Quinoline derivatives, processes for their preparation and uses thereof

Abstract

Disclosed are quinoline derivatives, methods for their preparation, and uses thereof. The compounds are of the formula (I), or each optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This invention belongs to the fields of pharmacology, medicinal chemistry and pharmacology, and more specifically, relates to quinoline derivatives and their preparation methods, and the use of such compounds to treat diseases caused by Mycobacterium tuberculosis infection, especially drug-resistant Mycobacterium tuberculosis. Background Technology

[0002] Tuberculosis is caused by infection with Mycobacterium tuberculosis (Mtb) and is one of the oldest diseases in human history.

[0003] In light of the above, there is an urgent need to develop novel anti-tuberculosis drugs. Such novel drugs should possess the following characteristics: effectiveness against drug-resistant bacteria, especially multidrug-resistant bacteria; compatibility with currently used first-line anti-tuberculosis drugs; ideal metabolic properties; and oral administration capability.

[0004] WO2004 / 011436 discloses many diarylquinoline anti-tuberculosis compounds, among which bedaquiline (TMC207) is a representative compound. Bedaquiline kills Mycobacterium tuberculosis by acting on the ATP synthase proton pump on the mitochondrial cell membrane of Mycobacterium tuberculosis, disrupting the coupling between transmembrane proton transport and ATP synthesis, and interfering with ATP synthesis in Mycobacterium tuberculosis. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved it as part of the combination therapy for multidrug-resistant tuberculosis in adults in late 2012 and March 2014, respectively. Due to its unique mechanism of action, strong anti-tuberculosis activity, no cross-resistance with other existing tuberculosis drugs, and good bactericidal activity against both replicating and non-replicating Mycobacterium tuberculosis, it has good clinical efficacy and was listed by the WHO as a first-line drug for the treatment of rifampin-resistant and multidrug-resistant tuberculosis at the end of 2017.

[0005]

[0006] However, like most other anti-tuberculosis drugs, bedaquiline has significant drawbacks, such as causing QTc interval prolongation on electrocardiograms, which may lead to serious cardiac safety risks. It is also noteworthy that the mortality rate in the bedaquiline group (12.7%) was higher than that in the placebo group (2.5%) in the phase 2 clinical trial C208, but the specific reasons are unclear. Currently, patients using bedaquiline still require frequent monitoring of their electrophysiological status and drug safety response throughout their 18-20 month treatment cycle. Furthermore, low bioavailability, significant hepatotoxicity, and drug-induced phospholipid disease are all side effects that limit the use of this novel mechanism drug in tuberculosis patients. In August 2019, the FDA announced the approval of pretomanid, developed by the non-profit organization TB Alliance, for use in combination with bedaquiline and linezolid to treat certain highly drug-resistant pulmonary tuberculosis (TB) patients. The QTc interval prolongation problem reported in clinical practice has been attributed to bedaquiline.

[0007] Therefore, there is an urgent need in this field to develop a new class of quinoline compounds that have better efficacy and safety than bedaquiline for the treatment of diseases caused by Mycobacterium tuberculosis, especially drug-resistant Mycobacterium tuberculosis. Summary of the invention.

[0009] The purpose of this invention is to provide a novel class of anti-tuberculosis compounds with a general structural formula as shown in (Ⅰ), or optical isomers thereof, pharmaceutically acceptable inorganic or organic salts thereof; In a second aspect, the present invention provides a method for preparing a compound of formula (I), or various optical isomers thereof, or pharmaceutically acceptable inorganic or organic salts thereof.

[0010] A third aspect of the invention provides the use of the above-described compounds of the invention, or their optical isomers, or pharmaceutically acceptable inorganic or organic salts as active ingredients in the preparation of pharmaceuticals for the treatment of diseases caused by Mycobacterium tuberculosis infection, particularly multidrug-resistant Mycobacterium tuberculosis. The invention also contains pharmacologically acceptable excipients or carriers, and the compounds of formula (I) of the invention, or their optical isomers, or pharmaceutically acceptable inorganic or organic salts as active ingredients.

[0011] In a first aspect of the invention, a compound of formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, is provided:

[0012] (I)

[0013] In the formula, m represents 1, 2, 3 or 4; R 1 Selected from aryl or heteroaryl groups, the aryl or heteroaryl group is unsubstituted or has 1-4 identical or different substituents: the substituents are selected from halogens, hydroxyl groups, cyano groups, unsubstituted or alkyl groups containing 1-6 halogen atoms. 1-6 Alkyl, unsubstituted, or alkyl groups containing 1-6 halogen atoms (C) 3-6 Cycloalkyl, unsubstituted, or C-shaped alkyl groups containing 1-6 halogen atoms 1-6 Alkoxy or C 3-6 The C atoms in cycloalkoxy, unsubstituted, or alkyl groups are replaced by 1-6 halogen atoms. 1-6 An alkylthio group, or two adjacent substituents linked together to form a five- or six-membered ring; R 2 and R 3 Whether identical or different, each is independently selected from: hydrogen, unsubstituted or alkyl groups substituted with 1-3 halogen atoms. 1-6 alkyl; R 4 Selected from aryl or heteroaryl groups, the aryl or heteroaryl group is unsubstituted or has 1 to 3 identical or different substituents selected from the following: halogen, unsubstituted, or C containing 1 to 6 halogen atoms on the alkyl group. 1-6 Alkyl, unsubstituted, or alkyl groups containing 1-6 halogen atoms (C) 3-6 Cycloalkyl, unsubstituted, or C-shaped alkyl groups containing 1-6 halogen atoms 1-6 Alkoxy; R 5 The substituent is non-directed and is selected from hydrogen, halogen, cyano, hydroxyl, C 1-4 alkoxy, or C 1-4 Alkylthio; R 6 Selected from unsubstituted or alkyl groups containing 1-6 halogen atoms C 1-6 The C-axis of the alkoxy group, or the unsubstituted or alkyl group, contains 1-6 halogen atoms. 1-6 Alkylthio group.

[0014] In another embodiment, the R 1 The substituents on the aryl or heteroaryl groups are selected from unsubstituted or C-shaped groups containing 1-3 halogen atoms on the alkyl group. 1-3 Alkyl, unsubstituted, or alkyl groups containing 1-3 halogen atoms (C) 1-3 An alkoxy group, or two adjacent substituents, are linked together to form a five-membered ring.

[0015] In another embodiment, the R 1 The halogen in the substituents on the aryl or heteroaryl group is fluorine or chlorine.

[0016] In another embodiment, the R 1The alkoxy group in the substituents of the aryl or heteroaryl group is a methoxy group.

[0017] In another embodiment, the R 1 The aryl or heteroaryl group has one, two, or three substituents.

[0018] In another embodiment, the R 1 The aryl or heteroaryl groups represented are selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, or thiopheneyl.

[0019] In another embodiment, the R 2 and R 3 Each C is independently selected from: C substituted with one to three halogens or unsubstituted C . 1-3 alkyl.

[0020] In another embodiment, the R 4 Selected from pyridyl or benzoxazole.

[0021] In another embodiment, the R 4 The substituents on the aryl or heteroaryl groups are selected from unsubstituted or C-shaped groups containing 1-3 halogen atoms on the alkyl group. 1-3 alkyl.

[0022] In another embodiment, the R 5 Selected from halogens or cyano groups.

[0023] In another embodiment, R 6 Selected from unsubstituted or alkyl groups containing 1-3 halogen atoms C 1-3 Alkyl group.

[0024] This invention provides a compound, or its optical isomers, or pharmaceutically acceptable salts thereof, said compound being selected from:

[0025] In another embodiment, the optical isomer of the compound is A-1, A-2, B-1, or B-2 configurations; preferably, the A-1 configuration.

[0026] .

[0027] In a second aspect of the invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and as an active ingredient a compound provided by the present invention as described above, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0028] In a third aspect of the invention, there is provided the use of the compound provided by the present invention as described above, or its optical isomers, or pharmaceutically acceptable salts, for the preparation of a preparation of a compound that inhibits Mycobacterium tuberculosis (…). Mycobacterium tuberculosis The composition of growth.

[0029] In a fourth aspect of the invention, there is provided the use of the compound provided by the present invention as described above, or its optical isomers, or pharmaceutically acceptable salts, for the preparation of a medicament for treating infections.

[0030] In another embodiment, the infection is Mycobacterium tuberculosis (Mycobacterium tuberculosis) Mycobacterium tuberculosis Infection; preferably, the infection is a drug-resistant tuberculosis infection.

[0031] In a fifth aspect of the invention, a method for preparing a compound of formula I is provided, the method comprising the steps of: (1) The compound shown in Formula II undergoes a nucleophilic substitution reaction to obtain the compound shown in Formula III; (2) The compound shown in Formula III reacts with an allyl metal reagent to form a tertiary alcohol; (3) The tertiary alcohol undergoes dihydroxylation in the presence of an oxidizing agent, followed by cleavage to yield the compound shown in formula V; and (4) The compound shown in Formula V is reduced to a primary alcohol, which is then activated and reacted with the corresponding amine to generate the compound shown in Formula I.

[0032] In each formula, R 1 R 2 R 3 R 4 R 5 R 6 The definitions of m and equation (Ⅰ) are the same.

[0033] In another embodiment, the compound of formula V is reacted with the corresponding amine to produce the compound of formula I; .

[0034] Accordingly, the present invention provides a new class of quinoline compounds that have better efficacy and safety than bedaquiline, for the treatment of diseases caused by Mycobacterium tuberculosis, especially drug-resistant Mycobacterium tuberculosis. Detailed Implementation

[0035] Through extensive and in-depth research, the inventors synthesized and screened a large number of compounds, and for the first time discovered that the compound of formula (I) has strong inhibitory activity against Mycobacterium tuberculosis both in vitro and in vivo, making it particularly suitable for the preparation of drugs to treat diseases caused by Mycobacterium tuberculosis infection. Based on this, the present invention was completed.

[0036] The names and structural formulas of representative compounds (or their salts) represented by formula (I) of this invention are shown in the table below:

[0037] (I)

[0038] Unless otherwise specified, the following terms used in the specification and claims shall have the following meanings: "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 8 carbon atoms. Examples include methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl.

[0039] "Cycloalkyl" refers to 3-8 membered aliphatic monocyclic rings, 4-12 membered aliphatic fused rings, 6-12 membered aliphatic bridged rings, or 6-12 membered aliphatic spirocyclic rings, in which one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, and cyclohexadiene. The cycloalkyl skeleton may have 1-3 carbon atoms replaced by the following heteroatoms or groups: -O-, -S-, -NR. 9 -(R 9 It can be H, C 1-6 Alkyl or C 1-6 cycloalkyl)

[0040] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0041] "Alkoxy" refers to an alkyl group bonded to the rest of the molecule via an ether oxygen atom. Representative alkoxy groups are those with 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes both unsubstituted and substituted alkoxy groups, especially those substituted by one or more halogens.

[0042] "Miscellaneous" refers to non-carbon atoms or groups: including -O-, -S-, -NR. 10 -(R) 10 Selected from H, C1-6 alkyl or cycloalkyl), -SO-, -SO2-, =O, and any combination thereof (such as -CONR-, -SO2NR-, -COO-, -NHCOO-, -NHCONH, etc.); the number of heteroatoms or groups can be 1-6.

[0043] "Aryl" refers to a group having at least one aromatic ring structure, that is, an aromatic ring with a conjugated π-electron system, including carbocyclic aryl and heterocyclic aryl. Substituents at different positions on an aryl group can be linked together to form a cyclic structure.

[0044] "Heteroaryl" refers to a structure in which the carbon atoms in the aryl skeleton are replaced by heteroatoms or groups. Heteroaryl groups include, but are not limited to, the following structures: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiopheneyl, furanyl, N-methylpyrroleyl, N-methylpyridinoneyl, N-methylpyrazolyl, N-methylimidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, benzofuranyl, benzothiopheneyl, indolyl, benzopyrazolyl, benzoimidazolyl, benzoisoindolone, benzothiazolyl, benzooxazolyl, benzo-1,2,3-triazolyl Quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzothiazinoneyl, benzooxazinoneyl, benzopyrimidinoneyl, pyridopyrroleyl, pyridofuranyl, pyridothiophenyl, pyridopyrazolyl, pyridoimidazoyl, pyridothiazoyl, pyridooxazolyl, pyridopyridyl, pyrido-1,2,3-triazolyl, pyridopyrazinyl, pyridopyrimidinyl, pyridopyridazinyl, pyridothiazinoneyl, pyridooxazinoneyl, pyridopyrimidinoneyl.

[0045] The term "pharmaceutically acceptable salt" as used herein includes: salts formed by compounds of general formula (I) and pharmaceutically acceptable inorganic or organic acids. These pharmaceutically acceptable inorganic or organic acids may include: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, or glutamic acid, etc.

[0046] "Integers between 1 and 3" refers to 1, 2, and 3; "Integers between 1 and 6" refers to 1, 2, 3, 4, 5, and 6.

[0047] The term "pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0048] In this invention, "active ingredient" refers to the compound represented by general formula (I), as well as pharmaceutically acceptable inorganic or organic salts of compounds of general formula (I). The compounds of this invention may contain one or more asymmetric centers and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention means including all such isomeric forms of these compounds.

[0049] Alternatively, the compounds of the present invention can be prepared by reacting them with a pharmaceutically acceptable acid in a polar protic solvent, such as methanol, ethanol, or isopropanol, to generate a pharmaceutically acceptable salt, as needed.

[0050] The term "caused by Mycobacterium tuberculosis, especially multidrug-resistant Mycobacterium tuberculosis" as used herein refers to infection caused by Mycobacterium tuberculosis that is sensitive to clinical tuberculosis drugs, resistant to a single clinical drug, resistant to multiple clinical drugs, or extensively drug-resistant Mycobacterium tuberculosis.

[0051] The terms “disease caused by Mycobacterium tuberculosis infection” or “infectious diseases caused by Mycobacterium tuberculosis” can be used interchangeably, as in this article, referring to pulmonary tuberculosis, lymph node tuberculosis, intestinal tuberculosis, bone tuberculosis, tuberculous pleurisy, and tuberculous meningitis, etc.

[0052] The compounds of this invention contain at least two asymmetric carbon atoms (optical centers), therefore racemic mixtures, diastereomers, and single isomers are all included within the scope of this invention. According to the R,S systematic nomenclature rule (Kahn-Ingle-Prelog rule), the configuration of the asymmetric carbon atom is related to the size of the substituent it is attached to. Different substituent sizes may result in different R or S values ​​for the same asymmetric carbon atom in the same series of compounds, but the spatial orientation of the substituent on the asymmetric carbon atom will not change. In the final purification and separation step of the reaction process of this invention, each target compound can be separated into two pairs of diastereomers by conventional separation methods (e.g., column chromatography or preparative thin-layer chromatography), labeled as compound A and compound B in the order of separation; each pair of diastereomers can be further separated into single enantiomers by chiral separation methods (e.g., preparative supercritical fluid chromatography (SFC) or chiral preparative HPLC), labeled as -1 and -2 in the order of separation. Four single isomers underwent multiple in vitro activity tests. A-1 showed the best activity, while some B-1 compounds exhibited weak activity. A-2 and B-2 showed virtually no activity. For example, for compound 1, after conventional separation, two pairs of diastereomers were obtained, labeled 1A and 1B, respectively. 1A, after chiral separation, yielded two single enantiomers, labeled 1A-1 and 1A-2, respectively. Similarly, 1B, after chiral separation, yielded two single enantiomers, labeled 1B-1 and 1B-2, respectively. Based on the structure of bedaquiline, its site of action, and the differences in isomer activity (Comprehensive Chirality, 2012, 54-69), and the in vitro activity test results of this invention, the spatial orientation and corresponding isomer definitions of the four single isomers involving the two key asymmetric carbon atoms are as follows:

[0053] Preparation method of the compound of the present invention

[0054] The compounds of the present invention and their various intermediates can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0055] The preparation method of the compound of general formula (I) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0056] The compounds of general formula (I) of this invention can be prepared by the following method; however, the conditions of this method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to those explained below. The compounds of this invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0057] In the preparation method of the present invention, the compound represented by formula (I) can also be prepared from compound (II) through the following steps: In the first step, compound (II) undergoes a nucleophilic substitution reaction in the presence of a base to give the key intermediate, namely compound (III). In the second step, compound (III) reacts with a suitable allyl metal reagent (e.g., but not limited to, allyl zinc) to form a tertiary alcohol, namely compound (IV). In the third step, compound (Ⅳ) undergoes dihydroxylation under a suitable oxidizing agent; The fourth step involves further cleavage under a suitable oxidizing agent to obtain compound (V); Fifth step: Compound (V) is reduced to an alcohol by a suitable reducing agent; Step 6: The primary alcohol in the alcohol obtained in step 5 is appropriately activated and then reacted with a suitable amine to obtain the target compound (Ⅰ).

[0058] The raw materials used in the first step reaction above, namely the compound of formula II, can be synthesized by referring to the method described in patent: CN201910933803.5.

[0059] The first step of the above reaction uses a compound of formula II as a starting material, under the influence of an alkali (e.g., potassium carbonate or sodium hydroxide) and a suitable temperature (e.g., 20-80°C). o Under conditions C), a nucleophilic substitution reaction occurs to yield the key intermediate, namely compound (Ⅲ).

[0060] The second step of the above reaction can be carried out using a suitable catalyst (e.g., but not limited to, CuBr.Me2S), a suitable solvent (e.g., but not limited to, anhydrous THF), and a suitable temperature (e.g., 0-75°C). o In C), it will be carried out.

[0061] The oxidants in the third step above include, but are not limited to, catalytic amounts of potassium osmium tetroxide dihydrate and N-methylmorpholine-N-oxide.

[0062] The oxidizing agents in step four above include, but are not limited to, sodium periodate.

[0063] The reducing agent in step 5 above includes, but is not limited to, sodium borohydride.

[0064] The activation of primary alcohols in step 6 above includes, but is not limited to, the formation of -OMs with MsCl; the amines used include, but are not limited to, dimethylamine.

[0065]

[0066] R 1 R 2 R 3 R 4 R 5 R 6 The definitions of m and equation (I) are the same.

[0067] The compound shown in formula (I) can also be prepared by reductive amination of the compound shown in formula (V) and the corresponding amine. This reaction is usually carried out in a suitable reducing agent (e.g., but not limited to, NaB(OAc)3), a suitable acid (e.g., but not limited to, acetic acid), a suitable solvent (e.g., but not limited to, 1,2-dichloroethane), and a suitable temperature (e.g., 0-75 °C).

[0068] R 1 R 2 R 3 R 4 R 5 R 6 The definitions of m and equation (I) are the same.

[0069] In one embodiment of the present invention, compounds 78 and 79 are prepared as follows:

[0070] Compounds 1 and 4 are coupled with a cyano reagent (e.g., zinc cyanide) in the presence of a palladium catalyst (e.g., Pd(PPh3)4), in a suitable solvent (e.g., DMF), and at a suitable temperature (e.g., 0-100 °C). o C) The reaction will proceed.

[0071] Pharmaceutical Compositions and Administration

[0072] Because the compounds of the present invention have excellent anti-tuberculosis activity, the compounds of the present invention and their optical isomers, pharmaceutically acceptable inorganic or organic salts, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat diseases caused by Mycobacterium tuberculosis, especially multidrug-resistant Mycobacterium tuberculosis infection.

[0073] The compounds of general formula (I) of this invention have a strong anti-tuberculosis effect. Compared with bedaquiline, the compounds of this invention have stronger in vitro bactericidal activity, stronger lung targeting, less potential cardiotoxicity, and excellent pharmacokinetic properties in animals. They are expected to achieve the same bactericidal effect at low or the same dosage, thus reducing treatment costs and toxicity, and improving patient compliance.

[0074] The pharmaceutical compositions of the present invention may use pharmaceutically acceptable excipients or carriers, as well as compounds of formula (I) of the present invention, or their optical isomers, or pharmaceutically acceptable inorganic or organic salts as active ingredients.

[0075] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, a quinoline compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-1000 mg of the compound of the present invention per dose, preferably 5-500 mg per dose, and more preferably 10-200 mg per dose. The safe and effective range of the compound is determined based on the age, condition, duration of treatment, and other specific circumstances of the patient.

[0076] Because the compounds of the present invention possess excellent anti-tuberculosis activity, the compounds of the present invention, their various crystal forms, pharmaceutically acceptable inorganic or organic salts, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat diseases related to Mycobacterium tuberculosis. According to the prior art, the compounds of the present invention can be used to treat tuberculosis and other infectious diseases.

[0077] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0078] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0079] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0080] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0081] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0082] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0083] When using the medicine of the present invention, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is usually 1–1000 mg, preferably 10–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0084] The main advantages of this invention include: 1. Compared with the control drug bedaquiline, the compound of the present invention has a superior in vitro bactericidal effect against Mycobacterium tuberculosis (including drug-resistant bacteria).

[0085] 2. Compared with the control drug bedaquiline, the compound of the present invention has weaker inhibition of hERG and less potential cardiotoxicity.

[0086] 3. The compounds of this invention have good metabolic properties and excellent lung targeting.

[0087] 4. Compared with the control drug bedaquiline, the compound of the present invention showed comparable in vivo bactericidal effect in mice infected with Mycobacterium tuberculosis H37Rv at the same dose. Combined with other information, this suggests that the compound of the present invention has better safety.

[0088] The above indicates that the compound of the present invention and bedaquiline can achieve the same therapeutic effect at the same dosage, which means that the compound of the present invention has better safety, lower toxicity, and better patient compliance.

[0089] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0090] The following description will elaborate on the specific aspects, characteristics, and advantages of the above-described compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples below depict specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these alterations or modifications also fall within the scope of this application.

[0091] The invention is explained in more detail in the following examples. However, it should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Experimental methods in the following examples, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages. All organic solvents used in the reactions of the examples have been treated with drying methods known in the art.

[0092] 1 ¹H NMR was recorded using a Varian Mercury 400 or 600 NMR spectrometer, and chemical shifts are expressed as δ (ppm). MS measurements were performed using a Shimadzu LC-MS-2020 mass spectrometer. Unless otherwise specified, all silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0093] The specific synthetic methods of the compounds invented above are described in detail below.

[0094] In the final purification and separation step of the reaction process of this invention, each target compound can be separated into two pairs of diastereomers by conventional separation methods (e.g., column chromatography or preparative thin-layer chromatography), labeled as compound A and compound B in the order of separation. Each pair of diastereomers can be further separated into single enantiomers by chiral separation methods (e.g., preparative supercritical fluid chromatography (SFC) or chiral preparative HPLC), labeled as -1 and -2 in the order of separation. After multiple in vitro activity tests, A-1 showed the best activity, some B-1 compounds showed weak activity, and A-2 and B-2 showed virtually no activity. For example, for compound 1, after conventional separation, two pairs of diastereomers can be labeled as 1A and 1B, respectively. After chiral separation, the two single enantiomers of 1A can be labeled as 1A-1 and 1A-2, respectively, and after chiral separation, the two single enantiomers of 1B can be labeled as 1B-1 and 1B-2, respectively.

[0095] Separation method: Column chromatography was performed using commercially available ordinary silica gel (200-300 mesh) or commercially available preparative plates, with UV-254nm detection. The eluent or developing solvent was commercially available untreated dichloromethane and methanol, with the ratio adjusted appropriately according to the polarity of the compounds.

[0096] Supercritical fluid chromatography (SFC): Instrument: SFC-200 (Thar, Waters); Column type: IG 20 250mm, 10um (Daicel); Detector: UV detector, wavelength 214nm; Temperature: 35℃; Mobile phase: CO2:EtOH (0.2% methanol ammonia) = 70:30; Flow rate: 130 g / min; Back pressure: 100 bar; Cycle time: 6.5min.

