-background cell culture plates. After incubation for 30 minutes, methyltrienolone (R1881 agonist, 1 nM) was added, and the plates were incubated at 5% CO₂ and 37°C. o C. Incubate under humid conditions for 24 hours, then remove the 384-well cell culture plate with a white background and allow it to equilibrate to room temperature for 30 minutes. Add 40 μL of the One-Lite assay reagent from the One-Lite Luciferase Assay System (Vazyme) to each well. Allow the cells to fully lyse at room temperature for at least 3 minutes. Then, read the full-wavelength fluorescence signal using SpectraMaxi3X. Calculate the IC50 of the test compound by fitting the inhibitor dose-response curve using a 4-parameter nonlinear regression program in GraphPad Prism 8. 50 value.

[0500] Using fenelazol (batch number: Fin-20230724) as a positive control, the cell viability versus drug concentration curves of compounds 46 and 55, as well as fenelazol, were determined. The experimental results are as follows: Figure 1 As shown.

[0501] Experimental conclusion: The flatter the curve in the graph, the higher the selectivity of the compound for the AR receptor. These results indicate that, in experiments targeting the AR receptor, compounds 46 and 55 exhibited superior selectivity for the AR receptor compared to the positive control drug fenelone.

[0502] (2) Single-luciferase reporter gene assay targeting the GR receptor Experimental procedure: S1: Cell Culture HEK293T cells were cultured at 5% CO2 and 37°C. o C. Cultured under humid conditions in DMEM medium (Gibco), which contains 10% fetal bovine serum (Gibco), 100 units / mL penicillin G, and 100 μg / mL streptomycin sulfate (Keygen) to obtain complete DMEM medium.

[0503] S2: HEK293T cells were transiently transfected with hGR / pcDNA3.1(+) and GRE / pGL3-basic plasmids. HEK293T cells were seeded in 6-well plates (6 × 10⁵ cells / well) one day before transfection, with 2 mL of DMEM complete medium per well, and cultured for 12–24 hours to 80%–90% cell density. The plasmid (hGR / pcDNA3.1(+):GRE / pGL3-basic = 1:5) and Lipofectamine® 2000 (Invitrogen) were dissolved separately in Opti-MEM (Gibco) medium at a 1:1 volume ratio to form a DNA-liposome complex. The mixture was incubated at room temperature for 5 minutes. The original HEK293T cell culture medium was then replaced with Opti-MEM medium. Subsequently, 250 μL of the DNA-liposome complex was added dropwise to each well. The final plasmid volume was 2500 ng / well, and the final Lipofectamine® 2000 volume was 9 μL / well. After 6 hours, the original culture medium was replaced with DMEM complete medium, and the cells were cultured for another 12–24 hours.

[0504] S3: Detection of the compound's inhibitory activity on cellular GR transcriptional activity HEK293T cells transiently expressing hGR (human glucocorticoid receptor) and luciferase reporter genes were collected and resuspended in DMEM complete medium at 5 × 10⁵ cells / mL. 20 μL of cell suspension and 20 μL of the test compound were seeded into 384-well white-background cell culture plates. After incubation for 30 minutes, dexamethasone ligand (0.5 nM) was added, and the plates were incubated at 37 °C under humid conditions for 24 hours at 5% CO₂. The plates were then removed and allowed to equilibrate to room temperature for 30 minutes. 40 μL of the One-Lite Luciferase Assay System (Vazyme) reagent was added to each well, and the cells were allowed to lyse at room temperature for at least 3 minutes. The full-wavelength fluorescence signal was then read using SpectraMaxi3X. The IC50 of the test compound was calculated by fitting the inhibitor dose-response curve using a 4-parameter nonlinear regression program in GraphPad Prism 8. 50 value.

[0505] Using fenelazol (batch number: Fin-20230724) as a positive control, the cell viability versus drug concentration curves of compounds 46 and 55, as well as fenelazol, were determined. The experimental results are as follows: Figure 2 As shown.

[0506] Experimental conclusion: The flatter the curve in the graph, the higher the selectivity for the AR receptor. These results indicate that, in experiments targeting the GR receptor, compounds 46 and 55 exhibited superior selectivity for the GR receptor compared to the positive control drug fenelone.

