TW202333745A - Nucleoside derivatives and use thereof - Google Patents

Abstract

A compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein R1 or R2 is independently H.

Description

Nucleoside derivatives and their uses

The present invention relates to a nucleoside derivative and its use, as well as the use of compositions related thereto.

Nucleoside derivatives mimic endogenous nucleosides, exploit cellular metabolism, and incorporate into DNA and RNA. This property enables nucleoside derivatives to effectively inhibit viral replication and prevent cancer cell proliferation. RNA-dependent RNA polymerase (RdRp) is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes the synthesis of RNA strands that are complementary to specific RNA templates. Viral RdRPs play an important role in viral genome replication and transcription. Although some nucleoside derivatives have been developed for the treatment of viral infections, including HBV, HCV, and SARS-CoV2 infections, there is still a need for more effective nucleoside derivatives to treat viral infections.

Overview

In one aspect, the invention relates to a compound of formula II, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula III, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the invention relates to a compound of formula IV, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula V, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula VI, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula VII, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula VIII, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula IX, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula X, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula XI, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, heteroaryl, -(CO)C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ Aryl, -(CO)C ₅ -C ₁₀ heteroaryl, -(CO)OC ₅ -C ₁₀ aryl, -(CO)OC ₅ -C ₁₀ heteroaryl, -(CO)NHC ₁ -C ₆ Alkyl, (CO)NHC ₅ -C ₁₀ aryl or (CO)NHC ₅ -C ₁₀ heteroaryl, the heteroaryl, -(CO)C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ aryl, -(CO)C ₅ -C ₁₀ heteroaryl, -(CO)OC ₅ -C ₁₀ aryl, -(CO)OC ₅ - C ₁₀ heteroaryl, -(CO)NHC ₁ -C ₆ alkyl, (CO)NHC ₅ -C ₁₀ aryl or (CO)NHC ₅ -C ₁₀ heteroaryl is optionally replaced by one or more halogens, OH, -OC ₁ -C ₆ alkyl, NR ₆ R ₅ , C ₁ -C ₆ alkyl, C ₅ -C ₁₀ aryl and heteroaryl substitution; R ₃ or R ₄ are independently selected from H, D, Halogen or C ₁ -C ₃ alkyl, the alkyl group is optionally substituted by one or more halogens; R ₅ or R ₆ is independently selected from H, OH, C ₁ -C ₆ alkyl, -(CO) C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ aryl, -(CO)C ₅ -C ₁₀ heteroaryl, C ₅ -C ₁₀ Aryl or C ₅ -C ₁₀ heteroaryl; link is independently selected from the following groups: , wherein R ₇ or R ₈ is independently selected from H and C ₁ -C ₆ alkyl, and R ₇ and R ₈ can be fused to each other to form a ring.

In some embodiments, R ₃ or R ₄ is independently selected from H, D, F, Cl, Br, CH ₃ or CF ₃ .

In some embodiments, R ₅ or R ₆ is independently selected from H, OH, C ₁ -C ₆ alkyl, -(CO)C ₁ -C ₆ alkyl, or -(CO)OC ₁ -C ₆ alkyl .

In yet another aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the present application.

In yet another aspect, the invention relates to a method of treating or preventing viral infection in a patient. The method includes the step of administering to a patient an effective amount of a compound of the present application.

In some embodiments, the viral infection is an infection with a coronavirus.

In some embodiments, the viral infection is an infection with SARS-CoV2 virus.

Elaborate

In the following description, certain specific details are included to provide a thorough understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that embodiments may be practiced without one or more of these specific details and using other methods, components, materials, etc.

Unless otherwise required herein, throughout this specification and the following claims, the words "include" and "include" are to be interpreted in an open-ended, inclusive sense, that is, "including but not limited to."

As used in the scope of this invention and the appended claims, singular references without an indication of quantity include plural references unless the context clearly dictates otherwise.

Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that at least one embodiment includes the same Relevant specific reference elements, structures or characteristics described above. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout the specification are not necessarily all referring to the same embodiment. . Furthermore, specific elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It is to be understood that, as used in the description of the invention and the appended claims, the singular form "a" (corresponding to "a", "an" and "the") includes plural referents unless the context otherwise requires. clearly stated. Thus, for example, reference to an extended-release tablet containing "pharmaceutically acceptable excipients" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

definition

Certain chemical groups named herein are preceded by a simplified symbol indicating the total number of carbon atoms found in the chemical group shown. For example, C ₇ -C ₁₂ alkyl describes an alkyl group having a total of 7 to 12 carbon atoms, as defined below, and a C ₄ -C ₁₂ cycloalkyl alkyl group describes an alkyl group having a total of 4 to 12 carbon atoms, as defined below Cycloalkylalkyl. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group in question.