[0097] Preparation Examples

[0098] Example 1: Preparation of Compound 1

[0099] (1) Intermediate II-1 (834 mg, 2.00 mmol) (synthetic method according to patent: 201910933803.5), piperonyl chloride (680 mg, 4.00 mmol), K2CO3 (829 mg, 6.00 mmol), and KI (33 mg, 0.20 mmol) were added to acetone (10 mL), and the mixture was reacted overnight at 50 °C under Ar protection. The reaction was detected by TLC and found to be complete. After cooling to room temperature, the mixture was directly concentrated by column chromatography (petroleum ether: ethyl acetate = 30:1-20:1) to give a pale yellow solid 1-1:750 mg, with a yield of 68.2%.

[0100] Intermediate 1-1: 1 H-NMR (600 MHz, CDCl3) δ 7.71 (s 1H), 7.66 – 7.54 (m, 3H), 6.60 (s, 3H), 6.56 (d, J = 7.9Hz, 1H), 6.54-6.45 (m, 1H), 5.81 (dd, J =2.6, 1.5 Hz, 2 Hz), 5.07 (dd, J = 8.2, 6.1 Hz, 1H), 4.01 (s, 3H), 3.79 (s, 6H), 3.34(dd, J =13.9, 8.3 Hz, 1H), 2.88 (dd, J= 113.9, 6.1 Hz, 1H). ESI-Ms:551.1[M +H] + .

[0101] (2) CuBr·Me2S (27 mg, 0.1 mmol) was added to a 25 mL three-necked flask. Under Ar protection, freshly prepared tetrahydrofuran solution of allyl zinc bromide (4 mL, 3.98 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for about 5 min. Then, intermediate 1-1 (730 mg, 1.33 mmol) THF (20 mL) solution was added dropwise. After the addition was complete, the reaction was allowed to continue at room temperature for about 20 min. TLC detection (petroleum ether: ethyl acetate = 10:1) showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution (10 mL). Water (15 mL) was added, and the mixture was extracted twice with EA (2 × 20 mL). The organic phase was washed once with saturated brine (20 mL), dried, concentrated, and then subjected to column chromatography (petroleum ether: ethyl acetate = 20:1-10:1) to give a pale yellow solid 1-2: 727 mg, with a yield of 92.3%.

[0102] Intermediate 1-2: 1 H-NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.82 (d, J =1.7Hz,1H), 7.58-7.54 (m, 2H), 6.46 (s, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 6.20 (d, J = 7.2 Hz, 1H), 570-5.65 (m, 2H), 5.18-5.10 (m, 1H), 4.91 (d, J =10.5 Hz, 1H), 4.79 (d, J = 16.9 Hz, 1H), 4.01-3.97 (m, 1H), 3.94 (s, 3H), 3.91 (s, 6H), 2.88 (t, J = 14.4Hz, 1H), 2.71-2.65 (m, 2H), 1.72(dd, J =13.8,3.6Hz, 1H). ESI-Ms:593.1[M + H] + .

[0103] (3) Intermediate 1-2 (711 mg, 1.20 mmol) was dissolved in THF / H2O (10 mL / 2 mL), and K2OsO4·2H2O (21 mg, 0.05 mmol) and NMO (1.43 g, 12.20 mmol) were added. The reaction was allowed to proceed overnight at room temperature. TLC analysis (petroleum ether: ethyl acetate = 10:1) showed that the reaction was complete. The reaction was quenched with saturated sodium thiosulfate aqueous solution (20 mL), and the mixture was extracted twice with water (20 mL) and ethyl acetate (2 × 20 mL). The organic phase was washed once with saturated brine (20 mL), dried, and concentrated to obtain oil 1-3, which was directly added to the next step.

[0104] Intermediates 1-3: ESI-Ms: 627.1 [M + H] + .

[0105] (4) Intermediate 1-3 (756 mg, 1.20 mmol) was dissolved in dichloromethane (10 mL), and NaIO4 (2.40 mmol) supported on silica gel was added. The reaction was carried out at room temperature for 1 h. TLC was used to detect the reaction (petroleum ether: ethyl acetate = 5:1). The reaction was complete. The mixture was filtered, the solid was washed with dichloromethane, the filtrates were collected and combined, and the solid 1-4 was concentrated and directly added to the next step.

[0106] Intermediates 1-4: ESI-Ms: 595.1 [M + H] + .

[0107] (5) Intermediate 1-4 (714 mg, 1.20 mmol) was dissolved in MeOH (10 mL), and NaBH4 (69 mg, 1.80 mmol) was added in portions under ice bath conditions, followed by reaction at room temperature for 1 h. TLC detection (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete. The reaction was quenched with water (0.5 mL), and the product was directly concentrated and column chromatography (petroleum ether: ethyl acetate = 15:1-10:1) to give a yellow bubbly solid 1-5: 544 mg, with a yield of 76% (three-step yield).

[0108] Intermediates 1-5: 1 H-NMR (600 MHz, CDCl3) δ 8.19 (s, 1H), 7.83 (d, J = 1.8 Hz,1H), 7.58 -7.52 (m, 2H), 6.60- 6.44 (m, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.28(s, 1H), 6.20 (d, J = 8.0 Hz, 1H), 5.69 (d,J =4.9 Hz, 2H), 4.34 (s, 1H), 3.93 (s, 3H), 3.92 (s, 6H), 3.49 (d, J = 8.4 Hz, 1H), 3.34- 3.30 (m, 1H), 2.96-2.82 (m, 1H), 2.62 (dd, J = 8.4, 3.0 Hz, 1H), 1.86-1.76 (m, 1H), 1.8 (s,1H). ESI-Ms:597.1[M + H] + .

[0109] (6) Dissolve intermediates 1-5 (508 mg, 0.85 mmol) in dichloromethane (10 mL), add triethylamine (428 mg, 4.25 mmol), and add methanesulfonyl chloride (290 mg, 2.55 mmol) dropwise under ice bath conditions. React at room temperature for 1 h, and the reaction is confirmed to be complete by TLC (petroleum ether: ethyl acetate = 5:1). Add water (10 mL), extract twice with dichloromethane (2 × 10 mL), combine the organic phases, dry, and concentrate intermediates 1-6 directly to the next step.

[0110] Intermediates 1-6: ESI-Ms: 675.1 [M + H] + .

[0111] (7) Intermediate 1-6 (580 mg, 0.85 mmol) was dissolved in dimethylamine THF solution (10 mL), and the mixture was sealed and reacted overnight at 50 °C. After cooling to room temperature, the reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 300:1 - 60:1) to give compound 1A (198 mg) and compound 1B (174 mg).

[0112] Compound 1A (184 mg) was resolved by SFC to obtain compound 1A-1 (68 mg) and compound 1A-2 (75 mg).

[0113] 1 H NMR (400 MHz, CDCl3) δ: 8.31 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H),7.64-7.57 (m, 2H), 6.83-6.46 (m, 2H), 6.40 (d, J = 8.0 Hz, 1H), 6.32 (s, 1H), 6.23 (d, J = 7.7 Hz, 1H), 5.74 (d,J =3.1Hz, 2H), 4.16-4.02(m, 1H), 3.97 (s,9H), 2.94-2.84 (m, 1H), 2.64-2.61 (m, 1H), 2.23-2.16 (m, 1H), 1.92 (s, 6H),1.60-1.53 (m, 2H). ESI-Ms: 624.2[M + H] + .

[0114] Compound 1B (119 mg) was resolved by SFC to obtain compound 1B-1 (48 mg) and compound 1B-2 (42 mg).

[0115] 1 H NMR (600 MHz, CDCl3) δ: 7.95 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H),7.53-7.45 (m, 2H), 6.46 (s, 1H), 6.42 (d, J =7.9Hz, 1H), 6.33 (d, J = 6.7 Hz,1H), 6.14 (s, 2H), 5.74 (s, 2H), 3.90-3.92(m, 1H), 3.70 (s, 6H), 3.68 (s,3H), 3.14-3.05 (m, 1H), 2.89-2.84 (m, 1H), 2.29-2.27 (m, 1H), 2.01 (s, 6H),1.67-1.61 (m, 2H). ESI-Ms: 624.2[M + H] + .

[0116] Example 2: Preparation of Compound 2

[0117] Compound 2 was prepared using the same method as in Example 1, yielding compounds 2A (114 mg) and 2B (103 mg).

[0118] 2A (114 mg) was split by SFC to obtain 2A-1 (43 mg) and 2A-2 (37 mg).

[0119] 1 H NMR (400 MHz, CDCl3) δ: 8.30 (s, 1H), 7.89 (d, J= 2.0 Hz, 1H),7.65-7.57 (m, 2H), 6.88 (s, 2H), 6.44 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 2.0Hz, 1H), 6.29-6.24 (m, 1H), 4.07 (s, 4H), 3.98 (s, 3H), 3.96 (s, 7H), 2.94-2.85 (m, 1H), 2.66-2.58 (m, 1H), 2.24-2.14 (m, 1H), 1.92(s, 6H), 1.45-1.40(m, 2H). ESI-Ms: 638.2[M + H] + .

[0120] 2B (85 mg) was split by SFC to obtain 2B-1 (26 mg) and 2B-2 (29 mg).

[0121] 1 H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.53-7.45 (m, 2H), 6.40 (s, 1H),,6.24 (s, 2H), 4.02 (s, 4H), 3.95 (s, 3H)3.93 (s, 7H), 2.97-2.89 (m, 1H), 2.70-2.61 (m, 1H), 2.31-2.25 (m, 1H), 1.97(s, 6H), 1.49-1.43 (m, 2H).ESI-Ms:638.2[M + H] + .

[0122] Example 3: Preparation of Compound 3

[0123] Compound 3 was prepared using the same method as in Example 1, yielding compounds 3A (82 mg) and 3B (89 mg).

[0124] 3A (82 mg) was split by SFC to obtain 3A-1 (28 mg) and 3A-2 (32 mg).

[0125] 1 H NMR (400 MHz, CDCl3) δ: 8.35 (s, 1H), 7.83 (d, J= 2.0 Hz, 1H),7.63-7.55 (m, 2H), 6.85 (s, 2H), 6.59 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 2.0Hz, 1H), 6.28-6.24 (m, 1H), 4.13 (d, J = 12Hz, 1H), 3.98 (s, 6H), 3.91 (s,3H), 3.71 (s, 3H), 3.55 (s, 3H), 3.07-3.04(m, 1H), 2.68 (d, J = 12 Hz, 1H),2.30-2.21 (m, 2H), 1.96 (s, 6H), 1.53-1.47 (m, 2H). ESI-Ms:640.2[M + H] + .

[0126] 3B (89 mg) was split by SFC to obtain 3B-1 (30 mg) and 3B-2 (25 mg).

[0127] 1 H NMR (400 MHz, CDCl3) δ: 7.97(s, 1H), 7.62 (d, J = 1.8 Hz, 1H),7.51-7.44 (m, 2H), 6.47 (s, 2H), 6.40 (d, J = 7.8 Hz, 1H), 6.20-6.17 (m, 2H), 3.99 (d, J = 12Hz, 1H), 3.90 (s, 6H), 3.86 (s, 3H), 3.67 (s, 3H), 3.45 (s, 3H), 3.05-3.01(m, 1H), 2.70 (d, J = 14.4 Hz, 1H), 2.35-2.27 (m, 2H), 2.01 (s,6H), 1.57-1.49 (m, 2H). ESI-Ms:640.2[M + H] + .

[0128] Example 4: Preparation of Compound 4

[0129] Compound 4 was prepared using the same method as in Example 1, yielding compounds 4A (96 mg) and 4B (102 mg).

[0130] 4A (96 mg) was split by SFC to obtain 4A-1 (35 mg) and 4A-2 (30 mg).

[0131] 1 H NMR (600 MHz, CDCl3) δ: 8.33 (s, 1H), 7.81 (d, J =1.8 Hz, 1H), 7.61– 7.45(m, 2H), 6.89-6.44 (m, 2H), 6.38 (t, J =7.8Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.25 (d, J = 7.8 Hz, 1H), 5.67 (d, J =1.2,1H), 5.39 (d, J =1.2Hz, 1H), 4.02(dd, J = 11.8,3.9 Hz, 1H), 3.91 (s, 6H), 3.88 (s, 3H), 3.01 (dd, J = 14.4, 12Hz, 1H), 2.50 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.88 (s, 6H), 1.85-1.83 (m, 1H), 1.48-1.43 (m, 2H). ESI-Ms:624.1[M + H] + .

[0132] 4B (79 mg) was split by SFC to obtain 4B-1 (29 mg) and 4B-2 (30 mg).

[0133] 1 H NMR (600 MHz, CDCl3) δ: 7.94 (s, 1H), 7.78 (d, J =2.0 Hz, 1H), 7.58– 7.35(m, 2H), 6.82 (d, J =8.0Hz 2H), 6.35 (t, J =7.8Hz, 1H), 6.30 (d, J = 7.3Hz, 1H), 6.20 (d, J = 7.8 Hz, 1H), 5.66 (d,J =1.2,1H), 5.37 (d, J =1.2Hz, 1H), 3.98(dd, J = 12.0,4.0 Hz, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.00 (dd, J =14.4, 12 Hz, 1H), 2.46 (dd, J = 14.4, 3.8 Hz, 1H), 2.20 (s, 6H), 2.17-2.15 (m,1H), 1.85-1.83 (m, 1H), 1.45-1.40 (m, 2H). ESI-Ms:624.1[M + H] + .

[0134] Example 5: Preparation of Compound 5

[0135] Compound 5 was prepared using the same method as in Example 1, yielding compounds 5A (104 mg) and 5B (95 mg).

[0136] 5A (104 mg) was split by SFC to obtain 5A-1 (45 mg) and 5A-2 (30 mg).

[0137] 1 H NMR (400 MHz, CDCl3) δ: 8.32 (s, 1H), 7.83 (s, 1H), 7.54 (d, J =1.0Hz,2H), 6.62- 6.45(m, 4H), 6.42 (dd, J = 6.8, 2.1 Hz, 1H), 4.08 (dd, J =12.1, 3.6 Hz, 1H), 3.92 (s, 6H), 3.86 (s, 3H), 3.04 (dd, J =14.3, 12.3 Hz, 1H), 2.61 (dd, J = 14.4, 3.7Hz, 1H), 2.18-2.15 (m, 1H), 1.94 (s, 6H), 1.85-1.83(m, 1H), 1.48-1.43 (m, 2H). ESI-Ms:660.1[M + H] + .

[0138] 5B (95 mg) was split by SFC to obtain 5B-1 (40 mg) and 5B-2 (32 mg).

[0139] 1 H NMR (400 MHz, CDCl3) δ: 7.95(s, 1H), 7.80(s, 1H), 7.47 (d, J =1.8Hz,2H), 6.59- 6.35(m, 4H), 6.30 (dd, J = 8.0, 3.3 Hz, 1H), 4.04 (dd, J = 11.8,3.9 Hz, 1H), 3.90 (s, 6H), 3.83 (s, 3H), 3.03(dd, J =14.3, 12.3 Hz, 1H), 2.57 (dd, J = 14.4, 3.7Hz, 1H), 2.22-2.17 (m, 1H), 2.01 (s, 6H), 1.89-1.85 (m,1H), 1.53-1.47 (m, 2H). ESI-Ms:660.1[M + H] + .

[0140] Example 6: Preparation of Compound 6

[0141] Compound 6 was prepared using the same method as in Example 1, yielding compounds 6A (76 mg) and 6B (86 mg).

[0142] 6A (76 mg) was split by SFC to obtain 6A-1 (25 mg) and 6A-2 (23 mg).

[0143] 1 H NMR (600 MHz, CDCl3) δ: 8.43 (s, 1H), 7.89 (d, J =2.0Hz, 1H), 7.65-7.58 (m, 2H), 6.85-6.58 (m, 2H), 6.46 (dd, J =8.1,1.4Hz,1H), 6.43-6.38 (m,1H), 6.25 (dd, J= 12.2, 6.8Hz,1H),4.19- 4.16 (m, 4H), 3.98 (s, 6H), 3.94-3.97(m,1H), 3.90 (s, 3H), 3.12-3.08 (m, 1H), 2.55-2.58 (m, 1H), 2.31-2.25 (m,1H), 2.15-2.10 (m, 1H),1.98 (s, 6H), 1.70 -1.57 (m, 2H).ESI-Ms:638.2 [M + H] + .

[0144] 6B (86 mg) was split by SFC to obtain 6B-1 (30 mg) and 6B-2 (28 mg).

[0145] 1 H NMR (600 MHz, CDCl3) δ: 7.98 (s, 1H), 7.69 (d, J =1.8Hz, 1H), 7.53-7.45 (m, 2H), 6.41 (s, 1H), 6.34 (d, J =7.9Hz, 1H), 6.31-6.27 (m, 1H), 4.13-4.04 (m, 4H), 3.95 (s, 6H), 3.95-3.91(m,1H), 3.87 (s, 3H), 3.15-3.09 (m, 1H),2.56-2.53 (m, 1H), 2.33-2.27 (m, 1H), 2.16-2.13 (m, 1H),1.96 (s, 6H), 1.77 -1.60 (m, 2H). ESI-Ms:638.2[M + H] + .

[0146] Example 7: Preparation of Compound 7

[0147] Compound 7 was prepared using the same method as in Example 1, yielding compounds 7A (103 mg) and 7B (114 mg).

[0148] 7A (103 mg) was split by SFC to obtain 7A-1 (40 mg) and 7A-2 (35 mg).

[0149] 11H NMR (400 MHz, CDCl3) δ: 8.35 (s, 1H), 7.82 (s,1H), 7.59-7.52 (m,2H), 6.85-6.58 (m, 2H),6.64 (t, J =7.8Hz, 1H), 6.33(d, J =7.8Hz, 1H), 6.17 (d, J =7.6Hz, 1H), 4.34 (dd, J =16.7, 8.8Hz, 1H), 4.22 (dd, J =17.7, 8.5Hz, 1H),3.95 (dd, J =11.9, 3.0Hz, 1H), 3.91(s, 6H), 3.86(s, 3H), 2.96-2.84 (m, 2H),2.60-2.52 (m, 2H), 2.16 (dd, J = 16.9,9.6 Hz, 2H), 1.94 (s, 6H), 1.64-1.58(m, 2H). ESI-Ms:622.2[M + H] + . .

[0150] 7B (114 mg) was separated by SFC to afford 7B-1 (45 mg) and 7B-2 (40 mg).

[0151] 1 1H NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 7.74 (d, J =1.9Hz,1H), 7.49-7.44 (m, 2H), 6.80 (d, J =7.8Hz, 2H),6.48 (t, J =7.9Hz, 1H), 6.41 (d, J =7.6Hz,1H), 6.25 (s, 2H), 4.45 (ddd, J =9.9, 8.7, 7.2Hz, 1H), 4.34-4.26 (m, 1H), 3.97(dd, J =10.7, 3.9Hz, 1H), 3.73(s, 6H), 3.63 (s, 3H),3.44 (dd, J =13.7,4.0Hz,1H), 3.16 (ddd, J= 9.9, 8.7, 7.2 Hz,1H), 2.95 (dd, J = 13.7,11.0 Hz, 1H),2.82-2.71(m,1H),2.23 (s, 6H), 1.65 (d, J =11.5Hz, 2H). ESI-Ms:622.2[M + H] + .

[0152] Example 8: Preparation of Compound 8

[0153] Compound 8 was prepared using the same method as in Example 1, yielding compounds 8A (120 mg) and 8B (140 mg).

[0154] 8A (120 mg) was split by SFC to obtain 8A-1 (57 mg) and 8A-2 (49 mg).

[0155] 1 H NMR (600 MHz, CDCl3) δ: 8.37 (s, 1H), 7.82 (d, J =1.5Hz,1H), 7.57-7.50 (m, 2H), 6.85-6.58 (m, 2H),6.69 (d, J =7.3Hz, 1H), 6.51(d, J =7.6Hz, 1H), 6.39 (t, J =7.5Hz, 1H),4.33-4.33 (m, 2H),4.01-3.96 (m, 1H), 3.91 (s, 3H), 3.90(s, 6H), 3.12-3.08 (m, 1H), 2.95-2.89 (m, 1H), 2.87-2.83 (m, 1H), 2.52-2.50(m, 2H), 2.16-2.13 (m, 1H), 1.92 (s, 6H), 1.64-1.58 (m, 2H). ESI-Ms:622.2[M +H] + .

[0156] 8B (140 mg) was split by SFC to obtain 8B-1 (55 mg) and 8B-2 (50 mg).

[0157] 1H NMR (600 MHz, CDCl3) δ: 8.17 (s, 1H), 7.75 (d, J =1.5Hz,1H), 7.47-7.43 (m, 2H), 6.81 (d, J =7.8Hz, 1H), 6.47 (t, J =7.9Hz, 1H), 6.44 (d, J =7.3Hz,1H), 6.30 (s, 2H),4.30-4.27 (m, 2H),4.0-3.95 (m, 1H), 3.89 (s, 3H), 3.87 (s,6H), 3.13-3.09 (m, 1H), 2.97-2.90 (m, 1H), 2.85-2.82 (m, 1H), 2.54-2.51 (m,2H), 2.17-2.14 (m, 1H), 1.94 (s, 6H), 1.63-1.58 (m, 2H). ESI-Ms:622.2[M + H] + .

[0158] Example 9: Preparation of Compound 9

[0159] Compound 8 was prepared using the same method as in Example 1, yielding compounds 9A (110 mg) and 9B (90 mg).

[0160] 9A (110 mg) was split by SFC to obtain 9A-1 (47 mg) and 9A-2 (44 mg).

[0161] 1 H NMR (400 MHz, CDCl3) δ: 8.43 (s, 1H), 7.90 (s, 1H), 7.60 (s, 2H), 6.84-6.60 (m, 2H), 6.58 -6.52 (m, 2H), 6.28 (d, J = 7.0 Hz, 1H), 5.12 (s,1H), 4.13 (d, J = 10.3 Hz, 1H), 3.98 (s, 6H), 3.91 (s, 3H), 3.71 (s, 3H), 3.55 (s, 3H), 3.07-3.04(m, 1H), 2.68 (d, J= 13.7Hz, 1H), 2.30-2.21 (m, 2H), 1.96 (s, 6H), 1.85-1.79 (m, 1H), 1.53-1.47 (m, 1H). ESI-Ms:640.2[M + H] + .

[0162] 9B (90 mg) was split by SFC to obtain 9B-1 (32 mg) and 9B-2 (35 mg).

[0163] 1 H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.78 (s, 1H), 7.56 (s, 2H), 6.65-6.57 (m, 2H), 6.52 -6.49 (m, 1H), 6.26 (s, 2H), 4.97 (s, 1H), 4.10 (d, J = 9.2 Hz, 1H), 3.82 (s, 6H), 3.74 (s, 3H), 3.62 (s, 3H), 3.50 (s, 3H), 3.05-3.03(m, 1H), 2.70 (d, J = 12.6Hz, 1H), 2.29-2.23 (m, 2H), 1.97 (s, 6H), 1.83-1.80 (m, 1H), 1.73-1.49 (m, 1H). ESI-Ms:640.2[M + H] + .

[0164] Example 10: Preparation of Compound 10

[0165] Compound 10 was prepared using the same method as in Example 1, yielding compounds 10A (78 mg) and 10B (82 mg).

[0166] 10A (78 mg) was split by SFC to obtain 10A-1 (22 mg) and 10A-2 (24 mg).

[0167] 1 H NMR (600 MHz, CDCl3) δ: 8.33 (s, 1H), 7.82 (d, J = 1.8 Hz, 1H),7.57 – 7.50 (m, 2H), 6.89 (s, 2H), 6.39 (d, J= 7.2 Hz, 1H), 6.35 (t, J = 7.8Hz, 1H), 6.27 (d, J = 7.2 Hz, 1H), 4.12 (dd, J = 11.5, 3.9 Hz, 1H), 3.90 (s,6H), 3.88 (s, 3H), 3.65 (s, 3H), 3.09 (dd, J = 14.4, 11.6 Hz, 1H), 2.60 (dd, J = 14.0, 3.0 Hz, 1H), 2.17-2.11 (m, 1H), 1.88 (s, 6H), 1.84-1.82 (m, 1H),1.55-1.52(m, 2H).ESI-Ms:626.2[M + H] + .

[0168] 10B (82 mg) was split by SFC to obtain 10B-1 (32 mg) and 10B-2 (30 mg).