[0507] III. Liver microsomal stability test Experimental process This study used diclofenac as a positive control to investigate the stability of liver microsomes in humans and rats. The liver microsome incubation solution contained 100 mM phosphate buffer (pH 7.4), 0.5 mg / mL human or rat liver microsomes, 1 µM of the test compound, and the positive control drug diclofenac. Three replicates were prepared for each test compound. The liver microsome incubation solution was placed in petri dishes and incubated at 37°C. o Preheat at 37°C for 5 minutes, then add reduced coenzyme II (NADPH) regeneration solution to begin the reaction. Incubate at 37°C. oThe mixture was incubated in a water bath at C. At 0, 5, 15, 30, and 60 minutes, 300 µL of a cold mixture of methanol and acetonitrile (v / v) containing the internal standard IS (50 ng / mL labetalol, 50 ng / mL toluenebutyramide) was added to stop the reaction. The sample was centrifuged at 4000 rpm for 10 minutes, and 100 µL of the supernatant was mixed with 100 µL of water for high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis. The in vitro half-life (t) was calculated. 1 / 2 The metabolic stability of a drug is described by its intrinsic clearance rate (CLint in vitro, in µL / min / mg protein).

[0508] In the metabolic stability assay of liver microsomes, the zero-time concentration of the analyte was taken as 100%, and the remaining percentage was obtained by comparing the concentration at each time point with the zero-time concentration. The natural logarithm of the substrate remaining percentage at each time point was linearly regressed with the incubation time to obtain the slope (k).

[0509] In vitro half-life (t 1 / 2 The slope value k determines t. 1 / 2 (min) = -(0.693 / k) In vitro half-life t 1 / 2 The formula for converting to intrinsic clearance rate (CLint) (average of repeated measurements): CLint (mL / min / kg) = (0.693 / t) 1 / 2 )×(1 / (microsomal protein concentration (0.5 mg / mL))×scaling factor Scaling factor = (microsomal protein per gram of liver) × (liver weight per kilogram of body weight) Using fenelitone (batch number: Fin-20230724) as a positive control, the liver microsomal stability data of some preferred compounds and fenelitone were determined. The experimental results are shown in Table 2.

[0510] Table 2. Experimental data on liver microsome stability

[0511] Experimental conclusion: The above results indicate that a low intrinsic clearance rate (CLint) suggests good stability. In the human liver microsomal stability experiment, compounds 7, 18, 25, 37, 38, 47, 54, 55, and 90 showed better stability than the positive control drug fenelone. In the mouse liver microsomal stability experiment, compounds 1-2, 47, 53, 37, and 90 showed good stability, and compounds 1-2, 47, 53, and 90 were all superior to the positive control drug fenelone.

[0512] IV. Drug Metabolism and Kinetic Studies Experimental procedure: This experiment aimed to evaluate the pharmacokinetic behavior of the test compound in rats after intravenous injection or gavage administration. For intravenous injection, a clear solution of the test compound at a concentration of 0.2 mg / mL was prepared using 10% ethanol, 40% polyethylene glycol 400, and 50% water as solvents. Plasma samples were collected at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. For gavage administration, a clear solution of the test compound at a concentration of 1 mg / mL was prepared using 10% ethanol, 40% polyethylene glycol 400, and 50% water as solvents. Plasma samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration.

[0513] The concentration of the analyte in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention times of the analyte and the internal standard (tolbutamide), chromatographic acquisition, and chromatographic integration were processed using Analyst (Applied Biosystems) software. Statistical analysis of the data was also performed using Analyst (Applied Biosystems) software.

[0514] Plasma concentrations were processed using a non-compartmental model of WinNonlin™ Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method.

[0515] Using fenelone (batch number: Fin-20230724) as a positive control, the pharmacokinetic parameters of the test compound and the positive control were obtained by intravenous injection of 1 mg / kg and oral gavage of 5 mg / kg in rats, as shown in Table 3.

[0516] Table 3. Pharmacokinetic (PK) data in rats

[0517] Experimental conclusion: The above results indicate that, in rat pharmacokinetic experiments, compounds 46 and 55 were superior to the positive control drug fenelone in terms of half-life, peak plasma concentration, area under the curve (exposure), and bioavailability. Specifically, their exposure and peak plasma concentration were significantly better than those of fenelone.