[0169] 1 H NMR (600 MHz, CDCl3) δ: 7.93 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H),7.55 – 7.40 (m, 2H), 6.65 (s, 2H), 6.31 (d, J = 7.2 Hz, 1H), 6.27 (s, 2H), 4.01 (dd, J = 11.5, 3.9 Hz, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 3.62 (s, 3H), 3.10 (dd, J = 14.4, 11.6 Hz, 1H), 2.57 (dd, J = 14.0, 3.0 Hz, 1H), 2.19-2.10(m, 1H), 1.90 (s, 6H), 1.86-1.83 (m, 1H),1.59-1.55(m, 2H). ESI-Ms:626.2[M +H] + .

[0170] Example 11: Preparation of Compound 11

[0171] Compound 11 was prepared using the same method as in Example 1, yielding compounds 11A (82 mg) and 11B (95 mg).

[0172] 11A (82 mg) was split by SFC to obtain 11A-1 (33 mg) and 11A-2 (25 mg).

[0173] 1 H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 7.88 (s, 1H), 7.60 (s, 2H), 6.83-6.61 (m, 2H), 6.57 -6.50 (m, 2H), 6.27 (d, J = 7.0 Hz, 1H), 5.11 (s,1H), 4.14 (d, J = 10.3 Hz, 1H), 3.99 (s, 6H), 3.89 (s, 3H), 3.56(s, 3H), 3.08-3.04(m, 1H), 2.67 (d, J = 13.7Hz, 1H), 2.30-2.20 (m, 2H), 1.95 (s, 6H), 1.85-1.77 (m, 1H), 1.54-1.47 (m, 1H). ESI-Ms:626.2[M + H] + .

[0174] 11B (95 mg) was split by SFC to obtain 11B-1 (35 mg) and 11B-2 (33 mg).

[0175] 1 H NMR (400 MHz, CDCl3) δ: 8.19 (s, 1H), 7.74 (s, 1H), 7.50 (s, 2H), 6.65-6.59 (m, 2H), 6.40 (s, 1H), 6.26 (s, 2H), 5.10 (s, 1H), 4.01 (d, J =11.5 Hz, 1H), 3.95 (s, 6H), 3.87 (s, 3H), 3.52(s, 3H), 3.10-3.05(m, 1H), 2.62(d, J= 13.7Hz, 1H), 2.27-2.23 (m, 2H), 1.97 (s, 6H), 1.84-1.79 (m, 1H), 1.64-1.51 (m, 1H). ESI-Ms:626.2[M + H] + .

[0176] Example 12: Preparation of Compound 12

[0177] Compound 12 was prepared using the same method as in Example 1, yielding compounds 12A (118 mg) and 12B (124 mg).

[0178] 12A (118 mg) was split by SFC to obtain 12A-1 (46 mg) and 12A-2 (40 mg).

[0179] 1 H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 7.91 (s, 1H), 7.61 (s, 2H), 7.05-6.40 (m, 4H), 6.35 (s, 1H), 4.10 (d, J = 11.3 Hz, 1H), 3.98 (s, 6H), 3.94 (s, 3H), 3.71 (s, 3H), 3.15 (t, J =12.7 Hz, 1H), 2.66 (d, J = 12.7 Hz,1H), 2.30-2.21 (m, 1H), 1.99 (s, 7H), 1.70-1.50 (m, 2H). ESI-Ms:627.2[M + H] + .

[0180] 12B (124 mg) was split by SFC to obtain 12B-1 (42 mg) and 12B-2 (50 mg).

[0181] 1 H NMR (400 MHz, CDCl3) δ: 8.18 (s, 1H), 7.77 (s, 1H), 7.57-7.40 (m,2H), 6.65 (d, J= 5.5 Hz, 2H), 6.26 (s, 3H), 4.01 (d, J=9.2Hz, 1H), 3.80 (s, 3H), 3.73 (s, 6H), 3.61 (s, 3H), 3.00 (t, J = 12.2 Hz, 1H), 2.68 (t, J =12.6Hz, 1H), 2.36 (d, J = 11.8 Hz, 1H), 2.25 (s, 7H), 1.71 (d, J = 13.6 Hz,1H). ESI-Ms:627.2[M + H] + .

[0182] Example 13: Preparation of Compound 13

[0183] Compound 13 was prepared using the same method as in Example 1, yielding compounds 13A (99 mg) and 13B (111 mg).

[0184] 13A (99 mg) was split by SFC to obtain 13A-1 (35 mg) and 13A-2 (32 mg).

[0185] 1 H NMR (500 MHz, CDCl3) δ: 8.39 (s, 1H), 7.90 (s, 1H), 7.60 (s, 2H), 7.10 – 6.52 (m, 4H), 6.37 (s, 1H), 4.11 (d, J = 11.4 Hz, 1H), 3.97 (s, 6H), 3.93 (s, 3H), 3.14 (t, J =12.7 Hz, 1H), 2.67 (d, J = 12.7 Hz, 1H), 2.31-2.22(m, 1H), 1.98 (s, 7H), 1.65- 1.48 (m, 2H).. ESI-Ms:698.1[M + H] + .

[0186] 13B (111 mg) was split by SFC to obtain 13B-1 (42 mg) and 13B-2 (43 mg).

[0187] 1H NMR (500 MHz, CDCl3) δ: 8.01 (s, 1H), 7.69 (s, 1H), 7.45 (s, 2H), 6.69 – 6.53 (m, 3H), 6.24 (s, 2H), 4.01 (d, J = 7.6 Hz, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.10 (t, J =12.7 Hz, 1H), 2.61 (d, J = 12.7 Hz, 1H), 2.33-2.25(m, 1H), 2.02 (s, 7H), 1.71- 1.50 (m, 2H). ESI-Ms:698.1[M + H] + .

[0188] Example 14: Preparation of Compound 14

[0189] Compound 14 was prepared using the same method as in Example 1, yielding compounds 14A (86 mg) and 14B (95 mg).

[0190] 14A (86 mg) was split by SFC to obtain 14A-1 (26 mg) and 14A-2 (28 mg).

[0191] 1 H NMR (400 MHz, CDCl3) δ: 8.43 (s, 1H), 7.92 (s, 1H), 7.61-7.53 (m,4H), 7.05- 6.40 (m, 3H), 6.34 (s, 1H), 4.11 (d, J = 11.4Hz, 1H), 3.97 (s,6H), 3.93 (s, 3H), 3.14 (t, J =12.7 Hz, 1H), 2.67(d, J = 12.7 Hz, 1H), 2.30-2.20 (m, 1H), 1.98 (s, 7H), 1.69-1.50 (m, 2H). ESI-Ms:605.2[M + H] + .

[0192] 14B (85 mg) was split by SFC to obtain 14B-1 (25 mg) and 14B-2 (29 mg).

[0193] 1 H NMR (400 MHz, CDCl3) δ: 8.02 (s, 1H), 7.75 (s, 1H), 7.49-7.37 (m,4H), 6.67- 6.51 (m, 2H), 6.27 (s, 2H), 4.02 (d, J = 12.7Hz, 1H), 3.90 (s,6H), 3.85 (s, 3H), 3.10 (t, J =12.7 Hz, 1H), 2.71(d, J = 12.7 Hz, 1H), 2.32-2.21 (m, 1H), 2.01 (s, 7H), 1.71-1.55 (m, 2H). ESI-Ms:605.2[M + H] + .

[0194] Example 15: Preparation of Compound 15

[0195] Compound 15 was prepared using the same method as in Example 1, yielding compounds 15A (102 mg) and 15B (116 mg).

[0196] 15A (102 mg) was split by SFC to obtain 15A-1 (41 mg) and 15A-2 (39 mg).

[0197] 1 H NMR (600 MHz, CDCl3) δ: 8.38 (s, 1H), 7.90 (s, 1H), 7.60 (s, 2H), 7.05 – 6.40 (m, 3H), 6.35 (s, 1H), 4.09 (d, J = 11.4Hz, 1H), 3.95 (s, 6H), 3.91 (s, 3H), 3.15 (t, J =12.7 Hz, 1H), 2.67(d, J = 12.7 Hz, 1H), 2.30-2.20(m, 1H), 1.98 (s, 7H), 1.70-1.52 (m, 2H). ESI-Ms:634.2[M + H] + .

[0198] 15B (116 mg) was split by SFC to obtain 15B-1 (40 mg) and 15B-2 (42 mg).

[0199] 1 H NMR (600 MHz, CDCl3) δ: 7.99 (s, 1H), 7.82 (s, 1H), 7.47 (s, 2H), 6.95 – 6.37 (m, 2H), 6.30 (s, 2H), 4.02 (d, J = 14.2Hz, 1H), 3.91 (s, 6H), 3.83 (s, 3H), 3.10 (t, J =12.2 Hz, 1H), 2.69(d, J = 12.7 Hz, 1H), 2.32-2.21(m, 1H), 2.01 (s, 7H), 1.75-1.56 (m, 2H). ESI-Ms:634.2[M + H] + .

[0200] Example 16: Preparation of Compound 16

[0201] Compound 16 was prepared using the same method as in Example 1, yielding compounds 16A (112 mg) and 16B (126 mg).

[0202] 16A (126 mg) was split by SFC to obtain 16A-1 (43 mg) and 16A-2 (45 mg).

[0203] 1 H NMR (400 MHz, CDCl3) δ: 8.38 (s, 1H), 7.87 (s, 1H), 7.59 (s, 2H), 7.27- 7.25 (m, 2H), 6.84-6.60 (m, 2H), 6.58 -6.52 (m, 2H), 6.28 (d, J = 7.0 Hz, 1H), 4.13 (d, J = 11.3 Hz, 1H), 3.98 (s, 6H), 3.91 (s, 3H), 3.71 (s, 3H), 3.07-3.04(m, 1H), 2.65 (d, J = 12.7Hz, 1H), 2.30-2.20 (m, 2H), 1.95 (s, 6H), 1.53-1.47 (m, 2H).ESI-Ms:580.2[M + H] + .

[0204] 16B (116 mg) was split by SFC to obtain 16B-1 (47 mg) and 16B-2 (45 mg).

[0205] 1 H NMR (600 MHz, CDCl3) δ: 8.03 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.9, 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.1,6.6 Hz, 2H), 6.96 – 6.90 (m, 3H), 6.19 (s, 2H), 3.92 (dd, J = 10.9, 4.2 Hz,1H), 3.68 (s, 6H), 3.60 (s, 3H), 3.49 (dd, J = 14.1, 4.2 Hz, 1H), 2.93 (dd, J = 14.0, 10.9 Hz, 1H), 2.56 (d, J = 12.7 Hz, 1H), 2.37 (s, 1H), 2.22 (s, 7H), 1.65 (d, J = 14.2 Hz, 1H).ESI-Ms:580.2[M + H] + .

[0206] Example 17: Preparation of Compound 17

[0207] Compound 17 was prepared using the same method as in Example 1, yielding compounds 17A (76 mg) and 17B (111 mg).

[0208] 17A (76 mg) was split by SFC to obtain 17A-1 (28 mg) and 17A-2 (26 mg).

[0209] 1 H NMR (600 MHz, CDCl3) δ: 8.39 (s, 1H), 7.87 (s, 1H), 7.59 (s, 2H), 7.10-6.45 (m, 4H), 6.35 (s, 1H), 4.09 (d, J= 11.3 Hz, 1H), 3.97 (s, 6H), 3.90 (s, 3H), 3.70 (s, 3H), 3.13 (t, J =12.7 Hz, 1H), 2.65 (d, J = 12.7 Hz,1H), 2.28-2.21 (m, 1H), 1.97 (s, 7H), 1.68-1.50 (m, 2H). ESI-Ms:570.2[M + H] + .

[0210] 17B (111 mg) was split by SFC to obtain 17B-1 (39 mg) and 17B-2 (38 mg).

[0211] 1 H NMR (600 MHz, CDCl3) δ: 7.99 (s, 1H), 7.71 (s, 1H), 7.45 (s, 2H), 7.04-6.43 (m, 3H), 6.30 (s, 2H), 4.01 (d, J = 7.90 Hz, 1H), 3.92 (s, 6H), 3.87 (s, 3H), 3.65 (s, 3H), 3.17 (t, J =14.1 Hz, 1H), 2.69 (d, J = 12.7 Hz,1H), 2.31-2.27 (m, 1H), 1.99 (s, 7H), 1.73-1.55 (m, 2H). ESI-Ms:570.2[M + H] + .

[0212] Example 18: Preparation of Compound 18

[0213] Compound 18 was prepared using the same method as in Example 1, yielding compounds 18A (89 mg) and 18B (107 mg).

[0214] 18A (89 mg) was split by SFC to obtain 18A-1 (35 mg) and 18A-2 (29 mg).

[0215] 1H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 7.88 (s, 1H), 7.57 (s, 2H), 7.05-6.40 (m, 4H), 6.33 (s, 1H), 4.08 (d, J = 11.3 Hz, 1H), 3.98 (s, 6H), 3.92 (s, 3H), 3.73 (s, 3H), 3.14 (t, J =12.7 Hz, 1H), 2.67 (d, J = 12.7 Hz,1H), 2.28-2.22 (m, 1H), 1.98 (s, 7H), 1.68-1.51 (m, 2H). ESI-Ms:586.1[M + H] + .

[0216] 18B (107 mg) was split by SFC to obtain 18B-1 (48 mg) and 18B-2 (46 mg).

[0217] 1 H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.72 (s, 1H), 7.43 (s, 2H), 6.95-6.80 (m, 3H), 6.26 (s, 2H), 4.01 (d, J = 11.3 Hz, 1H), 3.95 (s, 6H), 3.90 (s, 3H), 3.69 (s, 3H), 3.15 (t, J =14.1 Hz, 1H), 2.69 (d, J = 11.7 Hz,1H), 2.30-2.25 (m, 1H), 2.03 (s, 7H), 1.69-1.55 (m, 2H). ESI-Ms:586.1[M + H] + .

[0218] Example 19: Preparation of Compound 19

[0219] Compound 19 was prepared using the same method as in Example 1, yielding compounds 19A (135 mg) and 19B (146 mg).

[0220] 19A (135 mg) was split by SFC to obtain 19A-1 (44 mg) and 19A-2 (52 mg).

[0221] 1 H NMR (400 MHz, CDCl3) δ: 8.17 (s, 1H), 7.82 (d, J =1.3Hz, 1H), 7.60-7.52 (m, 2H), 6.68- 6.33 (m, 2H), 5.77 (s, 2H), 3.97 (s, 3H), 3.95 (d, J =3.5Hz, 1H), 3.91 (s, 6H), 3.64 (s, 6H), 2.91 (dd, J =14.8, 12.3 Hz, 1H), 2.55(dd, J = 14.7, 3.2 Hz, 1H), , 2.20 (s, 6H),1.96-1.84 (m, 4H). ESI-Ms:641.2[M+ H] + .

[0222] 19B (146 mg) was split by SFC to obtain 19B-1 (55 mg) and 19B-2 (48 mg).

[0223] 1 H NMR (400 MHz, CDCl3) δ: 7.87 (s, 1H), 7.72 (d, J =2.0Hz, 1H), 7.49-7.43 (m, 2H), 6.41- 6.35 (m, 2H), 6.19 (s, 2H), 3.95 (s, 3H), 3.93 (d, J =3.5Hz, 1H), 3.90 (s, 6H), 3.62 (s, 6H), 2.87 (dd, J =14.2, 11.7 Hz, 1H), 2.57(dd, J = 14.7, 3.2 Hz, 1H), , 2.23 (s, 6H),1.97-1.88 (m, 4H). ESI-Ms:641.2[M+ H] + .

[0224] Example 20: Preparation of Compound 20

[0225] Compound 20 was prepared using the same method as in Example 1, yielding compounds 20A (102 mg) and 20B (122 mg).

[0226] 20A (102 mg) was split by SFC to obtain 20A-1 (34 mg) and 20A-2 (38 mg).

[0227] 1 H NMR (400 MHz, CDCl3) δ: 8.31 (s, 1H), 7.84 (s, 1H), 7.55 (s, 2H),7.37(d, J =5.0Hz,1H), 6.68- 6.33 (m, 2H), 6.19 (d, J =5.3Hz, 1H), 4.02 (dd, J =11.5, 2.6 Hz, 1H), 3.92 (s, 6H), 3.88 (s, 3H), 3.77 (s, 3H), 3.51 (s, 3H), 3.05 (dd, J =13.6, 12.8 Hz, 1H), 2.54 (dd, J = 14.0, 3.0 Hz, 1H),2.12 (s, 6H), 1.92-1.76 (m, 4H).ESI-Ms:641.2[M + H] + .

[0228] 20B (122 mg) was split by SFC to obtain 20B-1 (42 mg) and 20B-2 (47 mg).

[0229] 1 H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.73 (s, 1H), 7.43 (s, 2H), 7.12(d, J =7.9Hz,1H), 6.33 (s, 1H), 6.19 (m,2H), 4.01 (dd, J =11.5, 2.6 Hz,1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.70 (s, 3H), 3.47 (s, 3H), 3.10 (dd, J =14.2, 3.5 Hz, 1H), 2.57 (dd, J = 14.0, 3.0 Hz, 1H),2.15 (s, 6H), 1.95-1.76(m, 4H). ESI-Ms:641.2[M + H] + .

[0230] Example 21: Preparation of compound 21

[0231] Compound 21 was prepared using the same method as in Example 1, yielding compounds 21A (81 mg) and 21B (96 mg).

[0232] 21A (81 mg) was split by SFC to obtain 21A-1 (25 mg) and 21A-2 (29 mg).

[0233] 1 H NMR (400 MHz, CDCl3) δ: 8.34 (s, 1H), 7.85 (s, 1H), 7.56 (s, 2H),7.37(d, J =5.0Hz,1H), 6.67- 6.34 (m, 2H), 6.17 (d, J =5.2Hz, 1H), 4.00 (dd, J =11.5, 2.6 Hz, 1H), 3.91 (s, 6H), 3.88 (s, 3H), 3.85 (s, 3H), 3.04 (dd, J =13.6, 12.8 Hz, 1H), 2.55 (dd, J = 14.2, 3.0 Hz, 1H), 2.02 (s, 6H), 1.90-1.74(m, 4H). ESI-Ms: 612.2 [M + H] + .

[0234] 21B (96 mg) was split by SFC to obtain 21B-1 (30 mg) and 21B-2 (33 mg).

[0235] 1 H NMR (400 MHz, CDCl3) δ: 8.03 (s, 1H), 7.74 (s, 1H), 7.45 (s, 2H), 7.20(d, J =5.2Hz,1H), 6.43- 6.35 (m, 1H), 6.18 (s,2H), 3.97 (dd, J =11.5, 2.6Hz, 1H), 3.85 (s, 6H), 3.78 (s, 3H), 3.63 (s, 3H), 3.01 (dd, J=13.6, 12.8 Hz, 1H), 2.53 (dd, J = 14.2, 3.0 Hz, 1H), 2.12 (s, 6H), 1.95-1.77 (m, 4H). ESI-Ms:612.2[M + H] + .

[0236] Example 22: Preparation of compound 22

[0237] Compound 22 was prepared using the same method as in Example 1, yielding compounds 22A (105 mg) and 22B (108 mg).

[0238] 22A (105 mg) was split by SFC to obtain 22A-1 (30 mg) and 22A-2 (35 mg).

[0239] 1 H NMR (400 MHz, CDCl3) δ: 8.34 (s, 1H), 7.83 (s, 1H), 7.53 (s, 2H),7.34(d, J =5.2Hz,1H), 6.68- 6.35 (m, 2H), 6.15 (d, J =5.3Hz, 1H), 3.98 (dd, J =11.6, 2.6 Hz, 1H), 3.90 (s, 6H), 3.88 (s, 3H), 3.84 (s, 3H), 3.06 (dd, J =13.6, 12.8 Hz, 1H), 2.55 (dd, J = 14.0, 3.0 Hz, 1H), 2.00 (s, 6H), 1.90-1.74(m, 4H). ESI-Ms: 612.2 [M + H] + .

[0240] 22B (108 mg) was split by SFC to obtain 22B-1 (35 mg) and 22B-2 (38 mg).

[0241] 1 H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1H), 7.67 (s, 1H), 7.39 (s, 2H), 7.07(d, J=5.2Hz,1H), 6.41 - 6.35 (m, 1H), 6.14 (s,2H), 3.95 (dd, J =11.5, 2.6Hz, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.78 (s, 3H), 3.10 (dd, J =13.6, 12.8 Hz, 1H), 2.51 (dd, J = 14.0, 3.0 Hz, 1H), 2.03 (s, 6H), 1.97-1.74 (m, 4H). ESI-Ms:612.2[M + H] + .

[0242] Example 23: Preparation of compound 23

[0243] Compound 23 was prepared using the same method as in Example 1, yielding compounds 23A (101 mg) and 23B (106 mg).

[0244] 23A (101 mg) was split by SFC to obtain 23A-1 (40 mg) and 23A-2 (38 mg).

[0245] 1 H NMR (600 MHz, CDCl3) δ: 8.33 (s, 1H), 8.13(s,1H),7.85 (s, 1H), 7.54(s, 2H), 7.15 (s, 1H), 6.66- 6.32 (m, 2H), 4.01 (dd, J =11.6, 2.6 Hz, 1H),3.92 (s, 6H), 3.87 (s, 3H), 3.83 (s, 3H), 3.03 (dd, J =13.6, 12.8 Hz, 1H), 2.56 (dd, J = 14.2, 3.0 Hz, 1H), 1.97 (s, 6H) ,1.90-1.79 (m, 4H). ESI-Ms:612.2[M + H] + .

[0246] 23B (106 mg) was split by SFC to obtain 23B-1 (37 mg) and 23B-2 (29 mg).

[0247] 1H NMR (600 MHz, CDCl3) δ: 8.11 (s, 1H), 7.97 (s, 1H), 7.71 (s, 1H), 7.42 (s, 2H), 6.95 (s, 1H), 6.31 (s, 2H), 3.90 (dd, J =10.0, 3.1 Hz, 1H), 3.75(s, 6H), 3.71 (s, 3H), 3.63 (s, 3H), 3.10 (dd, J =13.8, 12.6 Hz, 1H), 2.47(dd, J = 12.2, 3.0 Hz, 1H), 2.21 (s, 6H) ,2.07-1.81 (m, 4H). ESI-Ms:612.2[M +H] + .

[0248] Example 24: Preparation of compound 24

[0249] Compound 24 was prepared using the same method as in Example 1, yielding compounds 24A (85 mg) and 24B (72 mg).

[0250] 24A (85 mg) was split by SFC to obtain 24A-1 (28 mg) and 24A-2 (29 mg).

[0251] 1 H NMR (400 MHz, CDCl3) δ: 8.30 (s, 1H), 7.83 (s, 1H), 7.53 (s, 2H),7.39(d, J =5.2Hz,1H), 6.67- 6.36 (m, 2H), 6.20 (d, J =5.2Hz, 1H), 4.35 (dd, J =11.6, 3.2Hz, 1H), 4.09 (dd, J = 14.2, 7.2 Hz, 1H), 4.01 (s, 3H), 3.95 (s, 6H), 3.82 (s, 3H), 3.21 – 3.10 (m, 1H), 2.78 (dd, J = 14.8,3.2 Hz, 1H), 2.02 (s,6H), 1.98-1.67 (m, 4H).ESI-Ms: 611.2 [M + H] + .

[0252] 24B (72 mg) was split by SFC to obtain 24B-1 (21 mg) and 24B-2 (28 mg).

[0253] 1H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.71 (s, 1H), 7.41 (s, 2H), 7.18 (d, J=7.9Hz,1H), 6.60- 6.42 (m, 1H), 6.19 (s, 2H), 4.23 (dd, J = 13.8,4.2Hz, 1H), 4.01 (dd, J = 14.6, 7.0 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 6H), 3.85(s, 3H), 3.20 – 3.13 (m, 1H), 2.74 (dd, J = 13.8,4.2 Hz, 1H), 2.11 (s, 6H),1.97-1.69 (m, 4H). ESI-Ms:612.2[M + H]+.

[0254] Example 25: Preparation of Compound 25

[0255] Compound 25 was prepared using the same method as in Example 1, yielding compounds 25A (59 mg) and 25B (65 mg).

[0256] 25A (59 mg) was split by SFC to obtain 25A-1 (12 mg) and 25A-2 (15 mg).

[0257] 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.83 (s, 1H), 7.62 (d, J = 8.8Hz, 1H), 7.57 (dd, J = 8.9, 2.1 Hz, 1H), 7.17 – 7.09 (m, 1H), 6.80 – 6.41 (m,2H), 6.36 (d, J = 7.1Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 4.38 (dd, J = 11.8, 3.4 Hz, 1H), 4.10 (dd, J= 14.3, 7.2 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 6H), 3.69 (s, 3H), 3.20 – 3.10 (m, 1H), 2.75 (dd, J = 14.8,3.3 Hz, 1H), 2.20-2.15(m, 1H), 1.93 (s, 6H), 1.57-1.43 (m, 2H).

[0258] ESI-Ms: 611.2 [M + H] + .

[0259] 25B (65 mg) was split by SFC to obtain 25B-1 (20 mg) and 25B-2 (24 mg).

[0260] 1 H NMR (400 MHz, cdcl3) δ 8.00 (s, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.49(dd, J = 8.9, 2.1 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 10.1, 5.3Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 6.24 (s, 2H), 4.27 (dd, J = 10.0, 3.1 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 6H), 3.70 (s, 3H), 3.57 (dd, J = 14.2, 3.5 Hz, 1H), 3.11 (dd, J = 13.8, 10.8 Hz, 1H), 2.56 (dd, J = 13.5, 10.5 Hz, 1H), 2.38-2.30(m,2H), 2.21 (s, 6H), 2.18-2.13(m,1H). ESI-Ms:611.2[M + H] + .

[0261] Example 26: Preparation of Compound 26

[0262] Compound 26 was prepared using the same method as in Example 1, yielding compounds 26A (120 mg) and 26B (116 mg).

[0263] 26A (120 mg) was split by SFC to obtain 26A-1 (43 mg) and 26A-2 (38 mg).

[0264] 1 H NMR (400 MHz, CDCl3) δ: 8.23 ​​(s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.60 -7.53 (m, 2H), 6.79 - 6.43 (m, 2H), 6.31 (dd, J = 5.4, 1.4 Hz, 1H), 6.17 (s, 1H), 4.03-3.96 (m,1H), 3.94 (s, 3H), 3.91 (s,6H), 3.68 (s, 3H), 2.92 (dd, J = 14.8, 12.0 Hz, 1H), 2.59 (dd, J = 14.7, 3.4Hz, 1H), 2.14 (t, J = 12.6 Hz, 1H), 1.87 (s, 6H), 1.85-1.80 (m, 1H), 1.44 –1.35 (m, 2H).ESI-Ms: 611.2 [M + H] + .

[0265] 26B (116 mg) was split by SFC to obtain 26B-1 (40 mg) and 26B-2 (42 mg).

[0266] 1 H NMR (600 MHz, CDCl3) δ:7.93 (s, 1H), 7.78 (d, J = 5.3 Hz, 1H), 7.67(d, J = 2.2 Hz, 1H), 7.49 – 7.40 (m, 2H), 6.48 (d, J = 5.2 Hz, 1H), 6.36 (s,1H), 6.16 (s, 2H), 3.93 (dd, J= 11.0, 4.0 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J = 2.6 Hz, 9H), 3.42 (dd, J = 14.2, 4.0 Hz, 1H), 2.94 – 2.86 (m, 1H), 2.42 (t, J = 13.5 Hz, 1H), 2.25 (t, J = 12.7 Hz, 1H), 2.14 (brs, 7H), 1.63 – 1.53 (m,2H).ESI-Ms: 611.2 [M + H] + .

[0267] Example 27: Preparation of Compound 27

[0268] Compound 27 was prepared using the same method as in Example 1, yielding compound 27A (65 mg) and compound 27B (60 mg).

[0269] 27A (65 mg) was chirally separated to obtain 27A-1 (22 mg) and 27A-2 (24 mg).

[0270] 1 H NMR (400 MHz, CDCl3) δ: 8.37 (s, 1H), 7.89 (d, J = 2.3 Hz, 2H), 7.75- 7.71 (m, 1H), 7.63 (m, 2H), 6.95 (m, 1H), 6.62 (s, 1H), 6.57 -6.17 (m,1H), 4.04-4.00 (m, 1H), 3.99 (s, 6H), 3.96 (s, 3H), 3.61 (s, 3H), 3.06-2.95(m, 1H), 2.75-2.68 (m, 1H), 2.28-2.17 (m, 1H), 2.09-2.02 (m, 1H), 1.95 (s,6H), 1.93-1.88 (m, 1H), 1.70-1.60 (m, 1H).ESI-Ms:611.2[M + H] + .

[0271] 27B (60 mg) was chirally separated to yield 27B-1 (20 mg) and 27B-2 (24 mg).

[0272] 1 H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.81 (d, J = 1.5 Hz, 2H), 7.62- 7.59 (m, 1H), 7.51 (m, 2H), 6.62 (s, 1H), 6.17 (s, 2H), 4.01-3.97 (m,1H), 3.89 (s, 6H), 3.86 (s, 3H), 3.57 (s, 3H), 3.10-2.97 (m, 1H), 2.73-2.69(m, 1H), 2.31-2.20 (m, 1H), 2.07-2.04(m,1H), 2.01(s, 6H), 1.95-1.90 (m, 1H),1.69-1.64 (m, 1H).ESI-Ms:611.2[M + H]+.

[0273] Example 28: Preparation of Compound 28

[0274] Compound 28 was prepared using the same method as in Example 1, yielding compound 28A (72 mg) and compound 28B (78 mg).

[0275] 28A (72 mg) was chirally separated to obtain 28A-1 (25 mg) and 28A-2 (22 mg).

[0276] 1 H NMR (400 MHz, CDCl3) δ: 8.37 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H),7.57 – 7.51 (m, 2H), 6.89 – 6.68(m, 2H), 6.62 (t, J = 7.9 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 6.24 – 6.19 (m, 1H), 3.96 (dd, J = 11.9, 3.4 Hz, 1H), 3.91 (s,6H), 3.82 (s, 3H), 3.60 (s, 3H), 2.99 (dd, J = 14.6, 11.9 Hz, 1H), 2.63 (dd, J = 14.6, 3.4 Hz, 1H), 2.16 (td, J= 14.1, 12.6, 4.6 Hz, 1H), 1.89 (s, 6H),1.85 (d, J = 12.8 Hz, 1H), 1.82 (s, 3H),1.56 – 1.50(m, 2H). ESI-Ms:624.2[M +H] + .

[0277] 28B (78 mg) was chirally separated to obtain 28B-1 (25 mg) and 28B-2 (26 mg).

[0278] 1 H NMR (600 MHz, CDCl3) δ: 8.11 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 8.8, 2.2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.66 (t, J = 7.9Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.27 – 6.16 (m, 3H), 3.95 – 3.91 (m, 1H), 3.68 (s, 3H), 3.67 (s, 6H), 3.52 (s, 3H), 3.49 (d, J = 4.1 Hz, 1H), 2.96 (dd, J = 13.9, 11.0 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.26 (t, J = 12.7 Hz, 1H), 2.16(s, 6H), 2.15 (s, 3H), 2.13 (d, J = 3.2 Hz, 1H), 1.58 (d, J = 14.5 Hz, 1H).ESI-Ms:624.2[M + H] + .

[0279] Example 29: Preparation of compound 29

[0280] Compound 29 was prepared using the same method as in Example 1, yielding compounds 29A (58 mg) and 29B (65 mg).

[0281] 29A (58 mg) was chirally separated to obtain 29A-1 (19 mg) and 29A-2 (21 mg).

[0282] 1 H NMR (600 MHz, CDCl3) δ: 8.38 (s, 1H), 7.84 (s, 1H), 7.54 (d, J =1.8 Hz, 2H),6.98 - 6.70 (m, 2H) 6.69 (t, J = 8.0 Hz, 1H), 6.47 (dd, J = 8.3,1.4 Hz, 1H), 6.32 – 6.28 (m, 1H), 4.15 – 4.07 (m, 1H), 3.91 (s, 7H), 3.84 (s,3H), 3.68 (s, 3H), 3.19 (dd, J = 14.5, 12.0 Hz, 1H), 2.74 – 2.69 (m, 1H), 2.42 (d, J = 26.0 Hz, 1H), 2.17 (s, 1H), 1.89 (s, 6H), 1.65-1.53 ​​(m, 2H).ESI-Ms:644.1[M + H] + .

[0283] 29B (65 mg) was chirally separated to obtain 29B-1 (23 mg) and 29B-2 (18 mg).

[0284] 1H NMR (600 MHz, CDCl3) δ: 8.26 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.8, 2.3 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 6.73 (t, J = 7.9Hz, 1H), 6.64 (dd, J = 8.3, 1.3 Hz, 1H), 6.29 (s, 2H), 6.16 (dd, J = 7.7, 1.4Hz, 1H), 4.14 (dd, J = 11.6, 3.4 Hz, 1H), 3.85 (s, 3H), 3.77 (dd, J = 13.5,3.4 Hz, 1H), 3.73 (s, 6H), 3.54 (s, 3H), 3.12 -3.07 (m, 1H), 2.86 -2.58 (m,2H), 2.30 (s, 6H), 1.74 (d, J = 69.4 Hz, 2H). ESI-Ms:644.1 [M + H] + .

[0285] Example 30: Preparation of compound 30

[0286] Compound 30 was prepared using the same method as in Example 1, yielding compounds 30A (70 mg) and 30B (65 mg).

[0287] 30A (70 mg) was chirally separated to obtain 30A-1 (25 mg) and 30A-2 (28 mg).

[0288] 1 H NMR (400 MHz, CDCl3) δ: 8.38 (s, 1H), 7.84 (s, 1H), 7.54 (d, J =1.8 Hz, 2H),6.98 – 6.70 (m, 2H) 6.69 (t, J = 8.0 Hz, 1H), 6.47 (dd, J = 8.3,1.4 Hz, 1H), 6.32 – 6.28 (m, 1H), 4.15 – 4.07 (m, 1H), 3.91 (s, 7H), 3.84 (s,3H), 3.68 (s, 3H), 3.19 (dd, J= 14.5, 12.0 Hz, 1H), 2.74 – 2.69 (m, 1H), 2.42 (d, J = 26.0 Hz, 1H), 2.17 (s, 1H), 1.89 (s, 6H), 1.65-1.53 ​​(m, 2H).ESI-Ms:628.2[M + H] + .

[0289] 30B (65 mg) was chirally separated to obtain 30B-1 (21 mg) and 30B-2 (24 mg).

[0290] 1 H NMR (600 MHz, CDCl3) δ: 8.21 (s, 1H), 7.75 (s, 1H), 7.49 (d, J = 2.3Hz, 2H), 6.75 –6.67 (m, 2H), 6.29 (s, 1H), 6.16 (s, 2H), 4.14 (s, 1H), 3.85(s, 3H), 3.77 (dd, J = 13.5, 3.4 Hz, 1H), 3.73 (s, 6H), 3.54 (s, 3H), 3.10 -3.07 (m, 1H), 2.83 -2.59 (m, 2H), 2.23 (s, 6H), 1.77(d, J = 12.4 Hz, 2H).ESI-Ms:628.2[M + H] + .

[0291] Example 31: Preparation of compound 31

[0292] Compound 31 was prepared using the same method as in Example 1, yielding compounds 31A (67 mg) and 31B (76 mg).

[0293] 31A (67 mg) was chirally separated to obtain 31A-1 (21 mg) and 31A-2 (23 mg).

[0294] 1H NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.68 – 7.57 (m, 2H), 6.63 (s, 1H), 6.19 (s, 1H), 6.16 (d, J = 1.8 Hz, 1H),6.13 (s, 1H), 4.01 (s, 1H), 4.00 (s, 3H), 3.96 (s, 6H), 3.05 – 2.89 (m, 1H),2.76 – 2.61 (m, 1H), 2.21 (q, J = 7.5 Hz, 1H), 2.01 (s, 7H), 1.78 – 1.64 (m, 2H). ESI-Ms: 646.2 [M + H] + .

[0295] 31B (76 mg) was chirally separated to obtain 31B-1 (28 mg) and 31B-2 (25 mg).

[0296] 1 H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.61 – 7.53 (m, 2H), 6.53 (s, 1H), 6.19 (s, 1H), 6.14 (s, 2H), 3.98 (s, 1H),3.93 (s, 3H), 3.90 (s, 6H), 3.01 – 2.87 (m, 1H), 2.75 – 2.63 (m, 1H), 2.23(q, J = 7.9 Hz, 1H), 2.03 (s, 7H), 1.81 – 1.65 (m, 2H). ESI-Ms:646.2[M + H] + .

[0297] Example 32: Preparation of compound 32

[0298] Compound 32 was prepared using the same method as in Example 1, yielding compounds 32A (55 mg) and 32B (65 mg).

[0299] 32A (55 mg) was chirally separated to obtain 32A-1 (14 mg) and 32A-2 (17 mg).

[0300] 1H NMR (600 MHz, CDCl3) δ 8.27 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H),7.57-7.52 (m, 2H), 6.82 (t, J = 7.9 Hz, 1H), 6.73 – 6.45 (m, 2H), 6.41 (dd, J = 8.0, 2.3 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 3.97 (dd, J =12.0, 3.3 Hz, 1H), 3.91 (s, 6H), 3.90 (s, 3H), 3.50 (s, 3H), 2.93 (dd, J =14.7, 12.1 Hz, 1H), 2.65 (dd, J = 14.6, 3.1 Hz, 1H), 2.17-2.13 (m, 1H), 1.88(s, 6H), 1.85 – 1.83 (m, 1H), 1.47-1.40 (m, 2H). ESI-Ms: 610.2[M + H] + .

[0301] 32B (65 mg) was chirally separated to obtain 32B-1 (18 mg) and 32B-2 (21 mg).

[0302] 1 H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H),7.45-7.39 (m, 2H), 6.92 (t, J = 7.9 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.50 (dd, J = 8.1, 2.1 Hz, 1H), 6.47 (s, 1H), 6.19 (s, 2H), 3.92 (dd, J = 10.8,4.1 Hz, 1H), 3.68 (s, 6H), 3.63 (s, 3H), 3.53 (s, 3H), 3.46 (dd, J= 14.1, 4.1 Hz, 1H), 2.93 (dd, J = 14.0, 10.9 Hz, 1H), 2.52 – 2.45 (m, 1H), 2.27 (t, J = 12.6 Hz, 1H), 2.15 (s, 6H), 1.64 – 1.51 (m, 2H). ESI-Ms: 610.2[M + H] + .

[0303] Example 33: Preparation of compound 33

[0304] Compound 33 was prepared using the same method as in Example 1, yielding compounds 33A (68 mg) and 33A (68 mg).

[0305] 33A (68 mg) was chirally separated to obtain 33A-1 (25 mg) and 33A-2 (21 mg).

[0306] 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.92 (s, 1H), 7.64 -7.53 (m,2H), 7.14 - 6.99 (m, 1H), 6.94-6.83 (m, 1H), 6.80 -6.68 (m, 1H), 6.60 (d, J =8.3 Hz, 1H), 6.50 -6.37 (m, 2H), 4.04 (d, J = 9.5 Hz, 1H), 3.96 (s,6H), 3.88(s, 3H), 3.38-3.34 (m, 1H), 3.05-2.98 (m, 2H), 2.68-2.62 (m, 1H), 2.54-2.49(m, 1H), 2.30-2.44 (m, 2H), 1.88 (s, 6H), 0.64 – 0.44 (m, 4H). ESI-Ms:636.2[M+ H] + .

[0307] 33B (68 mg) was chirally separated to obtain 33B-1 (21 mg) and 33B-2 (19 mg).

[0308] 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.79 (s, 1H), 7.52 -7.33 (m,2H), 7.03 - 6.74 (m, 1H), 6.60-6.53 (m, 1H), 6.47 -6.38 (m, 1H), 6.31 (d, J =7.9 Hz, 1H), 6.30 (s, 2H), 4.01 (d, J = 9.5 Hz, 1H), 3.90 (s,6H), 3.85 (s,3H), 3.33-3.30 (m, 1H), 3.02-2.99 (m, 2H), 2.67-2.64 (m, 1H), 2.57-2.51 (m,1H), 2.31-2.23 (m, 2H), 2.01 (s, 6H), 0.74 – 0.47 (m, 4H). ESI-Ms:636.2[M +H] + .

[0309] Example 34: Preparation of compound 34

[0310] Compound 34 was prepared using the same method as in Example 1, yielding compounds 34A (62 mg) and 34B (70 mg).

[0311] 34A (62 mg) was chirally separated to obtain 34A-1 (19 mg) and 34A-2 (21 mg).

[0312] 1 H NMR (600 MHz, CDCl3) δ 8.66 (d, J = 8.6 Hz, 1H), 8.37 (s, 1H), 8.20(d, J = 7.2 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.58 – 7.43 (m, 5H), 6.25-6.23 (m, 2H), 6.00 (dd, J = 6.1, 2.6 Hz, 1H), 5.66 (d, J =1.2,1H), 5.38 (d, J=1.2Hz, 1H), 4.91 (dd, J = 11.4,3.6 Hz, 1H), 4.10 (s, 3H), 3.13 (dd, J = 14.5, 11.5 Hz, 1H), 2.38 (dd, J =14.6, 3.5 Hz, 1H), 2.15 (dd, J = 17.5, 7.7 Hz, 1H), 1.94 (brs, 6H), 1.63 –1.48 (m, 2H).ESI-Ms:613.2[M + H] + .

[0313] 34B (70 mg) was chirally separated to obtain 34B-1 (20 mg) and 34B-2 (25 mg).

[0314] 1 H NMR (600 MHz, CDCl3) δ 8.29 (d, J = 8.7 Hz, 1H), 8.17 (s, 1H), 7.70(d, J = 1.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.45– 7.33 (m, 3H), 7.30 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.47 – 6.42 (m, 2H), 6.39 (dd, J = 6.0, 2.9 Hz, 1H), 5.68(d, J =1.2,1H), 5.40 (d, J =1.2Hz, 1H), 4.75 (dd, J = 10.9, 4.0 Hz, 1H), 3.61(dd, J = 14.1, 4.1 Hz, 1H), 3.28 (dd, J = 13.9, 11.1 Hz, 1H), 2.82 (s, 3H), 2.69-2.64 (m, 1H), 2.58 (d,J = 14.9 Hz, 1H), 2.05 (s, 6H), 1.94 (t, J = 12.8Hz, 2H).ESI-Ms:613.2[M + H] + .

[0315] Example 35: Preparation of compound 35

[0316] Compound 35 was prepared using the same method as in Example 1, yielding compounds 35A (87 mg) and 35B (75 mg).

[0317] 35A (87 mg) was chirally separated to obtain 35A-1 (24 mg) and 35A-2 (21 mg).

[0318] 1 H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 8.7 Hz, 1H), 8.43 (s, 1H), 8.29(dd, J = 7.4, 1.2 Hz, 1H), 7.96 (dd, J = 4.4, 2.3 Hz, 2H), 7.84 (d, J = 8.1Hz, 1H), 7.69-7.51 (m, 5H), 6.92 – 6.79 (m, 3H), 6.66 – 6.59 (m, 2H), 4.95(dd, J = 11.8, 3.1 Hz, 1H), 4.15 (s, 3H), 3.48 (d, J = 2.6 Hz, 2H), 3.14 (dd, J = 14.5, 11.9 Hz, 1H), 2.62 (dd, J = 14.5, 3.0 Hz, 1H), 2.47 (d, J = 14.8Hz, 1H), 1.99 (d, J = 12.4 Hz, 1H), 1.90 (s, 6H), 1.64-1.58 (m, 2H).ESI-Ms:569.2[M + H] + .

[0319] 35B (75 mg) was chirally separated to obtain 35B-1 (26 mg) and 35B-2 (28 mg).

[0320] 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.6 Hz, 1H), 8.21 (s, 1H), 7.77(s, 1H), 7.70 (dd, J = 22.7, 7.7 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.44 –7.35 (m, 2H), 7.30 (d, J = 8.9 Hz, 1H), 7.12-7.07 (m, 5H), 7.05-7.00 (m, 1H), 4.75 (dd, J = 10.6, 4.2 Hz, 1H), 3.78 (dd, J = 14.1, 4.1 Hz, 1H), 3.37 (dd, J = 13.9, 10.9 Hz, 1H),3.88 (s, 3H), 2.76 – 2.54 (m, 2H), 2.11 (s, 6H), 2.05-1.97 (m, 2H).ESI-Ms:569.2[M + H] + .

[0321] Example 36: Preparation of compound 36

[0322] Compound 36 was prepared using the same method as in Example 1, yielding compounds 36A (63 mg) and 36B (57 mg).

[0323] 36A (63 mg) was chirally separated to obtain 36A-1 (21 mg) and 36A-2 (25 mg).

[0324] 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.18(dd, J = 7.3, 1.2 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.91 (dd, J= 8.2, 1.3Hz, 1H), 7.82-7.77 (m, 2H), 7.69 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (t, J = 7.7Hz, 1H), 7.50 – 7.38 (m, 2H), 6.96 – 6.88 (m, 3H), 6.56 (dd, J = 7.4, 1.0 Hz, 2H), 4.39 (dd, J = 11.3, 2.7 Hz, 1H), 4.21 (s, 3H), 2.27-2.21 (m, 2H), 1.99 –1.86 (m, 6H), 1.84 – 1.72 (m, 2H), 1.61-1.53 ​​(m, 2H), 1.37 – 1.27 (m, 2H).ESI-Ms:583.2[M + H] + .

[0325] 36B (57 mg) was chirally separated to obtain 36B-1 (20 mg) and 36B-2 (14 mg).

[0326] 1 H NMR (400 MHz, CDCl3) δ 8.23(d, J = 3.4 Hz, 1H), 8.16 (s, 1H), 8.05(dd, J = 7.0, 1.6 Hz, 1H), 7.93 (d, J = 3.1 Hz, 1H), 7.80 (dd, J = 8.2, 3.4Hz, 1H), 7.79-7.75 (m, 2H), 7.51 (dd, J = 13.4, 4.2 Hz, 1H), 7.33 (t, J = 7.9Hz, 1H), 7.30 – 7.18 (m, 2H), 6.76 – 6.58 (m, 3H), 6.36 (dd, J = 7.4, 1.0 Hz, 2H), 4.27 (dd, J = 11.7, 2.9 Hz, 1H), 4.10 (s, 3H), 2.21-2.17 (m, 2H), 1.95 –1.83 (m, 6H), 1.80 – 1.75 (m, 2H), 1.64-1.55 (m, 2H), 1.41 – 1.35 (m, 2H).ESI-Ms:583.2[M + H] + .

[0327] Example 37: Preparation of compound 37

[0328] Compound 37 was prepared using the same method as in Example 1, yielding compounds 37A (72 mg) and 37B (75 mg).

[0329] 37A (72 mg) was chirally separated to obtain 37A-1 (31 mg) and 37A-2 (27 mg).

[0330] 1 H NMR (400 MHz, CDCl3) δ: 8.28 (s, 1H), 7.95 (d, J =2.0 Hz, 1H), 7.72(d, J = 8.8 Hz, 1H), 7.70 – 7.61 (m, 3H), 7.54 (dd, J = 7.8, 0.9 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.39 (t, J =7.8Hz, 1H), 6.35 (d, J = 7.0 Hz, 1H), 6.26 (d, J = 7.8 Hz, 1H), 5.66 (d, J =1.2,1H), 5.38(d, J =1.2Hz, 1H), 3.99 (dd, J = 11.8,3.9 Hz, 1H), 3.89 (s, 3H), 3.00 (dd, J =14.4, 12 Hz, 1H), 2.51 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.90 (s,6H), 1.85-1.83 (m, 1H), 1.48-1.43 (m, 2H). ESI-Ms:603.1[M + H] + .

[0331] 37B (75 mg) was chirally separated to obtain 37B-1 (30 mg) and 37B-2 (28 mg).