[0518] V. In vivo CYP enzyme activity study experiment Experimental process Prepare the substrate solution according to Table 4. The liver microsome incubation solution contains 100 mM phosphate buffer solution at pH 7.4, 0.2 mg / ml human liver microsomes, and the substrate solution.

[0519] Working solutions of compounds 46, 55, and the positive control fenelone were prepared with dimethyl sulfoxide (DMSO) at concentrations of 0.05 µM, 0.15 µM, 0.5 µM, 1.5 µM, 5 µM, 15 µM, and 50 µM. Two parallel samples were prepared for each concentration of the working solution of compounds 46, 55, and the positive control.

[0520] Table 4 Preparation of substrate solutions

[0521] Working solutions of compounds 46 and 55 at different concentrations and the positive control drug fenelone were incubated with liver microsomal incubation medium at 37°C. o Incubate in a C-water bath. After pre-incubation, add reduced coenzyme II (NADPH) regeneration solution to all samples to initiate the reaction, and incubate in a water bath for 20 minutes. Quench the reaction with 200 µL of termination solution. Centrifuge at 3220 g for 10 minutes. Take 400 µL of supernatant for LC-MS / MS analysis. Data processing: Check the automated peak integration region of all samples and detect peak area. Export analyte peak area and internal standard peak area to an Excel spreadsheet. The inhibitory effect of each P450 enzyme in human liver microsomes compared with the uninhibited DMSO blank control group was measured by the percentage reduction in labeled metabolite formation activity (= 100% activity). Curves were fitted using a 4-parameter nonlinear regression program, and IC50 values ​​were calculated using GraphPad Prism 8. The Select. value was calculated as the ratio of the IC50 value of CYP enzyme to the IC50 value of MR inhibition.

[0522] Using fenelone (batch number: Fin-20230724) as a positive control, the CYP enzyme activity of some selected compounds and fenelone was determined. The experimental results are shown in Table 5.

[0523] Table 5. Data from in vivo CYP enzyme activity studies

[0524] Experimental conclusion: The above results indicate that inhibition of CYP enzymes leads to increased drug concentrations in the body, potentially causing toxic reactions. Therefore, the weaker the inhibitory effect on CYP enzymes, the higher the safety of the compound. Compounds 46 and 55 exhibited higher half-maximal inhibitory concentrations (IC50) against two subtypes of the major metabolic enzyme CYP3A4 (which metabolizes approximately 50% of drugs) in the human body, CYP3A4-Midazolam / CYP3A4-Testosterone. Compounds 46 and 55 also demonstrated higher safety compared to the positive control drug fenelone.

[0525] VI. In vivo efficacy study experiments Experiment 1: Detection of the antagonistic activity of the compound against MR in vivo Experimental process Male Wistar rats (approximately 300g) were acclimatized for one week and then randomly divided into groups of 3 rats each. The control group was given a normal maintenance diet (NaCl 0.9%) and free access to water, while the model group was given a low-salt maintenance diet (NaCl 0.02%) and free access to water. After 72 hours of feeding, all rats were placed individually in metabolic cages and administered a solvent or a compound of the corresponding concentration (10mg / kg, 3mg / kg, 1mg / kg) by gavage. The blank solvent consisted of 10% ethanol, 40% polyethylene glycol, and 50% water. The experimental groups and drug administration details are shown in Table 6.

[0526] Table 6. Grouping and Dosing of In Vivo MR Antagonistic Activity Experiments

[0527] Urine was collected and weighed over 24 hours, and the urine-to-body weight ratio of the rats was calculated. Blood was collected from the tail vein, and plasma was collected. The concentrations of sodium and potassium ions in urine and blood were measured to assess the antagonistic activity of the compound against MR in vivo. Results are as follows: Figure 3 , Figure 4 and Figure 5 As shown.

[0528] The formula for calculating the urine volume / body weight ratio is: Urine volume / body weight ratio = Urine volume (mL) / Body weight (kg) Experimental conclusion: The above results indicate that: Figure 3 The results showed that compounds 51, 52, and 54, at a dose of 10 mg / kg, and compound 46, at doses of 10 mg / kg and 1 mg / kg, had better diuretic effects than the positive compound fenelitonee at a dose of 10 mg / kg.