[0332] 1 H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.83 (d, J =3.4 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.56 – 7.43 (m, 3H), 7.34 (dd, J = 7.9, 1.9 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 3.4 Hz, 1H), 6.29 (t, J=7.8Hz,1H), 6.15 (d, J = 7.9 Hz, 1H), 6.11 (d, J = 7.8 Hz, 1H), 5.68 (d, J=1.2,1H),5.40 (d, J=1.2Hz, 1H), 3.95 (dd, J = 13.8,7.9 Hz, 1H), 3.85 (s, 3H), 3.01(dd, J = 14.4,12 Hz, 1H), 2.37 (dd, J = 14.4, 3.8 Hz, 1H), 2.25-2.19 (m, 1H),1.99 (s, 6H), 1.87-1.82 (m, 1H), 1.54-1.47 (m, 2H). ESI-Ms:603.1[M + H] + .

[0333] Example 38: Preparation of compound 38

[0334] Compound 38 was prepared using the same method as in Example 1, yielding compounds 38A (61 mg) and 38B (76 mg).

[0335] 38A (61 mg) was chirally separated to obtain 38A-1 (15 mg) and 38A-2 (17 mg).

[0336] 1 H NMR (600 MHz, CDCl3) δ: 8.31 (s, 1H), 7.80 (d, J =1.8 Hz, 1H), 7.60– 7.45(m, 2H), 6.85-6.44 (m, 2H), 6.35 (t, J =7.8Hz, 1H), 6.32 (d, J = 7.0 Hz, 1H), 6.24 (d, J= 7.8 Hz, 1H), 5.65 (d, J =1.2,1H), 5.37 (d, J =1.2Hz, 1H), 4.02(dd, J = 11.8, 3.9 Hz, 1H), 4.35 (q, J =6.9Hz, 4H), 3.87 (s, 3H), 3.00 (dd, J =14.4, 12 Hz, 1H), 2.51 (dd, J = 14.4, 3.8 Hz, 1H), 2.17-2.14 (m, 1H), 1.89 (s,6H), 1.84-1.82 (m, 1H), 1.49-1.44 (m, 2H),1.41(t, J =7.0Hz, 6H). ESI-Ms:652.2[M+ H] + .

[0337] 38B (76 mg) was chirally separated to obtain 38B-1 (22 mg) and 38B-2 (28 mg).

[0338] 1 H NMR (600 MHz, CDCl3) δ: 8.01 (s, 1H), 7.69 (d, J =2.4 Hz, 1H), 7.51– 7.41(m, 2H), 6.69-6.51 (m, 2H), 6.31 (t, J =3.4Hz, 1H), 6.27 (s,2H), 5.68(d, J=1.2,1H), 5.40 (d, J=1.2Hz, 1H), 3.95 (dd, J = 11.6, 3.7 Hz, 1H), 3.90(q, J =3.4Hz, 4H), 3.81 (s, 3H), 3.05 (dd, J = 14.4,12.2 Hz, 1H), 2.53 (dd, J =12.4, 2.8 Hz, 1H), 2.27-2.25 (m, 1H), 1.97 (s, 6H), 1.91-1.87 (m, 1H), 1.62-1.54 (m, 2H),1.51(t, J =7.0Hz, 6H). ESI-Ms:652.2[M + H]+ .

[0339] Example 39: Preparation of compound 39

[0340] Compound 39 was prepared using the same method as in Example 1, yielding compounds 39A (90 mg) and 39B (80 mg).

[0341] 39A (90 mg) was chirally separated to obtain 39A-1 (35 mg) and 39A-2 (32 mg).

[0342] 1 H NMR (600 MHz, CDCl3) δ: 8.34 (s, 1H), 7.82 (d, J =1.8 Hz, 1H), 7.61– 7.45(m, 2H), 6.95 (s, 1H), 6.93 (s, 1H), 6.39 (t, J =7.8Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.25 (d, J = 7.8 Hz, 1H), 5.66 (d, J =1.2,1H), 5.39 (d, J =1.2Hz, 1H), 4.01 (dd, J = 11.8,3.9 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.00(dd, J = 14.4, 12 Hz, 1H), 2.51 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H),1.89 (s, 6H), 1.85-1.82 (m, 1H), 1.48-1.44 (m, 2H). ESI-Ms:628.1[M + H] + .

[0343] 39B (80 mg) was chirally separated to obtain 39B-1 (25 mg) and 39B-2 (30 mg).

[0344] 1 H NMR (600 MHz, CDCl3) δ: 8.03 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.53– 7.39(m, 2H), 6.77 (s, 1H), 6.63 (s, 1H), 6.45 (t, J =11.8Hz, 1H), 6.25 (s,2H), 5.68 (d, J=1.2,1H), 5.40 (d, J=1.2Hz, 1H), 4.00 (dd, J = 7.8,3.9 Hz,1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.03 (dd, J = 4.4, 2.0 Hz, 1H), 2.56 (dd, J =14.4, 3.8 Hz, 1H), 2.27-2.24 (m, 1H), 2.01 (s, 6H), 1.93-1.87 (m, 1H), 1.67-1.51 (m, 2H). ESI-Ms:628.1[M + H] + .

[0345] Example 40: Preparation of Compound 40

[0346] Compound 40 was prepared using the same method as in Example 1, yielding compounds 40A (58 mg) and 40B (69 mg).

[0347] 40A (58 mg) was chirally separated to obtain 40A-1 (21 mg) and 40A-2 (20 mg).

[0348] 1 H NMR (400 MHz, CDCl3) δ: 8.36 (s, 1H), 7.82 (d, J =1.8 Hz, 1H), 7.63– 7.45(m, 2H), 7.38 (s, 1H), 6.38 (t, J =7.8Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.25 (d, J = 7.8 Hz, 1H), 5.66 (d, J =1.2,1H), 5.39 (d, J =1.2Hz, 1H), 4.00 (dd, J= 11.8,3.9 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.00 (dd, J =14.4, 12 Hz, 1H), 2.51 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.14 (m, 1H), 1.89 (s,6H), 1.85-1.83 (m, 1H), 1.48-1.44 (m, 2H). ESI-Ms:625.2[M + H] + .

[0349] 40B (69 mg) was chirally separated to obtain 40B-1 (25 mg) and 40B-2 (27 mg).

[0350] 1 H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.68 (d, J =7.9 Hz, 1H), 7.53– 7.39(m, 2H), 7.16 (s, 1H), 6.31 (t, J =4.3Hz, 1H), 6.27 (d, J = 7.9 Hz, 1H), 6.19 (d, J = 7.8 Hz, 1H), 5.68 (d, J=1.2,1H), 5.40 (d, J=1.2Hz, 1H), 4.01(dd, J = 14.2,7.8 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.82 (s, 3H), 3.05 (dd, J = 14.4,12.2 Hz, 1H), 2.57 (dd, J = 12., 3.4 Hz, 1H), 2.38-2.34 (m, 1H), 2.09 (s, 6H), 1.97-1.93 (m, 1H), 1.79-1.68 (m, 2H). ESI-Ms:625.2[M + H] + .

[0351] Example 41: Preparation of compound 41

[0352] Compound 41 was prepared using the same method as in Example 1, yielding compounds 41A (72 mg) and 41B (68 mg).

[0353] 41A (72 mg) was split by SFC to obtain 41A-1 (25 mg) and 41A-2 (27 mg).

[0354] 1 H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1H), 7.82 (d, J =1.8 Hz, 1H), 7.60– 7.45(m, 2H), 6.90-6.44 (m, 2H), 6.38 (t, J =7.8Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.24 (d, J = 7.8 Hz, 1H), 5.67 (d, J =1.2,1H), 5.40 (d, J =1.2Hz, 1H), 4.01(dd, J = 11.8,3.9 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.02 (dd, J = 14.4, 12Hz, 1H), 2.52 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.90 (s, 6H), 1.84-1.81 (m, 1H), 1.49-1.44 (m, 2H). ESI-Ms:625.2[M + H] + .

[0355] 41B (68 mg) was split by SFC to obtain 41B-1 (26 mg) and 41B-2 (20 mg).

[0356] 1 H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1H), 7.67 (d, J =2.0 Hz, 1H), 7.41– 7.35(m, 2H), 6.70-6.45 (m, 2H), 6.35 (t, J =7.9Hz, 1H), 6.30 (d, J = 3.9 Hz, 1H), 6.21 (d,J = 1.8 Hz, 1H), 5.68 (d, J=1.2,1H), 5.40 (d, J=1.2Hz, 1H), 3.98 (dd, J = 10.9,4.0 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.04 (dd, J =13.9, 11.1 Hz, 1H), 2.82 (dd, J = 14.4, 3.8 Hz, 1H), 2.38-2.25 (m, 1H), 2.11(s, 6H), 1.95-1.92 (m, 1H), 1.84-1.65 (m, 2H). ESI-Ms:595.2[M + H] + .

[0357] Example 42: Preparation of compound 42

[0358] Compound 42 was prepared using the same method as in Example 1, yielding compounds 42A (83 mg) and 42B (87 mg).

[0359] 42A (69 mg) was split by SFC to obtain 42A-1 (22 mg) and 42A-2 (21 mg).

[0360] 1 H NMR (600 MHz, CDCl3) δ: 8.34 (s, 1H), 7.82 (d, J =2.0 Hz, 1H), 7.61– 7.45(m, 2H), 7.37-7.32(m, 1H), 6.89-6.43 (m, 2H), 6.39 (t, J =7.9Hz, 1H), 6.35(d, J = 7.0 Hz, 1H), 6.26 (d, J = 7.9 Hz, 1H), 5.68 (d, J =1.2,1H), 5.41 (d, J =1.2Hz, 1H), 4.00 (dd, J = 11.8,3.9 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.00(dd, J = 14.4, 12 Hz, 1H), 2.52 (dd,J = 14.4, 3.8 Hz, 1H), 2.18-2.14 (m, 1H),1.89 (s, 6H), 1.85-1.84(m, 1H), 1.50-1.45 (m, 2H). ESI-Ms:660.1[M + H] + .

[0361] 42B (87 mg) was split by SFC to obtain 42B-1 (35 mg) and 42B-2 (29 mg).

[0362] 1 H NMR (600 MHz, CDCl3) δ: 8.01 (s, 1H), 7.67 (d, J =1.8 Hz, 1H), 7.53– 7.41(m, 2H), 7.32-7.30(m, 1H), 6.72-6.54 (m, 2H), 6.32 (t, J =7.4Hz, 1H), 6.20(s, 2H), 5.66(d, J =2.1,1H), 5.38 (d, J =1.2Hz, 1H), 3.98 (dd, J = 10.9,4.0 Hz,1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.05 (dd, J = 13.9,11.1 Hz, 1H), 2.63 (dd, J = 14.1, 4.1 Hz, 1H), 2.29-2.27(m,1H),2.01(s,6H), 1.97-1.95(m, 1H), 1.80-1.65(m, 2H). ESI-Ms:660.1[M + H] + .

[0363] Example 43: Preparation of compound 43

[0364] Compound 43 was prepared using the same method as in Example 1, yielding compounds 43A (83 mg) and 43B (97 mg).

[0365] 43A (83 mg) was split by SFC to obtain 43A-1 (29 mg) and 43A-2 (28 mg).

[0366] 1H NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 7.51 – 7.35(m, 3H), 6.89-6.44(m, 2H), 6.37 (t, J =7.8Hz, 1H), 6.33 (d, J = 7.0 Hz, 1H), 6.24 (d, J = 7.8Hz, 1H), 5.65 (d, J =1.2,1H), 5.37 (d, J =1.2Hz, 1H), 4.01 (dd, J = 11.8,3.9 Hz,1H), 3.90 (s, 6H), 3.87 (s, 3H), 3.00 (dd, J = 14.4, 12 Hz, 1H), 2.51(dd, J =14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.89 (s, 6H), 1.84-1.82 (m, 1H), 1.47-1.43 (m, 2H). ESI-Ms:546.3[M + H] + .

[0367] 43B (97 mg) was split by SFC to obtain 43B-1 (35 mg) and 43B-2 (36 mg).

[0368] 1 H NMR (400 MHz, CDCl3) δ: 7.97 (s, 1H), 7.47 – 7.31(m, 3H), 6.68-6.47(m, 2H), 6.35 (t, J =7.4Hz, 1H), 6.25 (s, 2H), 5.67 (d, J =1.2,1H), 5.40 (d, J =1.2Hz, 1H), 3.99 (dd, J = 10.9,4.0 Hz, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.05(dd, J =13.9, 11.1 Hz, 1H), 2.72(dd, J= 14.1, 4.1 Hz, 1H), 2.35-2.31 (m, 1H), 2.23 (s, 6H), 1.97-1.92 (m, 1H), 1.79-1.61 (m, 2H). ESI-Ms:546.3[M + H] + .

[0369] Example 44: Preparation of compound 44

[0370] Compound 44 was prepared using the same method as in Example 1, yielding compounds 44A (73 mg) and 44B (67 mg).

[0371] 44A (73 mg) was split by SFC to obtain 44A-1 (22 mg) and 44A-2 (21 mg).

[0372] 1 H NMR (400 MHz, CDCl3) δ: 8.32 (s, 1H), 7.81 (d, J =1.8 Hz, 1H), 7.71(dd, J =8.3, 1.8 Hz, 1H), 7.50 (d, J =8.8Hz,1H), 6.88-6.43 (m, 2H), 6.37 (t, J =7.8Hz, 1H), 6.35 (d, J = 7.0 Hz, 1H), 6.26 (d, J = 7.8 Hz, 1H), 5.68 (d, J =1.2,1H), 5.38 (d, J =1.2Hz, 1H), 4.01 (dd, J = 11.8,3.9 Hz, 1H), 3.92 (s, 6H), 3.89 (s, 3H), 3.00 (dd, J = 14.4, 12 Hz, 1H), 2.52 (dd, J = 14.4, 3.8 Hz, 1H),2.19-2.15 (m, 1H), 1.89 (s, 6H), 1.86-1.84 (m, 1H), 1.48-1.44(m, 2H). ESI-Ms:580.2[M + H] + .

[0373] 44B (67 mg) was split by SFC to obtain 44B-1 (22 mg) and 44B-2 (18 mg).

[0374] 1 H NMR (400 MHz, CDCl3) δ: 7.95 (s, 1H), 7.68 (d, J =7.2 Hz, 1H), 7.53 (dd, J =22.7, 7.7 Hz, 1H), 7.32 (d, J =1.8Hz,1H), 6.65-6.47 (m, 2H), 6.35 (t, J =7.8Hz, 1H), 6.20 (s, 2H), 5.65 (d, J =1.2,1H), 5.40 (d, J =1.2Hz, 1H), 3.95 (dd, J = 10.6,4.2 Hz, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.11 (dd, J = 13.9, 10.9 Hz, 1H), 2.47 (dd, J = 14.1, 4.1 Hz, 1H), 2.23-2.20 (m, 1H), 1.99 (s, 6H), 1.93-1.90 (m, 1H), 1.78-1.54(m, 2H). ESI-Ms:580.2[M + H] + .

[0375] Example 45: Preparation of compound 45

[0376] Compound 45 was prepared using the same method as in Example 1, yielding compounds 45A (90 mg) and 45B (95 mg).

[0377] 45A (90 mg) was split by SFC to obtain 45A-1 (33 mg) and 45A-2 (25 mg).

[0378] 1 H NMR (600 MHz, CDCl3) δ: 8.33 (s, 1H), 7.91 (d, J =2.0 Hz, 1H), 7.57– 7.42(m, 2H), 6.85-6.42 (m, 2H), 6.38 (t,J =7.8Hz, 1H), 6.35 (d, J = 7.0 Hz, 1H), 6.26 (d, J = 7.8 Hz, 1H), 5.68 (d, J =1.2,1H), 5.38 (d, J =1.2Hz, 1H), 4.00(dd, J = 11.8,3.9 Hz, 1H), 3.92 (s, 6H), 3.89 (s, 3H), 3.00 (dd, J = 14.4, 12Hz, 1H), 2.52 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.89 (s, 6H), 1.85-1.83 (m, 1H), 1.48-1.43 (m, 2H). ESI-Ms:624.2[M + H] + .

[0379] 45B (95 mg) was split by SFC to obtain 45B-1 (33 mg) and 45B-2 (34 mg).

[0380] 1 H NMR (600 MHz, CDCl3) δ: 8.01 (s, 1H), 7.81 (d, J =1.8 Hz, 1H), 7.45– 7.32(m, 2H), 6.65-6.45 (m, 2H), 6.36 (t, J =7.0Hz, 1H), 6.21 (s, 2H), 5.66(d, J =1.2,1H), 5.40 (d, J =1.2Hz, 1H), 3.99 (dd, J = 11.4,3.6 Hz, 1H), 3.90 (s,6H), 3.85 (s, 3H), 3.15 (dd, J = 14.5,11.5 Hz, 1H), 2.47 (dd, J = 13.9, 11.1Hz, 1H), 2.34-2.30 (m, 1H), 2.01 (s, 6H), 1.97-1.95 (m, 1H), 1.76-1.54 (m, 2H). ESI-Ms:624.2[M + H]+ .

[0381] Example 46: Preparation of Compound 46

[0382] Compound 46 was prepared using the same method as in Example 1, yielding compounds 46A (84 mg) and 46B (95 mg).

[0383] 46A (84 mg) was split by SFC to obtain 46A-1 (27 mg) and 46A-2 (32 mg).

[0384] 1 H NMR (400 MHz, CDCl3) δ:8.33 (s, 1H), 7.82 (d, J =1.8 Hz, 1H), 7.70(dd, J =7.4, 1.0 Hz, 1H), 7.52 (d, J =7.4Hz,1H), 6.88-6.44 (m, 2H), 6.35 (t, J =7.8Hz, 1H), 6.33 (d, J = 7.0 Hz, 1H), 6.27 (d, J = 7.8 Hz, 1H), 5.68 (d, J =1.2,1H), 5.39 (d, J =1.2Hz, 1H), 4.00 (dd, J = 11.8,3.9 Hz, 1H), 3.92 (s, 6H), 3.89 (s, 3H), 3.85 (s, 3H), 3.02 (dd, J = 14.4, 12 Hz, 1H), 2.53 (dd, J = 14.4,3.8 Hz, 1H), 2.18-2.14 (m, 1H), 1.87 (s, 6H), 1.86-1.83 (m, 1H), 1.48-1.43(m,2H). ESI-Ms:576.3[M + H] + .

[0385] 46B (95 mg) was split by SFC to obtain 46B-1 (34 mg) and 46B-2 (32 mg).

[0386] 1H NMR (400 MHz, CDCl3) δ:7.95 (s, 1H), 7.70 (d, J =7.2 Hz, 1H), 7.51(dd, J =7.8, 1.8 Hz, 1H), 7.32 (d, J =7.8Hz,1H), 6.63-6.47 (m, 2H), 6.32 (t, J =7.0Hz, 1H), 6.25 (s, 2H), 5.66 (d, J =1.2,1H), 5.41 (d, J =1.2Hz, 1H), 4.01 (dd, J = 10.9,4.0 Hz, 1H), 3.90 (s, 6H), 3.87 (s, 3H), 3.80 (s, 3H), 3.22 (dd, J =13.9, 11.1 Hz, 1H), 2.67 (dd, J = 14.4, 3.8 Hz, 1H), 2.29-2.27 (m, 1H), 2.23(s, 6H), 1.98-1.96 (m, 1H), 1.87-1.65(m, 2H).ESI-Ms:576.3[M + H] + .

[0387] Example 47: Preparation of Compound 47

[0388] Compound 47 was prepared using the same method as in Example 1, yielding compounds 47A (65 mg) and 47B (78 mg).

[0389] 47A (65 mg) was split by SFC to obtain 47A-1 (20 mg) and 47A-2 (28 mg).

[0390] 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.90 (s, 1H), 7.60 (d, J = 1.4Hz, 2H), 6.78 – 6.43 (m, 5H), 4.06 (dd, J = 12.1, 3.6 Hz, 1H), 3.97 (s, 6H), 3.91 (s, 3H), 3.11 (t, J = 13.1 Hz, 1H), 2.68 (d, J = 13.6 Hz, 1H), 2.19 (d,J = 36.2 Hz, 2H), 1.96 (s, 6H), 1.56 (s, 2H). ESI-Ms:616.2[M + H] + .

[0391] 47B (78 mg) was split by SFC to obtain 47B-1 (30 mg) and 47B-2 (31 mg).

[0392] 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.48 – 7.34 (m, 2H), 6.77 (q, J = 8.5 Hz, 1H), 6.61 – 6.52 (m, 1H), 6.32 (t,J = 6.9 Hz, 1H), 6.20 (s, 2H), 3.94 (dd, J = 11.4, 3.5 Hz, 1H), 3.67 (s, 6H), 3.56 (s, 3H), 2.95 (t, J = 12.6 Hz, 1H), 2.71 – 2.51 (m, 2H), 2.37-2.32 (m, 2H), 2.26 (brs, 7H). ESI-Ms: 616.2[M + H] + .

[0393] Example 48: Preparation of Compound 48

[0394] Compound 48 was prepared using the same method as in Example 1, yielding compounds 48A (75 mg) and 48B (88 mg).

[0395] 48A (75 mg) was split by SFC to obtain 48A-1 (25 mg) and 48A-2 (30 mg).

[0396] 1 H NMR (600 MHz, CDCl3) δ 8.33 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.59– 7.50 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.06 (s, 1H), 6.98 (t, J = 7.7 Hz,1H), 6.88 (d, J = 7.7 Hz, 1H),6.87 – 6.68(m, 2H), 3.97 (dd, J = 11.8, 3.7 Hz,1H), 3.92 (s, 6H), 3.86 (s, 3H), 2.99 (dd, J = 14.7, 11.8 Hz, 1H), 2.73 (dd,J = 14.7, 3.7 Hz, 1H), 2.17 (s, 1H), 1.90 (s, 6H), 1.86 (d, J = 12.9 Hz, 1H),1.59 – 1.42 (m, 2H). ESI-Ms:648.2[M + H] + .

[0397] 48B (88 mg) was split by SFC to obtain 48B-1 (32 mg) and 48B-2 (35 mg).

[0398] 1H NMR (600 MHz, CDCl3) 8.04 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.44 (dd, J = 8.8, 2.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 7.20 (d, J= 7.4 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.20 (s,2H), 3.95 – 3.90 (m, 1H), 3.68 (s, 6H), 3.58 (s, 3H), 3.53 (dd, J = 14.1, 4.0Hz, 1H), 3.02 (dd, J = 14.0, 11.3 Hz, 1H), 2.52-2.48 (m, 1H), 2.35 – 2.22 (m,1H), 2.16 (s, 6H), 2.14 – 2.12 (m, 1H), 1.60 (d, J = 14.6 Hz, 1H).ESI-Ms:648.2[M + H] + .

[0399] Example 49: Preparation of Compound 49

[0400] Compound 49 was prepared using the same method as in Example 1, yielding compounds 49A (85 mg) and 49B (89 mg).

[0401] 49A (85 mg) was split by SFC to obtain 49A-1 (32 mg) and 49A-2 (35 mg).

[0402] 1H NMR (600 MHz, CDCl3) δ 8.38 (s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.56– 7.50 (m, 2H), 6.84 (s, 1H), 6.62 – 6.80 (m, 2H), 6.55 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 4.06 (m, 1H), 3.92 (s, 6H), 3.80 (s,3H), 3.55 (s, 3H), 2.95 (dd, J = 13.9, 11.9 Hz, 1H), 2.60 (dd, J = 14.1, 3.1Hz, 1H), 2.19 – 2.13 (m, 1H), 1.89 (s, 6H), 1.84 (m, 1H), 1.56 – 1.52 (m,2H). ESI-Ms:610.2[M + H] + .

[0403] 49B (89 mg) was split by SFC to obtain 49B-1 (41 mg) and 49B-2 (35 mg).

[0404] 1 H NMR (400 MHz, CDCl3) δ: 8.18 (s, 1H), 7.74 (s, 1H), 7.55 (m, 2H), 6.63 (d, J = 5.8 Hz, 2H), 6.42 (m, 2H), 6.31 (s, 2H), 3.90 (dd, J = 11.4, 3.8Hz, 1H), 3.81 (s, 3H), 3.62 (s, 6H), 3.55 (s, 3H), 3.01 (dd, J = 14.1, 3.8Hz, 1H), 2.59 (m, 1H), 2.32 (m, 2H), 2.20 (s, 6H), 2.15 (m, 1H), 1.66 (m,1H). ESI-Ms: 610.2 [M + H] + .

[0405] Example 50: Preparation of Compound 50

[0406] Compound 50 was prepared using the same method as in Example 1, yielding compounds 50A (95 mg) and 50B (82 mg).

[0407] 50A (95 mg) was split by SFC to obtain 50A-1 (42 mg) and 50A-2 (32 mg).

[0408] 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 3.0Hz, 2H), 6.95 (t, J = 8.0 Hz, 1H), 6.77 (d, J = 9.6 Hz, 1H), 6.69 (d, J = 7.9Hz, 2H), 6.61 – 6.31 (m, 2H), 4.00 (d, J = 3.8 Hz, 1H), 3.97 (s, 6H), 3.92(s, 3H), 3.00 (m, 1H), 2.73 (m, 1H), 2.25 – 2.16 (m, 1H), 1.94 (s, 6H), 1.90– 1.87 (m, 1H), 1.62 – 1.57 (m, 2H). ESI-Ms:664.2[M + H] + .

[0409] 50B (82 mg) was split by SFC to obtain 50B-1 (31 mg) and 50B-2 (30 mg).

[0410] 1H NMR (600 MHz, CDCl3) δ: 8.01 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.8, 2.2 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 6.96 (t, J = 7.9Hz, 1H), 6.88 (s, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.18 (s, 2H), 3.90 (dd, J = 11.2, 4.0 Hz, 1H), 3.68 (s, 6H), 3.61 (s, 3H),3.49 (dd, J = 13.9, 4.1 Hz, 1H), 2.97 (dd, J = 14.0, 11.2 Hz, 1H), 2.54 –2.43 (m, 1H), 2.27 (t, J = 12.9 Hz, 1H), 2.16-2.12 (m, 7H), 1.59 (d, J = 14.5Hz, 2H)..ESI-Ms:664.2[M + H] + .

[0411] Example 51: Preparation of compound 51

[0412] Compound 51 was prepared using the same method as in Example 1, yielding compounds 51A (90 mg) and 51B (83 mg).

[0413] 51A (90 mg) was split by SFC to obtain 51A-1 (33 mg) and 51A-2 (28 mg).

[0414] 1H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.68– 7.57 (m, 2H), 6.63 (s, 2H), 6.19 (s, 1H), 6.16 (d, J = 1.8 Hz, 1H), 6.13(s, 1H), 4.01 (s, 1H), 4.00 (s, 3H), 3.96 (s, 6H), 3.05 – 2.89 (m, 1H), 2.76– 2.61 (m, 1H), 2.21 (q, J = 7.5 Hz, 1H), 2.01 (s, 7H), 1.78 – 1.64 (m, 2H). ESI-Ms: 628.2 [M + H] + .

[0415] 51B (83 mg) was split by SFC to obtain 51B-1 (31 mg) and 51B-2 (35 mg).

[0416] 1 H NMR (600 MHz, CDCl3) δ: 7.97 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.50 – 7.38 (m, 2H), 6.34 (d, J = 9.4 Hz, 1H), 6.21 (d, J = 5.6 Hz, 2H), 6.17(s, 2H), 3.92-3.89 (m, 1H), 3.68 (s, 9H), 3.50 (s, 3H), 3.44 (dd, J = 14.3,4.2 Hz, 1H), 2.95 – 2.87 (m, 1H), 2.45 (t, J = 13.7 Hz, 1H), 2.25 (t, J =14.7 Hz, 1H), 2.15 (s, 7H), 1.57 (d, J = 14.8 Hz, 1H). ESI-Ms:628.2[M + H] + .

[0417] Example 52: Preparation of compound 52

[0418] Compound 52 was prepared using the same method as in Example 1, yielding compounds 52A (70 mg) and 52B (73 mg).

[0419] 52A (70 mg) was split by SFC to obtain 52A-1 (20 mg) and 52A-2 (28 mg).

[0420] 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 1.8Hz, 2H), 7.48 (d, J = 5.2 Hz, 1H), 6.89 – 6.63 (m, 2H), 6.33 (t, J = 4.9 Hz,1H), 4.05 (dd, J = 12.0, 3.6 Hz, 1H), 3.96 (d, J = 2.3 Hz, 9H), 3.83 (s, 3H),3.28 – 3.11 (m, 1H), 2.59 (d, J = 11.6 Hz, 1H), 2.20 (s, 1H), 1.93 (s, 7H), 1.64 – 1.59 (m, 2H). ESI-Ms:629.2[M + H] + .

[0421] 52B (73 mg) was split by SFC to obtain 52B-1 (31 mg) and 52B-2 (27 mg).

[0422] 1 H NMR (600 MHz, CDCl3) δ 8.16 (s, 1H), 7.72 (s, 1H), 7.58 (m, 1H),7.42 (m, J = 1.6 Hz, 2H), 6.40 (m, 1H), 6.15 (s, 2H), 4.11 (dd, J = 9.8, 6.6Hz, 1H), 3.88 (s, 3H), 3.71 (s, 6H), 3.61 (s, 3H), 3.10 (dd, J = 14.0, 4.1Hz, 1H), 3.00 – 2.94 (m, 1H), 2.26 (s, 6H), 1.80 – 1.70 (m, 2H), 1.65 – 1.58(m, 2H). ESI-Ms:629.2[M + H] + .

[0423] Example 53: Preparation of compound 53

[0424] Compound 53 was prepared using the same method as in Example 1, yielding compounds 53A (78 mg) and 53B (83 mg).

[0425] 53A (78 mg) was split by SFC to obtain 53A-1 (25 mg) and 53A-2 (27 mg).

[0426] 1 H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.58– 7.51 (m, 2H), 6.79 – 6.61 (m, 2H), 6.57 (t, J = 9.1 Hz, 1H), 6.34 (dt, J =8.8, 3.5 Hz, 1H), 6.21 (dd, J = 5.9, 3.1 Hz, 1H), 4.01 (dd, J = 12.0, 3.6 Hz,1H), 3.91 (s, 6H), 3.88 (s, 3H), 3.43 (s, 3H), 3.02 (dd, J = 14.4, 12.1 Hz,1H), 2.56 (dd, J = 14.6, 3.4 Hz, 1H), 2.20 – 2.12 (m, 1H), 1.88 (s, 6H), 1.86– 1.81 (m, 1H), 1.57 – 1.52 (m, 2H). ESI-Ms:627.2[M + H]+.

[0427] 53B (83 mg) was split by SFC to obtain 53B-1 (28 mg) and 53B-2 (27 mg).

[0428] 1 H NMR (400 MHz, CDCl3) δ: 8.18 (s, 1H), 7.77 (s, 1H), 7.57-7.40 (m,2H), 6.65 (m, 2H), 6.35 (d, J = 1.6 Hz, 1H), 6.26 (s, 2H), 4.01 (d, J=9.1Hz,1H), 3.80 (s, 3H), 3.73 (s, 6H), 3.60 (s, 3H), 3.00 (t, J = 12.2 Hz, 1H), 2.68 (t, J = 12.5Hz, 1H), 2.36 (d, J= 11.8 Hz, 1H), 2.25 (s, 7H), 1.71 (d, J = 13.6 Hz, 2H). ESI-Ms:627.2[M + H] + .

[0429] Example 54: Preparation of compound 54

[0430] Compound 54 was prepared using the same method as in Example 1, yielding compounds 54A (82 mg) and 54B (83 mg).

[0431] 54A (82 mg) was split by SFC to obtain 54A-1 (27 mg) and 54A-2 (26 mg).

[0432] 1 H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 7.85 (s, 1H), 7.54 (d, J = 1.2Hz, 2H), 7.03 – 6.63 (m, 2H), 6.46 – 6.33 (m, 2H), 4.13 (dd, J = 12.0, 4.0Hz, 1H), 3.91 (s, 6H), 3.85 (s, 3H), 3.58 (s, 3H), 3.24 – 3.17 (m, 1H), 2.50(dd, J = 14.0, 3.7 Hz, 1H), 2.15 (t, J = 12.7 Hz, 1H), 1.88 (s, 6H), 1.85 –1.81 (m, 1H), 1.47 – 1.40 (m, 2H). ESI-Ms:646.2[M + H] + .

[0433] 54B (83 mg) was split by SFC to obtain 54B-1 (28 mg) and 54B-2 (25 mg).

[0434] 1H NMR (400 MHz, CDCl3) δ: 8.25 (s, 1H), 7.85 (s, 1H), 7.61-7.50 (m,2H), 7.25 (m, 2H), 6.28 (s, 2H), 4.11 (d, J=9.0Hz, 1H), 3.86 (s, 3H), 3.74(s, 6H), 3.60 (s, 3H), 3.10 (m, 1H), 2.69 (m, 1H), 2.36 (d, J = 11.8 Hz, 1H),2.26 (s, 7H), 1.73 (m, 2H). ESI-Ms:646.2[M + H] + .

[0435] Example 55: Preparation of compound 55

[0436] Compound 55 was prepared using the same method as in Example 1, yielding compounds 55A (82 mg) and 55B (83 mg).

[0437] 55A (82 mg) was split by SFC to obtain 55A-1 (32 mg) and 55A-2 (31 mg).

[0438] 1 H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 7.93 – 7.88 (m, 1H), 7.62 (t,J = 1.5 Hz, 2H), 6.91 – 6.68(m, 2H), 6.46 (ddd, J = 10.2, 8.7, 1.6 Hz, 1H), 6.37 (td, J = 8.1, 5.8 Hz, 1H), 4.05 – 4.02 (m, 1H), 3.99 (s, 6H), 3.93 (s, 3H), 3.75 (s, 3H), 3.04 (dd, J = 14.1, 12.2 Hz, 1H), 2.63 (dd, J = 14.5, 3.8Hz, 1H), 2.22 (s, 1H), 1.96 (s, 6H), 1.92 (d, J = 12.9 Hz, 1H), 1.59 (m,2H). ESI-Ms:646.2[M + H] + .

[0439] 55B (83 mg) was split by SFC to obtain 55B-1 (30 mg) and 55B-2 (25 mg).

[0440] 1 H NMR (400 MHz, CDCl3) δ: 8.26 (s, 1H), 7.88 (s, 1H), 7.61-7.55 (m,2H), 7.35 (m, 2H), 6.25 (s, 2H), 4.10 (d, J=9.0Hz, 1H), 3.88 (s, 3H), 3.72(s, 6H), 3.61 (s, 3H), 3.05 (m, 1H), 2.69 (m, 1H), 2.36 (d, J = 11.6 Hz, 1H),2.26 (s, 7H), 1.70 (m, 2H). ESI-Ms:646.2[M + H] + .

[0441] Example 56: Preparation of Compound 56

[0442] Compound 56 was prepared using the same method as in Example 1, yielding compounds 56A (92 mg) and 56B (103 mg).

[0443] 56A (92 mg) was split by SFC to obtain 56A-1 (37 mg) and 56A-2 (36 mg).

[0444] 1 H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H), 7.84 (s, 1H), 7.56 (d, J = 1.6Hz, 2H), 6.97 – 6.66 (m, 2H), 6.47 (q, J = 8.0, 7.5 Hz, 1H), 6.40 – 6.32 (m,1H), 3.96 (dd, J = 11.9, 3.7 Hz, 1H), 3.92 (s, 6H), 3.87 (s, 3H), 3.02 – 2.96(m, 1H), 2.60 (dd, J = 14.5, 3.4 Hz, 1H), 2.18 – 2.13 (m, 1H), 1.89 (s, 6H),1.85 (m, 1H), 1.51 – 1.46 (m, 2H). ESI-Ms:634.2[M + H] + .

[0445] 56B (103 mg) was split by SFC to obtain 56B-1 (38 mg) and 56B-2 (35 mg).

[0446] 1 H NMR (400 MHz, CDCl3) δ: 8.28 (s, 1H), 7.89 (s, 1H), 7.70-7.52 (m, 4H), 6.23 (s, 2H), 4.10 (d, J=9.1Hz, 1H), 3.89 (s, 6H), 3.71 (s, 3H), 3.10(m, 1H), 2.68 (m, 1H), 2.46 (d, J = 11.6 Hz, 1H), 2.35 (m, 1H), 2.26 (s, 6H), 1.70 (m, 2H). ESI-Ms:634.2[M + H] + .

[0447] Example 57: Preparation of Compound 57

[0448] Compound 57 was prepared using the same method as in Example 1, yielding compounds 57A (132 mg) and 57B (123 mg).

[0449] 57A (132 mg) was split by SFC to obtain 57A-1 (47 mg) and 57A-2 (46 mg).

[0450] 1 H NMR (600 MHz, CDCl3) δ 8.39 (s, 1H), 7.84 (s, 1H), 7.55 (s, 2H), 6.82 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 7.9 Hz, 1H), 6.57 (t, J = 6.6 Hz, 1H), 6.49 – 6.19 (m, 2H), 4.01 (dd, J = 12.0, 3.7 Hz, 1H), 3.92 (s, 6H), 3.82 (s,3H), 3.05 – 2.98 (m, 1H), 2.67 (dd, J = 14.3, 3.4 Hz, 1H), 2.17 – 2.13 (m,1H), 1.90 (s, 6H), 1.85 (m, 1H), 1.54 – 1.51 (m, 2H). ESI-Ms:682.2[M + H] +.

[0451] 57B (123 mg) was split by SFC to obtain 57B-1 (48 mg) and 57B-2 (55 mg).

[0452] 1 H NMR (400 MHz, CDCl3) δ: 8.20 (s, 1H), 7.79 (s, 1H), 7.61-7.50 (m,2H), 6.90 – 6.65 (m, 3H), 6.23 (s, 2H), 4.05 (d, J=9.0Hz, 1H), 3.86 (s, 6H),3.60 (s, 3H), 3.02 (m, 1H), 2.65 (m, 1H), 2.33 (m, 2H), 2.24 (s, 6H), 1.70(m, 2H). ESI-Ms:682.2[M + H] + .

[0453] Example 58: Preparation of compound 58

[0454] Compound 58 was prepared using the same method as in Example 1, yielding compounds 58A (72 mg) and 58B (79 mg).

[0455] 58A (72 mg) was split by SFC to obtain 58A-1 (27 mg) and 58A-2 (23 mg).

[0456] 1 H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.60 (d, J = 2.0Hz, 2H), 6.73 (t, J = 6.2 Hz, 1H), 6.7 – 6.6 (m, 2H), 6.61 – 6.52 (m, 2H), 4.09 (dd, k = 12.0, 3.7 Hz, 1H), 3.97 (s, 6H), 3.91 (s, 3H), 3.11 – 2.99 (m,1H), 2.70 – 2.62 (m, 1H), 2.21 (t, J = 12.4 Hz, 1H), 2.05 (d, J = 2.1 Hz, 3H), 1.94 (s, 6H), 1.88 (s, 1H), 1.60 (s, 2H). ESI-Ms:612.2[M + H] + .

[0457] 58B (79 mg) was split by SFC to obtain 58B-1 (28 mg) and 58B-2 (35 mg).

[0458] 1 H NMR (400 MHz, CDCl3) δ: 8.21 (s, 1H), 7.79 (s, 1H), 7.60-7.50 (m,2H), 6.70 (t, J = 6.0 Hz, 1H), 6.56 – 6.43 (m, 2H), 6.27 (s, 2H), 4.04 (d, J=9.2Hz, 1H), 3.81 (s, 6H), 3.74 (s, 3H), 3.10 (m, 1H), 2.69 (t, J = 12.4Hz, 1H), 2.42 (d, J = 11.6 Hz, 1H), 2.25 (s, 7H), 2.01 (s, 3H), 1.72 (m, 2H). ESI-Ms: 612.2 [M + H] + .

[0459] Example 59: Preparation of compound 59

[0460] Compound 59 was prepared using the same method as in Example 1, yielding compounds 59A (92 mg) and 59B (105 mg).

[0461] 59A (92 mg) was split by SFC to obtain 59A-1 (30 mg) and 59A-2 (43 mg).

[0462] 1 H NMR (600 MHz, CDCl3) δ 8.31 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.58– 7.53 (m, 2H), 7.0-6.75(m,2H), 6.67 (dd, J = 8.5, 5.6 Hz,1H), 6.59 (d, J =8.8 Hz, 2H), 3.92 (s, 6H), 3.90(m, 1H), 3.86 (s, 3H), 2.92-2.85(m, 1H), 2.80(s, 1H), 2.62(dd, 1H), 2.1(m, 1H), 1.89 (s, 6H), 1.8(s,1H), 1.6(s,2H). ESI-Ms:616.2[M + H] + .

[0463] 59B (105 mg) was split by SFC to obtain 59B-1 (40 mg) and 59B-2 (45 mg).

[0464] 1 H NMR (400 MHz, CDCl3) δ: 8.21 (s, 1H), 7.79 (s, 1H), 7.64-7.55 (m,2H), 7.08 – 6.83 (m, 3H),, 6.29 (s, 2H), 4.14 (d, J=9.1Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.14 (m, 1H), 2.73 (t, J = 12.1Hz, 1H), 2.36 (m, 1H), 2.25 (s,7H), 1.74 (m, 2H). ESI-Ms:616.2[M + H] + .

[0465] Example 60: Preparation of Compound 60

[0466] Compound 60 was prepared using the same method as in Example 1, yielding compounds 60A (72 mg) and 60B (85 mg).

[0467] 60A (92 mg) was split by SFC to obtain 60A-1 (21 mg) and 60A-2 (23 mg).

[0468] 1H NMR (600 MHz, CDCl3) δ 8.31 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.0-6.75(m, 2H), 6.67 (dd, J = 8.5, 5.6 Hz, 2H), 6.59 (d,J = 8.8 Hz, 2H), 3.92 (s, 6H), 3.90(m, 1H), 3.86 (s, 3H), 2.92-2.85(m, 1H), 2.80(s, 1H), 2.62(dd, 1H), 2.1(m, 1H), 1.89 (s, 6H), 1.8(s, 1H), 1.6(m, 2H). ESI-Ms: 598.2 [M + H] + .

[0469] 60B (85 mg) was split by SFC to obtain 60B-1 (30 mg) and 60B-2 (31 mg).

[0470] 1 H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 7.75 (s, 1H), 7.55-7.47 (m,2H), 6.85(m,2H), 6.60 (m, 2H), 5.98 (s, 2H), 3.94 (d, J=9.2Hz, 1H), 3.72 (s,6H), 3.66 (s, 3H), 2.95 (m, 1H), 2.60 (t, J = 12.4Hz, 1H), 2.52 (d, J = 11.6Hz, 1H), 2.15 (s, 7H), 1.73 (m, 2H). ESI-Ms:598.2[M + H] + .

[0471] Example 61: Preparation of compound 61

[0472] Compound 61 was prepared using the same method as in Example 1, yielding compounds 61A (82 mg) and 61B (85 mg).

[0473] 61A (82 mg) was split by SFC to obtain 61A-1 (30 mg) and 61A-2 (33 mg).

[0474] 1 H NMR (600 MHz, CDCl3) δ 8.33 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.62– 7.50 (m, 2H), 6.9(m, 1H), 6.7-6.6(m, 2H), 6.53 (m, 2H), 4.15(dd, 1H), 3.92(s, 6H), 3.91 (s, 3H), 3.01 (dd, J = 14.6, 11.9 Hz, 1H), 2.75 (dd, J = 14.7,3.8 Hz, 1H), 2.45 (dd, 1H), 1.88 (s, 6H), 1.85(m, 1H), 1.61 – 1.49 (m, 3H). ESI-Ms: 634.1 [M + H] + .

[0475] 61B (85 mg) was split by SFC to obtain 61B-1 (30 mg) and 61B-2 (32 mg).

[0476] 1 H NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 7.79 (s, 1H), 7.60-7.49 (m,2H), 6.95(m,2H), 6.62 (m, 2H), 6.10 (s, 2H), 3.93 (m, 1H), 3.75 (s, 6H), 3.60(s, 3H), 3.05 (m, 1H), 2.66 (m, 1H), 2.45 (d, J = 11.6 Hz, 1H), 2.25 (s, 6H), 2.15 (s, 1H), 1.75 (m, 2H). ESI-Ms:634.1[M + H] + .

[0477] Example 62: Preparation of compound 62

[0478] Compound 62 was prepared using the same method as in Example 1, yielding compounds 62A (62 mg) and 62B (65 mg).

[0479] 62A (62 mg) was split by SFC to obtain 62A-1 (27 mg) and 62A-2 (20 mg).

[0480] 1 H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 8.05 (m, 3H), 7.72 (d, J = 5.3Hz, 2H), 7.60 – 7.53 (m, 2H), 6.79 – 6.43 (m, 2H), 4.15 (d, J = 3.2 Hz, 1H), 3.98 (s, 3H), 3.85 (s, 6H), 3.15 (dd, J = 14.7, 12.2 Hz, 1H), 2.75 (dd, J =14.8, 3.2 Hz, 1H), 2.24 (t, J = 12.9 Hz, 1H), 1.98 (s, 6H), 1.85 (m, 1H),1.54 – 1.45 (m, 2H). ESI-Ms:581.2[M + H] + .

[0481] 62B (65 mg) was split by SFC to obtain 62B-1 (20 mg) and 62B-2 (27 mg).

[0482] 1 H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 5.2 Hz, 2H), 7.97 (s, 1H), 7.69(d, J = 2.2 Hz, 1H), 7.51 – 7.37 (m, 2H), 6.87 (d, J = 5.4 Hz, 2H), 6.16 (s,2H), 3.94 (dd, J = 11.5, 3.9 Hz, 1H), 3.69 (s, 6H), 3.64 (s, 3H), 3.48 (dd, J= 14.2, 3.9 Hz, 1H), 3.00 – 2.87 (m, 1H), 2.59 – 2.47 (m, 2H), 2.28 (s, 6H),2.22 (d, J = 12.8 Hz, 1H), 1.73 (d, J = 14.3 Hz, 1H). ESI-Ms:581.2[M + H] + .

[0483] Example 63: Preparation of compound 63

[0484] Compound 63 was prepared using the same method as in Example 1, yielding compounds 63A (58 mg) and 63B (65 mg).

[0485] 63A (58 mg) was split by SFC to obtain 63A-1 (17 mg) and 63A-2 (20 mg).

[0486] 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 7.60 (m, 2H), 6.61 – 6.53 (m, 2H), 6.29 – 6.21 (m, 3H), 4.04 (dd, J = 11.9, 3.4 Hz, 1H),3.97 (s, 6H), 3.91 (s, 3H), 3.14 – 3.03 (m, 1H), 2.64 (dd, J = 14.3, 3.7 Hz,1H), 2.28 – 2.15 (m, 1H), 1.95 (s, 6H), 1.88 (m, 1H), 1.56 – 1.50 (m, 2H). ESI-Ms: 614.2 [M + H] + .

[0487] 63B (65 mg) was split by SFC to obtain 63B-1 (20 mg) and 63B-2 (23 mg).

[0488] 1 H NMR (400 MHz, CDCl3) δ: 8.21 (s, 1H), 7.80 (s, 1H), 7.48-7.40 (m,2H), 6.29 – 6.15 (m, 3H), 5.98 (s, 2H), 3.98 (d, J=9.1Hz, 1H), 3.78 (s, 6H),3.62 (s, 3H), 3.02 (m, 1H), 2.63 (m, 1H), 2.36 (d, J = 11.6 Hz, 1H), 2.20 (s,7H), 1.70 (m, 2H). ESI-Ms:614.2[M + H] + .

[0489] Example 64: Preparation of Compound 64

[0490] Compound 64 was prepared using the same method as in Example 1, yielding compounds 64A (88 mg) and 64B (93 mg).

[0491] 64A (88 mg) was split by SFC to obtain 64A-1 (37 mg) and 64A-2 (33 mg).