[0529] from Figure 4The results showed that compounds 37 and 51 significantly reduced blood sodium ion concentration at a dose of 10 mg / kg, while compound 52 at 10 mg / kg and compound 46 at 3 mg / kg and 10 mg / kg also reduced blood sodium ion concentration, all superior to the positive control compound fenelone. Meanwhile, from... Figure 5 The results showed that none of the administered compounds significantly increased the plasma potassium ion concentration, which was comparable to that of fenelone, indicating that the above compounds have good safety.

[0530] The results above indicate that compounds 37, 46, 51, 52, and 54 possess good in vivo MR antagonistic activity. These compounds exhibit good MR antagonistic activity; inhibition of MR reduces renal reabsorption of sodium ions, leading to a decrease in plasma sodium ion concentration.

[0531] Experiment 2: Pharmacological study of the compound on a salt-sensitive rat model of hypertensive chronic kidney disease. Experimental process Several 8-week-old salt-sensitive rats (Dahl / ss rats) and SS-Chr13BN / McwiCrl rats (SS-13BN rats), weighing between 300g and 350g, were purchased from Vital River Laboratory Animal Technology Co., Ltd. The control group consisted of SS-13BN rats, and the model group consisted of Dahl / ss rats. After one week of acclimatization, a hypertensive chronic kidney disease model was induced. The control group (SS-13BN rats) was fed a normal diet, while the model group (Dahl / ss rats) was fed a high-salt diet (8% NaCl) for 4 weeks. The experimental groupings and drug administration are shown in Table 7.

[0532] Table 7. Grouping and Dosing of Drugs in Rat Model Drug Efficacy Experiment

[0533] The administration method was gavage. The blank solvent consisted of 10% ethanol, 40% polyethylene glycol, and 50% water. The administration period was 8 weeks, once daily. Blood pressure was monitored before and after administration every week, and plasma potassium ion concentration was measured by tail vein sampling. After the last administration, rats were housed in metabolic cages, and 8-hour urine was collected. The urine was weighed, and changes in urine volume were compared. An automated analyzer was used to measure three indicators in the urine: blood urea nitrogen (BUN), creatinine, and proteinuria. The UACR was calculated to evaluate the effect of the compound on renal function. After urine collection, rats were euthanized, and kidneys and hearts were harvested, weighed, fixed in 10% formalin, embedded, and sectioned. The sections were then stained with hematoxylin and eosin (HE staining) and Masson's trichrome staining. Histopathological damage, such as vascular lesions, glomerular lesions, renal tubular degeneration, renal tubular dilation, and protein-like precipitation, was observed in the kidney tissue. Myocardial fibrosis and inflammatory infiltration were observed in the heart tissue to evaluate the protective effects of the compound on the heart and kidneys.

[0534] UACR calculation formula: UACR = Urinary albumin (mg / L) ÷ Urinary creatinine (g / L) = Urinary albumin (mg / L) ÷ Urinary creatinine (umol / L) × 8840 Experimental results: Compounds 37, 46, 51 and 52 all showed significant hypotensive effects, reduced the UACR ratio, and reduced the level of cardiac and renal inflammation in the model group rats.

[0535] Experiment 3: Study on the protective effects of compounds on the heart and kidneys of Zucker Spontaneous Fatty-1 rats with cardiorenal syndrome Experimental process Zucker Spontaneous Fatty-1 rats (ZSF1 rats) were purchased from Vital River Laboratory Animal Technology Co., Ltd. The model group consisted of obese ZSF1 rats, and the control group consisted of lean ZSF1 rats. Both rats were approximately 10 weeks old and weighed approximately 350–450 g. The experimental groupings and drug administration details are shown in Table 8.

[0536] Table 8. Experimental grouping and drug administration in the study of cardioprotective and renal protective effects in rat models.

[0537] Specifically, after one week of acclimatization, the animals were given medication via gavage. The control and model control groups received the same amount of blank solvent (10% ethanol, 40% dissolving alcohol, 50% water), while the model control group received the corresponding compound orally via gavage (10 mg / kg / day). This administration continued for 8 weeks. After the last administration, the rats were housed in metabolic cages, and 8-hour urine samples were collected and weighed to compare changes in urine volume. Echocardiography was then performed. After the echocardiography, the rats were euthanized, and their heart, kidneys, and brain tissue were harvested for histopathological examination.