[0492] 1H NMR (600 MHz, CDCl3) δ 8.20 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.65(d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 1H), 7.0-6.65(m, 2H), 6.60 – 6.46 (m, 2H), 6.26 (dd, J = 7.7, 1.3 Hz, 1H), 5.70 – 5.58 (m, 2H), 3.99 (s, 3H), 3.89 (s, 6H), 3.48 (dd, J = 11.5, 2.8 Hz, 1H), 2.22 (m, 1H), 2.0(m,1H),1.84 (s, 6H), 1.69(m,2H), 1.38 (m, 1H), 0.81 (m, 1H). ESI-Ms: 638.2[M + H] + .

[0493] 64B (93 mg) was split by SFC to obtain 64B-1 (40 mg) and 64B-2 (32 mg).

[0494] 1 H NMR (600 MHz, CDCl3) δ: 7.96 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.55-7.46 (m, 2H), 6.46 - 6.33 (m, 3H), 6.10 (s, 2H), 5.70 (s, 2H), 3.92(m,1H), 3.75 (s, 6H), 3.68 (s, 3H), 2.45 (m, 2H), 2.29-2.27 (m, 3H), 2.01 (s,6H), 1.61-1.45 (m, 4H). ESI-Ms: 638.2[M + H] + .

[0495] Example 65: Preparation of Compound 65

[0496] Compound 65 was prepared using the same method as in Example 1, yielding compounds 65A (80 mg) and 65B (83 mg).

[0497] 65A (80 mg) was split by SFC to obtain 65A-1 (33 mg) and 65A-2 (33 mg).

[0498] 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.88 (s, 1H), 7.61 (d, J = 2.9Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.70 – 6.40 (m,2H), 4.00 (d, J = 3.4 Hz, 1H), 3.97 (s, 6H), 3.90 (s, 3H), 3.03 (dd, J =14.3, 11.7 Hz, 1H), 2.77 (dd, J = 14.8, 3.4 Hz, 1H), 2.27 – 2.21 (m, 1H),1.94 (s, 6H), 1.91 – 1.86 (m, 1H), 1.56 – 1.43 (m, 2H). ESI-Ms:648.2[M + H] + .

[0499] 65B (83 mg) was split by SFC to obtain 65B-1 (30 mg) and 65B-2 (36 mg).

[0500] 1 H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1H), 7.76 (s, 1H), 7.63 (m, 2H), 7.12 (m, 1H), 7.06 (m, 2H), 6.30 (s, 2H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H),3.86 (s, 3H), 3.65 (s, 6H), 3.44 (dd, J = 14.0, 3.7 Hz, 1H), 2.95 (m, 1H),2.56 – 2.47 (m, 2H), 2.25 (s, 6H), 2.17 (m, 1H), 1.72 (m, 1H). ESI-Ms:648.2[M+ H] + .

[0501] Example 66: Preparation of Compound 66

[0502] Compound 66 was prepared using the same method as in Example 1, yielding compounds 66A (100 mg) and 66B (120 mg).

[0503] 66A (100 mg) was split by SFC to obtain 66A-1 (43 mg) and 66A-2 (40 mg).

[0504] 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.89 (s, 1H), 7.59 (d, J = 1.2Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H), 6.86 (t, J = 6.9 Hz, 1H), 6.73 (t, J = 7.9Hz, 1H), 6.65 – 6.29 (m, 2H), 4.09 (dd, J = 11.8, 3.9 Hz, 1H), 3.96 (s, 6H), 3.86 (s, 3H), 3.08 – 2.98 (m, 1H), 2.77 (dd, J = 14.8, 3.8 Hz, 1H), 2.24 –2.16 (m, 1H), 1.96 (s, 6H), 1.92 – 1.86 (m, 1H), 1.59 – 1.55 (m, 2H). ESI-Ms:666.2[M + H] + .

[0505] 66B (120 mg) was split by SFC to obtain 66B-1 (48 mg) and 66B-2 (46 mg).

[0506] 1 H NMR (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.75 (s, 1H), 7.61 (m, 1H), 7.42 (m, 1H), 7.26 – 7.07 (m, 2H), 6.12 (s, 2H), 3.94 (m, 1H), 3.82 (s, 3H),3.66 (s, 6H), 3.24 (dd, J = 14.0, 3.7 Hz, 1H), 3.10 (m, 1H), 2.57 (m, 2H),2.20 (s, 7H), 1.72 (m, 1H). ESI-Ms:666.2[M + H] + .

[0507] Example 67: Preparation of Compound 67

[0508] Compound 67 was prepared using the same method as in Example 1, yielding compounds 67A (110 mg) and 67B (115 mg).

[0509] 67A (110 mg) was split by SFC to obtain 67A-1 (41 mg) and 67A-2 (42 mg).

[0510] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.64– 7.56 (m, 2H), 6.91 – 6.85 (m, 1H), 6.60 (m, 1H), 6.57 – 6.50 (m, 2H), 6.47– 6.13 (m, 2H), 4.00 (d, J = 3.4 Hz, 1H), 3.97 (s, 6H), 3.94 (s, 3H), 2.98 (dd, J = 14.6, 12.1 Hz, 1H), 2.70 (dd, J = 14.3, 3.2 Hz, 1H), 2.22 – 2.16 (m,1H), 1.93 (s, 6H), 1.89 (m, 1H), 1.50 (m, 2H). ESI-Ms:598.2[M + H] + .

[0511] 67B (115 mg) was split by SFC to obtain 67B-1 (44 mg) and 67B-2 (46 mg).

[0512] 1 H NMR (400 MHz, CDCl3) δ: 8.14 (s, 1H), 7.79 (s, 1H), 7.56-7.47 (m,2H), 6.85(m,3H), 6.60 (d, J=2.1Hz, 1H), 5.98 (s, 2H), 3.94 (d, J=9.2Hz, 1H),3.72 (s, 6H), 3.63 (s, 3H), 2.95 (m, 1H), 2.61 (t, J = 12.4Hz, 1H), 2.52 (d,J = 11.4 Hz, 1H), 2.15 (s, 7H), 1.72 (m, 2H). ESI-Ms:598.2[M + H] + .

[0513] Example 68: Preparation of Compound 68

[0514] Compound 68 was prepared using the same method as in Example 1, yielding compounds 68A (50 mg) and 68B (55 mg).

[0515] 68A (50 mg) was split by SFC to obtain 68A-1 (18 mg) and 68A-2 (20 mg).

[0516] 1 H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.62– 7.51 (m, 2H), 7.0-6.5(m,2H), 6.22 (d, J = 9.4 Hz, 1H), 6.18 (d, J = 4.8 Hz,1H), 5.74 (d, J = 1.5 Hz, 1H), 5.45 (d, J = 1.5 Hz, 1H), 3.97 (dd, 1H), 3.91(s, 6H), 3.89 (s, 3H), 2.94 (dd, J = 14.4, 11.7 Hz, 1H), 2.48 (dd, 1H), 1.88(s, 6H), 1.84 (m, 1H), 1.53(m, 2H). ESI-Ms: 642.2[M + H] + .

[0517] 68B (55 mg) was split by SFC to obtain 68B-1 (20 mg) and 68B-2 (16 mg).

[0518] 1 H NMR (600 MHz, CDCl3) δ: 8.05 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H),7.56-7.45 (m, 2H), 6.40 (d, J =7.9Hz, 1H), 6.31 (d, J= 7.9 Hz, 1H), 6.11 (s, 2H), 5.75 (s, 2H), 3.94 (m, 1H), 3.71 (s, 6H), 3.69 (s, 3H), 3.11 (m, 1H), 2.89-2.82 (m, 1H), 2.29-2.26 (m, 1H), 2.05 (s, 6H), 1.67-1.60 (m, 2H). ESI-Ms: 642.2[M + H] + .

[0519] Example 69: Preparation of Compound 69

[0520] Compound 69 was prepared using the same method as in Example 1, yielding compounds 69A (90 mg) and 69B (96 mg).

[0521] 69A (90 mg) was split by SFC to obtain 69A-1 (30 mg) and 69A-2 (32 mg).

[0522] 1 H NMR (600 MHz, CDCl3) δ 8.30 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.63– 7.46 (m, 2H), 7.2-7.0(m,2H),6.96 – 6.81 (m, 2H), 6.65 (d, J = 8.2 Hz, 2H),3.92 (s, 6H), 3.90(dd,1H),3.86 (s, 3H), 2.89 (dd, J = 14.4, 12.0 Hz, 1H),2.62 (dd, J = 14.4, 3.4 Hz, 1H), 2.15 (d, J = 12.6 Hz, 1H), 1.98 (m, 1H),1.89 (s, 6H), 1.85 (m, 1H), 1.52 (m, 1H). ESI-Ms:616.1[M + H] + .

[0523] 69B (96 mg) was split by SFC to obtain 69B-1 (43 mg) and 69B-2 (40 mg).

[0524] 1H NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.72 (s, 1H), 7.52-7.44 (m,2H), 6.80 (m,2H), 6.61 (m, 2H), 5.97 (s, 2H), 3.94 (d, J=9.1Hz, 1H), 3.70 (s,6H), 3.62 (s, 3H), 2.96 (m, 1H), 2.62 (t, J = 12.3Hz, 1H), 2.52 (d, J = 11.5Hz, 1H), 2.17 (s, 7H), 1.70 (m, 2H). ESI-Ms:616.1[M + H] + .

[0525] Example 70: Preparation of Compound 70

[0526] Compound 70 was prepared using the same method as in Example 1, yielding compounds 70A (105 mg) and 70B (116 mg).

[0527] 70A (105 mg) was split by SFC to obtain 70A-1 (40 mg) and 70A-2 (44 mg).

[0528] 1 H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.69– 7.57 (m, 2H), 7.25-7.0(m,2H), 6.77 (d, J = 7.8 Hz, 2H), 6.70 (d, J = 7.9 Hz,2H), 4.1(m,1H),3.99 (s, 6H), 3.95 (s, 3H), 3.01 – 2.94 (m, 1H), 2.86 (s, 4H),2.78 (s, 2H), 2.69 (dd, J = 14.6, 3.3 Hz, 1H), 2.22(m,1H), 2.12 (m, 1H), 1.95(s, 6H), 1.54(m,2H). ESI-Ms:594.2[M + H] + .

[0529] 70B (116 mg) was split by SFC to obtain 70B-1 (43 mg) and 70B-2 (44 mg).

[0530] 1 H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 7.75 (s, 1H), 7.54-7.44 (m,2H), 6.85 (m,2H), 6.60 (m, 2H), 5.99 (s, 2H), 3.98 (d, J=9.2Hz, 1H), 3.74 (s, 6H), 3.65 (s, 3H), 2.99 (m, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 2.25 (s, 3H), 2.15 (s, 6H), 2.08 (s, 1H), 1.70 (m, 2H). ESI-Ms:594.2[M + H] + .

[0531] Example 71: Preparation of Compound 71

[0532] Compound 71 was prepared using the same method as in Example 1, yielding compounds 71A (95 mg) and 71B (96 mg).

[0533] 71A (95 mg) was split by SFC to obtain 71A-1 (30 mg) and 71A-2 (35 mg).

[0534] 1 H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.58– 7.51 (m, 2H),7.0-6.8(m,2H),6.64 (d, J = 8.6 Hz, 2H), 6.47 – 6.40 (m, 2H),3.92 (s, 6H), 3.90 (d, J = 3.3 Hz, 1H), 3.87 (s, 3H),3.55(s,3H), 2.87 (dd, J= 14.5, 12.1 Hz, 1H), 2.61 (d, J = 3.3 Hz, 1H), 2.15(m,1H),1.88(s, 6H),1.85(m,1H),1.55(m,2H). ESI-Ms:610.2[M + H] + .

[0535] 71B (96 mg) was split by SFC to obtain 71B-1 (33 mg) and 71B-2 (34 mg).

[0536] 1 H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.70 (s, 1H), 7.50-7.41 (m,2H), 6.75 (m,2H), 6.50 (m, 2H), 5.95 (s, 2H), 3.90 (d, J=9.2Hz, 1H), 3.80 (s,3H), 3.73 (s, 6H), 3.60 (s, 3H), 2.95 (m, 1H), 2.60 (m, 1H), 2.54 (m, 1H),2.25 (s, 1H), 2.15 (s, 7H), 1.73 (m, 2H). ESI-Ms:610.2[M + H] + .

[0537] Example 72: Preparation of compound 72

[0538] Compound 72 was prepared using the same method as in Example 1, yielding compounds 72A (85 mg) and 72B (90 mg).

[0539] 72A (85 mg) was split by SFC to obtain 72A-1 (30 mg) and 72A-2 (31 mg).

[0540] 1 H NMR (400 MHz, CDCl3 ) δ 8.50 (s, 1H), 7.91 (s, 1H), 7.61 (d, J =1.4 Hz, 2H), 7.5-7.1(m,2H),7.08 (dd, J = 7.9, 1.3 Hz, 1H), 6.78 (d, J = 1.4Hz, 1H), 6.72 – 6.62 (m, 2H), 4.20(m,1H), 4.15 (s, 6H), 3.88 (s, 3H), 3.24 –3.11 (m, 2H), 2.25(m,1H),1.97 (s, 6H),1.9(m,1H), 1.59(m,2H). ESI-Ms: 616.1 [M+ H] + .

[0541] 72B (90 mg) was split by SFC to obtain 72B-1 (33 mg) and 72B-2 (39 mg).

[0542] 1H NMR (400 MHz, CDCl3) δ: 8.20 (s, 1H), 7.79 (s, 1H), 7.56-7.44 (m,2H), 6.86 (m,2H), 6.65 (m, 2H), 6.05 (s, 2H), 3.98 (d, J=9.1Hz, 1H), 3.71 (s, 6H), 3.60 (s, 3H), 3.02 (m, 1H), 2.62 (t, J = 12.3Hz, 1H), 2.52 (d, J = 11.5Hz, 1H), 2.17 (s, 7H), 1.70 (m, 2H). ESI-Ms:616.1[M + H] + .

[0543] Example 73: Preparation of Compound 73

[0544] Compound 73 was prepared using the same method as in Example 1, yielding compounds 73A (77 mg) and 73B (85 mg).

[0545] 73A (77 mg) was split by SFC to obtain 73A-1 (23 mg) and 73A-2 (31 mg).

[0546] 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.88 (t, J = 1.3 Hz, 1H), 7.62– 7.54 (m, 2H), 7.2-6.9(m, 2H), 6.87 – 6.77 (m, 2H), 6.71 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.02 (dd, J = 12.0, 3.3 Hz, 1H), 3.96 (s, 6H), 3.87 (s, 3H), 3.03 (dd, J = 14.6, 12.0 Hz, 1H), 2.68 – 2.63 (m, 1H), 2.2(m,1H), 2.01 (s, 3H), 1.95 (s, 6H), 1.62(m,2H). ESI-Ms:594.2[M + H] + .

[0547] 73B (85 mg) was split by SFC to obtain 73B-1 (25 mg) and 73B-2 (29 mg).

[0548] 1 H NMR (400 MHz, CDCl3) δ: 8.16 (s, 1H), 7.78 (s, 1H), 7.58-7.46 (m,2H), 6.88 (m,2H), 6.65 (m, 2H), 6.10 (s, 2H), 3.98 (d, J=9.1Hz, 1H), 3.77 (s, 6H), 3.61 (s, 3H), 2.97 (m, 1H), 2.68 (m, 1H), 2.55 (m, 1H), 2.25 (s, 3H), 2.15 (s, 6H), 2.08 (s, 1H), 1.73 (m, 2H). ESI-Ms:594.2[M + H] + .

[0549] Example 74: Preparation of Compound 74

[0550] Compound 74 was prepared using the same method as in Example 1, yielding compounds 74A (97 mg) and 74B (95 mg).

[0551] 74A (97 mg) was split by SFC to obtain 74A-1 (30 mg) and 74A-2 (35 mg).

[0552] 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.91 (s, 1H), 7.61 (d, J =1.6 Hz, 2H), 6.90 (m, 1H), 6.72 (m, 3H), 4.07 (m, 1H), 3.99 (s, 6H), 3.90 (s,3H), 3.08 (d, J = 13.1 Hz, 1H), 2.67 (d, J = 14.8 Hz, 1H), 2.21 (d, J = 11.4Hz, 1H), 1.96 (s, 6H), 1.90 (s, 1H), 1.60 (m, 2H). ESI-Ms:598.2[M + H] + .

[0553] 74B (95 mg) was split by SFC to obtain 74B-1 (40 mg) and 74B-2 (40 mg).

[0554] 1H NMR (400 MHz, CDCl3) δ: 8.22 (s, 1H), 7.81 (s, 1H), 7.55-7.44 (m,2H), 6.85 (m,2H), 6.66 (m, 2H), 6.15 (s, 2H), 3.98 (d, J=9.4Hz, 1H), 3.75 (s,6H), 3.65 (s, 3H), 3.01 (m, 1H), 2.62 (m, 1H), 2.52 (d, J = 11.4 Hz, 1H), 2.19 (s, 7H), 1.73 (m, 2H). ESI-Ms:598.2[M + H] + .

[0555] Example 75: Preparation of Compound 75

[0556] Compound 75 was prepared using the same method as in Example 1, yielding compounds 75A (67 mg) and 75B (75 mg).

[0557] 75A (67 mg) was split by SFC to obtain 75A-1 (30 mg) and 75A-2 (26 mg).

[0558] 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.30 (s, 1H), 8.12 (d, J =2.2 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 6.56 (dd, J= 8.5, 5.8 Hz, 1H), 6.49 (s, 2H), 6.27 (t, J = 8.5 Hz, 1H), 5.62 (s, 1H), 4.11 – 4.06 (m, 1H), 3.92 (s, 3H), 3.87 (s, 6H), 3.08 – 2.96 (m, 3H), 2.85 (m, 1H), 2.48 (p, J = 1.8 Hz, 6H), 2.4(d, 1H), 2.25(m,1H). ESI-Ms:640.2[M + H] + .

[0559] 75B (75 mg) was split by SFC to obtain 75B-1 (25 mg) and 75B-2 (32 mg).

[0560] 1 H NMR (400 MHz, DMSO-d6) δ: 8.65 (s, 1H), 8.24 (d, J =1.9Hz,1H), 7.89-7.74 (m, 2H), 7.48 (t, J =7.9Hz, 1H), 7.41 (d, J =7.6Hz, 1H), 6.45 (s, 2H), 4.55 (m, 1H), 4.44-4.36 (m, 1H), 4.07 (dd, J =10.8, 3.8Hz, 1H), 3.78(s, 6H),3.65 (s, 3H),3.44 (dd, J =13.8,4.2Hz, 1H), 3.14 (m, 1H), 2.92 (dd, J = 13.7,11.1 Hz, 1H), 2.78(m, 1H), 2.26 (s, 6H), 1.65 (m, 2H). ESI-Ms:640.2[M + H] + .

[0561] Example 76: Preparation of Compound 76

[0562] Compound 76 was prepared using the same method as in Example 1, yielding compounds 76A (57 mg) and 76B (85 mg).

[0563] 76A (57 mg) was split by SFC to obtain 76A-1 (20 mg) and 76A-2 (22 mg).

[0564] 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 2.2 Hz, 2H), 6.28 – 6.12 (m, 2H), 5.83 (dd, J = 10.0, 1.5 Hz, 2H), 4.04 (dd, J = 12.0, 3.7 Hz, 1H), 3.98 (s, 6H), 3.96 (s, 3H), 3.04 (dd, J =14.4, 12.1 Hz, 1H), 2.61 (dd, J = 14.5, 3.6 Hz, 1H), 1.95 (s, 6H), 1.89 (s, 1H), 1.59 (d, J = 14.8 Hz, 2H). ESI-Ms: 642.2[M + H] + .

[0565] 76B (85 mg) was split by SFC to obtain 76B-1 (35 mg) and 76B-2 (31 mg).

[0566] 1 H NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H),7.66-7.51 (m, 2H), 6.50 (d, J =7.9Hz, 1H), 6.32 (d, J = 7.9 Hz, 1H), 6.21 (s,2H), 5.78 (s, 2H), 3.98(m, 1H), 3.70 (s, 6H), 3.69 (s, 3H), 3.10 (m, 1H),2.80 (m, 1H), 2.35-2.28 (m, 1H), 2.15 (s, 7H), 1.70 (m, 2H). ESI-Ms: 642.2[M+ H] + .

[0567] Example 77: Preparation of Compound 77

[0568] Compound 4-4 (424 mg, 0.714 mmol) was dissolved in 1,2-dichloroethane (10 ml), and methylamine hydrochloride (54 mg, 0.786 mmol), triethylamine (360 mg, 3.57 mmol), and AcOH (129 mg, 2.142 mmol) were added. The mixture was stirred for 2 h, and sodium triacetoxyborohydride (756 mg, 3.57 mmol) was added. The mixture was reacted overnight at room temperature and monitored by TLC. The reaction solution was added to water (30 ml), extracted with DCM (30 ml × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column-chromatographically purified (dichloromethane:methanol = 100:1 - 40:1) to give compound 77 (98 mg) and compound 77B (84 mg).

[0569] 77A (98 mg) was split by SFC to obtain 77A-1 (37 mg) and 77A-2 (40 mg).

[0570] 1 H NMR (600 MHz, CDCl3) δ: 8.31 (s, 1H), 7.80 (d, J =1.8 Hz, 1H), 7.61– 7.45(m, 2H), 6.88-6.44 (m, 2H), 6.39 (t, J =7.8Hz, 1H), 6.35 (d, J = 7.0 Hz, 1H), 6.26 (d, J = 7.8 Hz, 1H), 5.68 (d, J =1.2,1H), 5.39 (d, J =1.2Hz, 1H), 4.00(dd, J = 11.8,3.9 Hz, 1H), 3.92 (s, 6H), 3.89 (s, 3H), 3.00 (dd, J = 14.4, 12Hz, 1H), 2.51 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.98 (s, 3H), 1.85-1.83 (m, 1H), 1.48-1.43 (m, 2H).ESI-Ms:610.2[M + H] + .

[0571] 77B (84 mg) was split by SFC to obtain 77B-1 (29 mg) and 77B-2 (31 mg).

[0572] 1 H NMR (600 MHz, CDCl3) δ: 7.99 (s, 1H), 7.79 (d, J =2.1 Hz, 1H), 7.56 – 7.38 (m, 2H), 6.88 (d, J=8.6Hz, 2H), 6.39 (m, 1H), 6.30 (s, 2H), 5.66(d, J=1.2,1H), 5.37 (d, J=1.2Hz,1H), 3.99(dd, J = 12.1,4.2 Hz, 1H), 3.88 (s,6H), 3.76 (s, 3H), 3.00 (m, 1H), 2.46 (m, 1H), 2.15 (s, 3H), 2.04-1.95 (m, 1H), 1.80 (m, 1H), 1.45 (m, 2H). ESI-Ms:610.2[M + H] + .

[0573] Example 78: Preparation of Compound 78

[0574] The unseparated compound 1 (181 mg, 0.29 mmol) was dissolved in DMF (20 mL) and stirred. Zn(CN)₂ (24 mg, 0.20 mmol) and Pd(PPh₃)₄ (40 mg, 0.036 mmol) were then added. 90 o The reaction was carried out overnight at C, and TLC was used to confirm the completeness of the reaction. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane:methanol = 200:1 - 50:1) to give yellow solid 78A (50 mg) and yellow solid 78B (53 mg).

[0575] 78A (50 mg) was split by SFC to obtain 78A-1 (18 mg) and 78A-2 (13 mg).

[0576] 1 H NMR (400 MHz, CDCl3) δ: 8.58 (s, 1H), 7.90 (d, J = 1.8 Hz, 1H),7.67-7.59 (m, 2H), 6.85-6.47 (m, 2H), 6.41 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 6.24 (d, J= 7.7 Hz, 1H), 5.75 (d, J =3.1Hz, 2H), 4.15-4.02(m, 1H), 3.98 (s,9H), 2.95-2.84 (m, 1H), 2.65-2.61 (m, 1H), 2.24-2.16 (m, 1H), 1.95 (s, 6H),1.60-1.53 (m, 2H). ESI-Ms: 571.3[M + H] + .