[0538] Testing indicators: (1) Blood pressure was measured before and after administration every week to evaluate the antihypertensive effect of the compound; (2) Collect urine in a metabolic cage and detect three indicators: urine nitrogen, creatinine and proteinuria with a biochemical analyzer. Calculate UACR using the formula described in Experiment 2. (3) Echocardiography, including left ventricular anterior wall thickness, left ventricular end-diastolic diameter, left ventricular myocardial mass, cardiac diastolic function, and left ventricular ejection fraction, to evaluate the protective effect of the compound against cardiac injury; (4) Pathological section examination: The rats were euthanized and the heart, kidney and brain tissues were taken and subjected to HE staining, Sirius red staining and periodic acid Schiff staining (PAS staining). The kidney tissue was observed to observe pathological damage, such as vascular lesions, glomerular lesions, renal tubular degeneration, renal tubular dilation and protein-like precipitation, etc. The heart tissue was observed to observe myocardial fibrosis, inflammatory infiltration and other conditions, and the brain tissue was observed to observe microglial cell inflammatory infiltration, brain tissue lesions and other conditions, so as to evaluate the protective effect of the compound on the heart, kidney and brain.

[0539] Experimental results: Both compounds 46 and 51 were able to improve the level of cardiac and renal inflammation in rats, thus playing a protective role for the heart and kidneys.

[0540] In summary, this application synthesized a series of novel structural compounds with good affinity for MR receptors, which have broad application prospects in the preparation of drugs for the treatment, prevention or relief of diseases such as hyperaldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, cirrhosis, renal failure and stroke.

[0541] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of formula I, II, or III, or a pharmaceutically acceptable salt, stable isotope derivative, isomer, or mixture thereof. In the formula, R1 is selected from C1-C6 alkyl, halo- or deuterated C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, halo- or deuterated C3-C7 cycloalkyl, halo- or deuterated C3-C7 heterocycloalkyl, C3-C7 cycloalkenyl, C3-C8 cycloalkyl C1-C6 alkyl, halo- or deuterated C3-C8 cycloalkyl C1-C6 alkyl, C2-C5 alkenyl C1-C6 alkyl, C2-C5 allenyl C1-C6 alkyl; or R1 is a single bond; R2, R3, and R4 are each independently selected from H, deuterium, halogen, phenyl, tolyl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl, halogenated or deuterated C1-C6 alkyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C3-C6 heterocyclic alkyl, or R2 and R3 can form C3-C8 cycloolefins or heterocyclic olefins with double bonds; R5 and R6 are independently selected from H, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, aminoacyl, aminosulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkanoyl, C1-C6 alkoxyacyl, C1-C6 acylamino, C1-C6 alkenylC3-C6 cycloalkyl, halogenated or deuterated C1-C6 alkyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C1-C6 alkoxy, C6-C 10 Aryl, heterocyclic groups consisting of 3-8 atoms, and heteroaryl groups consisting of 5-10 atoms; R9 is independently selected from H, halogen, cyano, or C1-C6 alkyl, or halogenated or deuterated C1-C6 alkyl; R7 is selected from halogens, C1-C3 alkyl groups, halogenated or deuterated C1-C3 alkyl groups, C1-C3 alkoxy groups, C1-C3 alkoxy-C1-C3 alkyl groups, and C1-C3 alkylamino-C1-C3 alkyl groups. R8 is selected from CN-, aminoacyl, aminosulfonyl, aminophosphonic acid, aminoC3-C6 cycloalkyl, aminoC3-C6 heterocycloalkyl, aminoC 1- C5 alkyl, amino halogenated C 1- C5 alkyl, C 1- C5 alkylamino, halogenated or amino-substituted C 1- A C5 alkylamino group or a heteroaryl group consisting of 5-10 atoms. , , ;in, The amino hydrogen in the aminoacyl, aminosulfonyl, and aminophosphonic acid groups is either not substituted or is replaced by R. z Substitution, Rz is selected from halogen, hydroxyl, amino, carbamoyl, C1-C3 alkoxy, C3-C6 cycloalkyl, heterocyclic group composed of 3-8 atoms, or amino group in which 2 hydrogens are replaced and form a 5-6 membered heterocycle with N atom; Or R7 and R8 can form a C3-C8 heterocycle; R 10 Selected from H, deuterium, halogens or C1-C3 alkyl groups, R 11 Selected from C1-C3 alkoxy, or halogenated C1-C3 alkoxy, C3-C5 cycloalkoxy; Or R 10 and R 11 Formation of C5-C8 cyclic hydrocarbons or C5-C8 heterocyclic hydrocarbons; X is either O or S; Y1 and Y2 are independently C or N, where Y1 and Y2 are not simultaneously N; Z is selected from C3-6 cycloalkyl-C1-3 alkyl, C3-C7 cycloalkenyl, bicycloalkyl-C1-C3 alkyl, and azide-C1-C3 alkyl. or The hydrogen in C3-6 cycloalkyl C1-3 alkyl and bicycloalkyl C1-C3 alkyl is either not substituted or is substituted by halogen, deuterium or C1-3 alkyl.

2. The compound as claimed in claim 1, or its pharmaceutically usable salts, stable isotope derivatives, isomers, and mixtures thereof, characterized in that, R1 is selected from C1-C4 alkyl, halo- or deuterated C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, halo- or deuterated C3-C6 cycloalkyl, halo- or deuterated C3-C6 heterocycloalkyl, or C3-C6 cycloalkyl C1-C3 alkyl, halo- or deuterated C3-C6 cycloalkyl C1-C3 alkyl, halo- or deuterated C2-C5 alkenyl C1-C3 alkyl, C2-C5 allenyl C1-C3 alkyl, or R1 is a single bond; R2, R3, and R4 are each independently selected from H, deuterium, halogen, phenyl, tolyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl, halogenated or deuterated C1-C3 alkyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C3-C6 heterocyclic alkyl, or R2 and R3 can form C3-C8 cycloolefins or heterocyclic olefins with double bonds; R5 and R6 are independently selected from H, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, C1-C4 alkyl, or halogenated or deuterated C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkanoyl, C1-C4 alkoxyacyl, C1-C4 acylamino, C1-C3 alkenyl C3-C6 cycloalkyl, heterocyclic groups consisting of 3-6 atoms, and heteroaryl groups consisting of 5-6 atoms; The R 10 and R 11 Formation of C5-C8 cyclic hydrocarbons or C5-C8 heterocyclic hydrocarbons, wherein the C5-C8 heterocyclic hydrocarbons are or .

3. The compound as claimed in claim 1, or its pharmaceutically usable salts, stable isotope derivatives, isomers, and mixtures thereof, characterized in that, R1 is a single bond or selected from the following groups, where any hydrogen atoms on each group are not substituted, or any 1-4 hydrogen atoms are substituted with halogens or deuterium: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, , , , , , , or ; R2, R3, and R4 are independently H, deuterium, F, Cl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, and epoxyethyl, respectively. R5 and R6 are independently selected from H, F, Cl, methyl, ethyl, propyl, cyclopropyl, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, methoxy, ethoxy, formyl, dimethylamino, methanesulfonyl, cycloethoxy, vinylcyclopropyl, carbamoyl, aminoacetyl, methoxyacyl, propoxyacyl, formylamino, acetylamino. ; R9 is selected from H, F, chloro, cyano, methyl, propyl, and ethyl. R7 is selected from F, Cl, methyl, ethyl, propyl, methoxymethyl, and methylaminomethyl. R8 is selected from CN-, , , , , , , , , , , , , , , , , , , , or ; Alternatively, R7 and R8 can form a C3-C8 heterocycle, where the C3-C8 heterocycle is... ; R 10 Selected from H, deuterium, methyl, ethyl, or propyl; R 11 Selected from ethoxy, methoxy, and cyclopropoxy; Or the R 10 and R 11 form or ; Z is selected from methyl, ethyl, , , , , , , , azide-methyl, azide-ethyl, azide- , , , , , , , , , , , , , , , , , , or .