[0577] 78B (53 mg) was split by SFC to obtain 78B-1 (19 mg) and 78B-2 (15 mg).

[0578] 1 H NMR (600 MHz, CDCl3) δ: 8.15 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H),7.55 (m, 2H), 6.68 (s, 1H), 6.52 (m, 1H), 6.33 (d, J = 6.9 Hz, 1H), 6.18 (s,2H), 5.75 (s, 2H), 3.92(m, 1H), 3.75 (s, 6H), 3.65 (s, 3H), 3.10 (m, 1H),2.86-2.82 (m, 1H), 2.27 (m, 1H), 2.15 (s, 6H), 1.87-1.71 (m, 2H). ESI-Ms:571.3[M + H] + .

[0579] Example 79: Preparation of Compound 79

[0580] Compound 79 was prepared using the same method as in Example 78, yielding compounds 79A (44 mg) and 79B (45 mg).

[0581] 79A (44 mg) was split by SFC to obtain 79A-1 (13 mg) and 79A-2 (15 mg).

[0582] 1 H NMR (600 MHz, CDCl3) δ: 8.56 (s, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.65– 7.48(m, 2H), 6.89-6.44 (m, 2H), 6.40 (t, J =7.8Hz, 1H), 6.36 (d, J = 7.0 Hz, 1H), 6.27 (d, J = 7.8 Hz, 1H), 5.67 (d, J =1.2,1H), 5.39 (d, J =1.2Hz, 1H), 4.03(dd, J = 11.8,3.9 Hz, 1H), 3.92 (s, 6H), 3.90 (s, 3H), 3.02 (dd, J = 14.4, 12Hz, 1H), 2.52 (dd, J = 14.4, 3.8 Hz, 1H), 2.18-2.15 (m, 1H), 1.90 (s, 6H), 1.85-1.83 (m, 1H), 1.50-1.45 (m, 2H).ESI-Ms:571.3[M + H] + .

[0583] 79B (45 mg) was split by SFC to obtain 79B-1 (14 mg) and 79B-2 (17 mg).

[0584] 1H NMR (600 MHz, CDCl3) δ: 8.16 (s, 1H), 7.98 (d, J =2.2 Hz, 1H), 7.68 – 7.55 (m, 2H), 6.90 (d, J=8.1Hz 2H), 6.55 (m, 1H), 6.40 (s, 2H), 5.76(d, J=1.2,1H), 5.47 (d, J=1.2Hz,1H), 4.05(dd, J = 12.0,4.1 Hz, 1H), 3.95 (s,6H), 3.83 (s, 3H), 3.00 (dd, J = 14.2,12.2 Hz, 1H), 2.55 (m, 1H), 2.25 (s,6H),2.19-2.13 (m, 1H), 1.88-1.85 (m, 1H), 1.55-1.40 (m, 2H). ESI-Ms:571.3[M +H] + .

[0585] Pharmacological Examples

[0586] Example 80: In vitro efficacy of some compounds against Mycobacterium tuberculosis strain H37Rv

[0587] The test strain H37Rv was transferred to liquid culture medium and incubated at 37°C for 2 weeks. A small amount of the culture was transferred to 4 mL of liquid culture medium, and 10–20 sterile glass beads (2–3 mm in diameter) were added. The mixture was shaken for 20–30 seconds, allowed to stand for 10–20 minutes, and the supernatant was collected. The turbidity was adjusted to 1 McFarland unit (equivalent to 1 × 10⁷ CFU / mL) with liquid culture medium for later use. Each drug was dissolved in an appropriate amount of DMSO to a concentration of 1 mg / mL and filtered through a 0.22 μm filter. The solution was then diluted with liquid culture medium to the required experimental concentration. The final concentrations of the test drug were set as follows: 0.0039 μg / mL, 0.0078 μg / mL, 0.0165 μg / mL, 0.03125 μg / mL, 0.0625 μg / mL, 0.125 μg / mL, 0.25 μg / mL, 0.5 μg / mL, 1 μg / mL, 2 μg / mL, and 4 μg / mL, for a total of 11 concentration gradients. 100 μL of each of the above drug solutions was added to a 96-well microplate, followed by 100 μL of bacterial suspension at a concentration of 1 mg / mL to reach the set final concentration. The plates were then incubated at 37°C. Three parallel control groups were set for the same drug dilution, with no drug added to the control group. The inoculation amounts were set at 100%, 10%, and 1%, respectively. After 14 days of incubation at 37°C, colony growth was observed in each group. The lowest concentration of the drug group with no colony growth was taken as the MIC value of the test compound for that strain. The minimum inhibitory concentration (MIC) of each compound against Mycobacterium tuberculosis was observed and compared with the MIC of the control drug bedaquiline. The results are shown in Table 1.

[0588] Table 1. In vitro activity of Mycobacterium tuberculosis H37Rv - Minimum inhibitory concentration (MIC)

[0589] As shown in Table 1, some compounds of the present invention exhibit significantly superior in vitro MICs compared to the control drug bedaquiline. For example, the in vitro activity (MIC) of compounds 4A-1, 6A-1, 55A-1, 75A-1, and 79A-1 is less than or equal to 0.0078 μg / mL, and their antibacterial activity is greater than or equal to 16 times that of the control drug bedaquiline; the in vitro activity (MIC) of compounds 9A-1, 25A-1, 76A-1, and 37A-1 is 0.0156 μg / mL, and their antibacterial activity is 8 times that of the control drug bedaquiline.

[0590] Example 81: In vitro efficacy of some compounds against drug-resistant Mycobacterium tuberculosis strains

[0591] The tested strains (246: streptomycin resistant; 242: isoniazid resistant; 261: rifampin resistant; B11, MDR-TB; B53, XDR-TB) of Mycobacterium tuberculosis were clinically isolated from Shanghai Pulmonary Hospital. The steps were as follows: a. Sputum samples were collected from inpatients in the Department of Tuberculosis at Shanghai Pulmonary Hospital, treated with alkali, and inoculated onto modified Löwenstein-Frankel medium for 2 weeks; b. Drug susceptibility was determined by absolute concentration method: fresh culture was scraped from the slant of the medium, turbidized with physiological saline to 1 McFarland unit (1 mg / mL), diluted to 10⁻² mg / mL, and 0.1 mL was inoculated onto the drug susceptibility medium. The results were observed after four weeks. Reference: *Laboratory Testing Procedures for Tuberculosis Diagnosis*, compiled by the Basic Professional Committee of the Chinese Association for Tuberculosis Prevention and Control, China Education and Culture Press, January 2006. Transfer the culture to liquid culture medium and incubate at 37℃ for 2 weeks. Take a small amount of the culture and place it in 4 mL of liquid culture medium. Add 10-20 sterile glass beads (2-3 mm in diameter), shake for 20-30 seconds, allow to settle for 10-20 minutes, and collect the supernatant. Adjust the turbidity to 1 McFarland unit (equivalent to 1 × 10⁷ CFU / mL) with liquid culture medium for later use. Dissolve each drug in an appropriate amount of DMSO to 1 mg / mL and filter through a 0.22 μm filter. Then dilute with liquid culture medium to the required experimental concentration. The final concentrations of the test drugs were set as follows: 0.0039 μg / mL, 0.0078 μg / mL, 0.0165 μg / mL, 0.03125 μg / mL, 0.0625 μg / mL, 0.125 μg / mL, 0.25 μg / mL, 0.5 μg / mL, 1 μg / mL, 2 μg / mL, and 4 μg / mL, a total of 11 concentration gradients. For each gradient, 100 μL of the drug solution was added to a 96-well microplate, followed by 100 μL of bacterial suspension at a concentration of 1 mg / mL to reach the set final concentration. The plates were then incubated at 37°C. Three parallel control groups were set for the same drug dilution, with no drug added to the control group. The inoculation amounts were set at 100%, 10%, and 1%, respectively. The minimum inhibitory concentration (MIC) of each drug against Mycobacterium tuberculosis was observed and compared with the MIC results of bedaquiline. The results are shown in Table 2.

[0592] Table 2. In vitro activity against drug-resistant Mycobacterium tuberculosis - minimum inhibitory concentration (MIC)

[0593] S: Streptomycin, H: Isoniazid, R: Rifampin, B11: MDR-TB, B53: XDR-TB.

[0594] As shown in Table 2, compounds 4A-1 and 12A-1 of the present invention, along with the control compound bedaquiline, exhibited excellent in vitro antibacterial activity against streptomycin-resistant, isoniazid-resistant, rifampicin-resistant, multidrug-resistant (B11), and extensively drug-resistant (B53) strains. Their in vitro antibacterial activity was comparable to that against susceptible strains, indicating that the in vitro activity of the compounds of the present invention is superior to that of the control drug bedaquiline. This suggests that, like bedaquiline, the compounds of the present invention can be used to treat diseases caused by drug-resistant Mycobacterium tuberculosis, especially multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis.

[0595] Furthermore, the compounds of this invention share the same mechanism of action as bedaquiline, representing a novel mechanism of action, and do not exhibit cross-resistance with existing drugs. Therefore, apart from the compounds listed in Table 2, other compounds described in this invention, as long as they exhibit inhibitory activity against H37Rv strain, also exhibit inhibitory activity against various drug-resistant strains.

[0596] Example 82: Test on the inhibitory effect of the compound on hERG potassium ion channels

[0597] HEK-293 cells (Creacell™, France) stably expressing hERG were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. The voltage stimulation protocol for recording whole-cell hERG potassium currents using whole-cell patch-clamp was as follows: after whole-cell sealing, the cell membrane voltage was clamped at -80 mV. The clamping voltage was depolarized from -80 mV to -50 mV and maintained for 0.5 s (as a leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to elicit the tail current of the hERG channel. Data were collected every 10 s to observe the effect of drugs on the hERG tail current. A 0.5 s stimulation at -50 mV was used as a leakage current detection. Experimental data were acquired using an EPC-10 amplifier (HEKA) and stored in PATchMaster (HEKA) software.

[0598] Data analysis: First, the current and blank control current after each drug concentration were standardized. Then calculate the inhibition rate corresponding to each drug concentration. For each concentration, calculate the mean and standard error, and then calculate the half-inhibitory concentration for each compound using the following equation:

[0599] The dose-dependent effect was nonlinearly fitted using the above equations, where C represents the drug concentration, IC50 is the half-inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC50 calculation were performed using IGOR software.

[0600] Sample preparation: 1. Weigh the test sample and prepare a stock solution of the corresponding concentration using DMSO; 2. Dilute the test sample stock solution sequentially with DMSO to obtain 0.5 mM, 2 mM, and 8 mM diluents; 3. Dilute the test sample diluent sequentially with extracellular fluid to obtain 0.5 µM, 2 µM, 8 µM, and 32 µM liquids, and sonicate all concentrations for 20 min; 4. Visually inspect and microscopically examine the solubility of the sample to be tested, and then perform the test.

[0601] Results Interpretation: We used a common standard to determine the inhibitory effect of the test sample on hERG (Roche O. et al. ChemBioChem. 2002, 3: 455-459): Extremely strong inhibition: IC50 50 < 0.1µM; Strong inhibition: 0.1µM ≤ IC50 50 ≤ 1 μM; Moderate inhibition: 1 μM < IC50 50 ≤ 10 μM; weak or no inhibition: IC50 50 > 10µM.

[0602] Table 3. Inhibition of hERG by some compounds

[0603] Table 3 shows that the compounds of the present invention have weak or no inhibition of hERG potassium current, indicating that the compounds of the present invention have good safety for the cardiovascular system, and their safety is superior to that of the control drug bedaquiline.

[0604] Example 83: In vivo pharmacokinetic experiments and tissue distribution (kp) of some compounds

[0605] The test compound was prepared into a homogeneous suspension with a final concentration of 2 mg / mL using a 0.5% CMC-Na aqueous solution for oral administration. The oral administration was administered via gavage at a single dose of 20 mg / kg, with a volume of 10 mL / kg. Blood samples of 0.15 mL were collected from the retroocular venous plexus of mice at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 10 h, 12 h, and 24 h post-administration.

[0606] The test sample was prepared to a final concentration of 0.5 mg / mL for intravenous administration. The solvent for preparing the test sample was an aqueous solution of 5% DMSO + 20% EA + 50% PEG400 + 25% Saline (physiological saline). The single dose was 2 mg / kg. Blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

[0607] Male CD-1 mice, aged 6-8 weeks and weighing 20-30 g at the start of drug administration, were selected and numbered with a marker. Animal weight was measured before drug administration, and healthy animals of similar weight were selected for the experiment. No randomization was performed, and all animals had free access to water during the experiment.

[0608] After collection, the samples were placed in labeled centrifuge tubes and the plasma was rapidly separated at 3500 rpm for 10 minutes at 4°C. The plasma was then stored at -40°C or below for analysis. The drug concentration in the plasma was determined by LC-MS / MS, and its pharmacokinetic parameters were calculated.

[0609] Six hours after oral administration, blood samples were collected and dissected. Liver and lung tissue samples were obtained, washed with physiological saline, dried with medical gauze, and placed in labeled small resealable bags for storage below -40°C until analysis. The drug concentration in the tissue was determined by LC-MS / MS, and the tissue distribution Kp value was obtained by dividing by the corresponding plasma concentration at the corresponding time point.

[0610] Table 4. Pharmacokinetic results in CD-1 mice

[0611] As can be seen from Table 4, after a single oral administration, some compounds of the present invention, 4A-1, exhibit good bioavailability, although C max While the AUC value was slightly lower, the lung plasma concentration (Kp) at 6 hours was significantly higher than the blood plasma concentration. Favorable metabolic properties and excellent lung targeting suggest good in vivo efficacy. Simultaneously, the low Cmax and weak hERG inhibition indicate that this compound has a higher safety profile than bedaquiline.

[0612] Example 84: In vivo efficacy of some compounds tested in a mouse acute infection model

[0613] Female BALB / c mice, weighing approximately 20 grams, were infected with Mycobacterium tuberculosis H37Rv (ATCC strain 27274) via an aerosol route using an inhalation exposure system, with an infectious dose of approximately 5000 CFU. Five untreated mice were euthanized on the day of treatment to determine the infectious dose. The test drug was prepared as a suspension using 0.5% w / v carboxymethyl cellulose (CMC). It was stored at 4 °C before use. Control mice were treated with only 0.5% CMC.

[0614] Mice were divided into groups of five, weighed, and administered the drug via gavage once daily for four weeks, five days a week. After a three-day clearance period following the last administration, the mice were euthanized, their lungs were aseptically removed, ground, and homogenized in 3 mL of Hank's balanced salt solution (HBSS). The HBSS solution was diluted tenfold and cultured on Middlebrook 7H11 agar plates for three weeks, and colony-forming units were counted. Results are expressed as the mean LogCFU value for each group of mice.

[0615] Table 5. In vivo efficacy studies in female BALB / c mice acutely infected with H37Rv

[0616] a: Due to the outbreak of infection, five untreated mice were euthanized on day 24 post-infection. b: Bedaquiline dosage is calculated based on free base; c: Two out of five mice tested negative; d: Two out of five mice tested negative; In BALB / c female mice acutely infected with H37Rv, no mice died in either the bedaquiline or compound 4A-1 administration groups after the administration period. Table 5 shows that at the end of the high-dose bedaquiline group (25 mg / kg), the lung CFU count was 0, indicating complete eradication of Mycobacterium tuberculosis. The medium-dose bedaquiline group (12.5 mg / kg) and the high-dose 4A-1 group (12.5 mg / kg) significantly reduced the lung CFU count, and some mice showed negative results for Mycobacterium tuberculosis, indicating comparable efficacy. The lung CFU count in the medium-dose 4A-1 group (6.25 mg / kg) was lower than that in the low-dose bedaquiline group (6.25 mg / kg), indicating that at the same dose, 4A-1 was more effective than the control. Although the lung CFU count increased in the low-dose 4A-1 group (3.13 mg / kg) (compared to day 0), none of the mice died, indicating that the drug provided good protection to the mice.

[0617] These data indicate that the compounds of this invention exhibit comparable in vivo bactericidal activity to bedaquiline at the same dosage. Combined with other properties, this suggests that the compounds of this invention possess better safety.

[0618] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. An optical isomer of the compound represented by formula (I), or a pharmaceutically acceptable salt thereof: (I) In the formula, m represents 1; R 1 Selected from aryl or heteroaryl groups, the aryl or heteroaryl group is unsubstituted or has 1-4 identical or different substituents, the substituents being selected from: halogen, hydroxyl, cyano, unsubstituted or alkyl groups containing 1-6 halogen atoms. 1-6 Alkyl, unsubstituted, or alkyl groups containing 1-6 halogen atoms (C) 3-6 Cycloalkyl, unsubstituted, or C-shaped alkyl groups containing 1-6 halogen atoms 1-6 Alkyl groups, unsubstituted or C groups containing 1-6 halogen atoms 3-6 The C atoms in cycloalkoxy, unsubstituted, or alkyl groups are replaced by 1-6 halogen atoms. 1-6 The alkylthio group, or two adjacent substituents linked together to form a five- or six-membered ring; the aryl group is phenyl; the heteroaryl group is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiopheneyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, benzofuranyl, benzothiopheneyl, indolyl, benzopyrazolyl, benzoimidazolyl, benzothiazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyridinopyrroleyl, pyridinofuranyl, pyridinothiopheneyl, pyridinopyrazolyl, pyridinoimidazolyl, pyridinothiazolyl, pyridinooxazolyl, pyridinopyridyl, pyridinopyrazinyl, pyridinopyrimidinyl, pyridinopyridazinyl; R 2 and R 3 Whether identical or different, each is independently selected from: hydrogen, unsubstituted or alkyl groups substituted with 1-3 halogen atoms. 1-6 alkyl; R 4 Selected from aryl or heteroaryl groups, the aryl or heteroaryl group is unsubstituted or has 1 to 3 identical or different substituents selected from the following: halogen, unsubstituted, or C containing 1 to 6 halogen atoms on the alkyl group. 1-6 Alkyl, unsubstituted, or C containing 1-6 halogen atoms 3-6 Cycloalkyl, unsubstituted, or C-shaped alkyl groups containing 1-6 halogen atoms 1-6 Alkoxy; aryl group is naphthyl; heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiopheneyl, furanyl, thiazolyl, oxazinyl, isoxazinyl, benzofuranyl, benzothiopheneyl, indolyl, benzopyrazolyl, benzoimidazolyl, benzothiazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyridinopyrroleyl, pyridinofuranyl, pyridinothiapheneyl, pyridinopyrazolyl, pyridinoimidazolyl, pyridinothiazolyl, pyridinooxazolyl, pyridinopyridyl, pyridinopyrazinyl, pyridinopyrimidinyl, pyridinopyridazinyl; R 5 The substituent is non-directed and is selected from hydrogen, halogen, cyano, hydroxyl, C 1-4 alkoxy, or C 1-4 Alkylthio; R 6 Selected from unsubstituted or alkyl groups containing 1-6 halogen atoms C 1-6 The C-axis of the alkoxy group, or the unsubstituted or alkyl group, contains 1-6 halogen atoms. 1-6 Alkylthio; The optical isomer is of configuration A-1 or configuration B-1: 、 。 2. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 The substituents on the aryl or heteroaryl groups are selected from unsubstituted or C-shaped groups containing 1-3 halogen atoms on the alkyl group. 1-3 Alkyl, unsubstituted, or alkyl groups containing 1-3 halogen atoms (C) 1-3 An alkoxy group, or two adjacent substituents, are linked together to form a five-membered ring.

3. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 The halogen in the substituents on the aryl or heteroaryl group is fluorine or chlorine.

4. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 The alkoxy group in the substituents of the aryl or heteroaryl group is a methoxy group.

5. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 The aryl or heteroaryl group has one, two, or three substituents.

6. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 The aryl or heteroaryl groups represented are selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, or thiopheneyl.

7. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R mentioned 2 and R 3 Each C is independently selected from: C substituted with one to three halogens or unsubstituted C . 1-3 alkyl.

8. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R mentioned 4 Selected from pyridinyl or benzoxazolyl.

9. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R mentioned 4 The substituents on the aryl or heteroaryl groups are selected from unsubstituted or C-shaped groups containing 1-3 halogen atoms on the alkyl group. 1-3 alkyl.

10. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R mentioned 5 Selected from halogens or cyano groups.

11. The optical isomer of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 6 Selected from unsubstituted or alkyl groups containing 1-3 halogen atoms C 1-3 Alkyl group.

12. An optical isomer of a compound, or a pharmaceutically acceptable salt, characterized in that, The compound is selected from: The optical isomer is of configuration A-1 or configuration B-1: 、 。 13. The optical isomer of the compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, characterized in that, The optical isomer of the compound is the A-1 configuration.

14. A pharmaceutical composition, characterized in that, It contains pharmaceutically acceptable excipients, and as an active ingredient an optical isomer of the compound as described in any one of claims 1-13, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 14, characterized in that, The excipient is a carrier.

16. Use of an optical isomer of the compound as described in any one of claims 1-13, or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare inhibitors of Mycobacterium tuberculosis ( Mycobacterium tuberculosis The composition of growth.

17. Use of an optical isomer of the compound as described in any one of claims 1-13, or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare treatments for Mycobacterium tuberculosis ( Mycobacterium tuberculosis ) drugs for infection.

18. The use as described in claim 17, characterized in that, The tuberculosis infection mentioned is a drug-resistant tuberculosis infection.

19. A method for preparing an optical isomer of the compound of formula I according to any one of claims 1-11, characterized in that, The method includes the following steps: (1) The compound shown in Formula II undergoes a nucleophilic substitution reaction in the presence of a base to obtain the compound shown in Formula III; (2) The compound shown in Formula III reacts with an allyl metal reagent to form a tertiary alcohol; (3) Tertiary alcohols undergo dihydroxylation in the presence of an oxidizing agent; (4) Further cleavage occurs under the action of an oxidant to obtain the compound shown in formula V; (5) The compound shown in formula V is reduced to a primary alcohol, which is then activated and reacted with the corresponding amine to generate the compound shown in formula I. The structures of compounds of formulas II, III and V are shown in the following formulas: 、 、 In each formula, R 1 R 4 R 5 R 6 The definitions of m and equation (Ⅰ) are the same.

20. The method as described in claim 19, characterized in that, In step (1), compound (III) is obtained by nucleophilic substitution reaction of compound II as raw material under alkaline conditions and 20-80℃.

21. The method as described in claim 19, characterized in that, In step (1), the alkali is potassium carbonate or sodium hydroxide.

22. The method as described in claim 19, characterized in that: In step (2), the allyl metal reagent is allyl zinc; and / or, In step (2), the reaction is carried out in the presence of a catalyst; and / or, In step (2), the solvent for the reaction is anhydrous THF; and / or, In step (2), the reaction is carried out at 0-75°C.

23. The method as described in claim 22, characterized in that, The catalyst is CuBr.Me2S.

24. The method as described in claim 19, characterized in that, In step (3), the oxidant is selected from one or both of potassium osmium dihydrate and N-methylmorpholine-N-oxide.

25. The method as described in claim 19, characterized in that, In step (4), the oxidant is sodium periodate.

26. The method as described in claim 19, characterized in that, In step (5), the reducing agent is sodium borohydride.

27. The method as described in claim 19, characterized in that, In step (5), the primary alcohol is activated to react with MsCl to form -OMs; and / or, the amine is dimethylamine.

28. A method for preparing an optical isomer of the compound shown in Formula I, characterized in that, The method includes the steps of: the optical isomer of the compound shown in formula (I) is formed by the compound shown in formula (V) and R 2 R 3 NH is prepared by reductive amination; R 1 R 2 R 3 R 4 R 5 R 6 The definitions of m, formula (I), and optical isomers are as described in any one of claims 1-11.

29. The method as described in claim 28, characterized in that, The method is carried out in the presence of a reducing agent, an acid, and a solvent.

30. The method as described in claim 29, characterized in that: The reducing agent is NaB(OAc)3; and / or, The acid is acetic acid; and / or, The solvent is 1,2-dichloroethane; and / or, The reaction temperature of the method is 0-75℃.

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