4. The compound according to any one of claims 1-3, or its pharmaceutically usable salt, stable isotope derivative, isomer, or mixture thereof, characterized in that, The compound has a structural formula as shown in formula Ia or Ib, formula IIa or IIb, or formula IIIa or IIIb, with the preferred formulas being Ib, IIb, or IIIb. or .

5. The compound according to any one of claims 1-4, or its pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, characterized in that, The compound is: In the formula, R1 is selected from the following unsubstituted, deuterated or halogenated groups: C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl, C1-C3 alkyl; R4 is selected from H, deuterium, halogen, methyl, halomethyl or deuterated methyl; R5, R6 and R9 are each independently selected from H, halogens, or C1-C3 alkyl groups, or halogenated or deuterated C1-C3 alkyl groups.

6. The compound as claimed in claim 5, or its pharmaceutically usable salts, stable isotope derivatives, isomers, and mixtures thereof, characterized in that, R1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, , , , , , It may be a single bond; R4 is H, deuterium, F, chloro, or methyl; R5 and R6 are independently selected from H, halogen, methyl or ethyl; R9 is selected from H, halogen or methyl.

7. The compound of claim 6 or its pharmaceutically usable salt, stable isotope derivative, isomer, and mixture thereof, characterized in that, X is O; R6 is methyl or propyl, and R5 is hydrogen, fluorine or chlorine; R7 is ;R 11 It is a methoxy group.

8. The compound according to any one of claims 1-4, or its pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, characterized in that, The compound is: In the formula, R1 is selected from C1-C6 alkyl, C1-C6 alkenyl, halogenated or deuterated C1-C6 alkyl, halogenated or deuterated C1-C6 alkenyl, C3-C6 cycloalkyl, C3-C7 cycloalkenyl, halogenated or deuterated C3-C6 cycloalkyl, halogenated or deuterated C3-C7 cycloalkenyl, or C3-C6 cycloalkyl-C1-C3 alkyl. R2, R3, and R4 are each independently selected from H, deuterium, halogen, phenyl, C1-C3 alkyl, halogenated, or deuterated C1-C3 alkyl.

9. The compound of claim 8 or its pharmaceutically usable salt, stable isotope derivative, isomer, and mixture thereof, characterized in that, In the formula, R1 is a group selected from the following unsubstituted, halogenated, or deuterated groups: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, , , , , , , or . R2 is H, deuterium, F, Cl, methyl, or ethyl; R3 and R4 are independently H, deuterium, F, Cl, methyl, ethyl or phenyl, wherein R3 and R4 are not both phenyl; R 10 Selected from H, deuterium, halogen, methyl or ethyl, R 11 It is a methoxy group; R7 is methyl, R8 is CN-, , , or R8 preferred .

10. The compound according to any one of claims 1-4, or its pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, characterized in that, The compound is: Z is selected from azidomethyl, azidoethyl, bicyclo[1,1,1]pentylmethylene, or .

11. The compound of claim 10 or its pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof, characterized in that, R 10 Selected from H, deuterium, halogen, methyl or ethyl, R 11 Selected from methoxy groups; R7 is methyl, R8 is CN-, , , or .

12. The compound of claim 1 or its pharmaceutically usable salt, stable isotope derivative, isomer, and mixture thereof, characterized in that, The compound is selected from:

13. A pharmaceutical composition, characterized in that, It comprises a pharmaceutically acceptable carrier, excipient, or combination thereof, and as an active ingredient the compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stable isotope derivative, isomer, or mixture thereof; it further comprises one or more other active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, β-receptor blockers, acetylsalicylic acid, diuretics, calcium channel blockers, statins, digitalis derivatives, calcium sensitizers, nitrates, and antithrombotic agents.

14. The pharmaceutical composition according to claim 13, characterized in that, The dosage form of the pharmaceutical composition is a pharmaceutically acceptable dosage form, including tablets, granules, capsules, powders, or injections.

15. The compound of any one of claims 1-5 or its pharmaceutically usable salt, stable isotope derivative, isomer and mixture thereof, or the pharmaceutical composition of any one of claims 13-14, for use in the treatment, prevention or relief of patients with the following conditions: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

16. Use of the compound according to any one of claims 1-12 or the pharmaceutical composition according to claim 13 or 14 in the preparation of a medicament, wherein, The drug is used as a mineralocorticoid receptor antagonist.

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