Therefore, unless otherwise stated to the contrary, the following terms used in the specification and appended claims have the following meanings.

The term "oxo" as used herein refers to the =O group.

The term "cyano" as used herein refers to the -CN group.

The term "nitro" as used herein refers to the -NO ₂ group.

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" used in the present invention refers to a linear or branched hydrocarbon chain group, consisting only of carbon and hydrogen atoms, without unsaturated bonds, with 1 to 12 carbon atoms, and it is composed of a single Bonds connect to the rest of the molecule. In certain embodiments, alkyl groups have 1 to 8 carbon atoms. In certain embodiments, alkyl groups have 1 to 6 carbon atoms. In certain embodiments, alkyl groups have 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, 1,1 -Dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. In certain embodiments, alkyl groups may be optionally substituted, that is, substituted or unsubstituted.

Whenever a group is described as "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted," if substituted, the substituent may be selected from one or more of the indicated substituents. If a substituent is not specified, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted by one or more groups singly or independently selected from alkyl, alkenyl, alkyne Base, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroarylalkyl, (heteroalicyclic)alkyl, hydroxyl, protected hydroxyl, Alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamate, N-carbamate, O-thiocarbamate, N-Thiocarbamate, C-carboxylic acid, N-carboxylic acid, S-sulfonamide, N-sulfonamide, C-carboxylic acid, protected C-carboxylic acid, O-carboxylic acid, isocyanate Acid group, thiocyanate, isothiocyanato group, nitro group, silyl group, sulfonyl group, sulfenyl group, sulfonyl group, haloalkyl group, haloalkoxy group, trihalomethanesulfonyl group, trihalo Methanesulfonamide group, amino group, mono-substituted amino group and disubstituted amino group and their protected derivatives.

The term "alkoxy" as used herein refers to the general formula -OR, where R is alkyl as defined above. In certain embodiments, alkoxy groups have 1 to 8 carbon atoms. In certain embodiments, alkoxy groups have 1 to 6 carbon atoms. In certain embodiments, alkoxy groups have 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, Isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, etc. In certain embodiments, alkoxy groups may be optionally substituted, that is, substituted or unsubstituted.

The term "cycloalkyl" as used in the present invention refers to a stable non-aromatic monocyclic or polycyclic alkyl group consisting only of carbon and hydrogen atoms, which may contain fused or bridged ring systems, with 3 to 18 carbon atoms, in some embodiments from 3 to 15 carbon atoms, in some embodiments from 3 to 10 carbon atoms, and is saturated and connected to the rest of the molecule by a single bond . In certain embodiments, illustrative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Illustrative examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. In certain embodiments, cycloalkyl groups can be optionally substituted, that is, substituted or unsubstituted.

The term "heterocycloalkyl" used in the present invention refers to three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, nine-membered, ten-membered, up to 18-membered monocyclic, bicyclic and tricyclic rings. Systems in which carbon atoms and 1 to 5 heteroatoms constitute the ring system. Heteroatoms are elements other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may also contain one or more carbonyl or thiocarbonyl functional groups such that the definition includes oxo and thio systems such as lactams, lactones, cycloimines, cyclothioimines and cyclic carbamates. . When consisting of two or more rings, the rings may be joined together in a fused manner. Additionally, any nitrogen in the heterocycloalkyl group may be quaternized. Heterocycloalkyl groups may be unsubstituted or substituted. Examples of such "heterocyclyl" include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1, 3-dioxolane, 1,4-dioxolane, 1,3-oxathiolane, 1,4-oxathiolane, 1,3-oxathiolane ( oxathiolane), 1,3-dithiolane, 1,3-dithiolane, 1,4-oxathiolane, tetrahydro-1,4-thiazine, 2H-1,2 -Oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopyrazine, hydantoin, dihydrouracil, trioxane, hexahydrogen- 1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, ethylene oxide Alkane, pyridine N-oxide, pyridine, pyridine, pyrrolidine, pyrrolidone, pyrrolidone, 4-pyridinone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H- Pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholinyl terine, thiomorpholinyl terine, and their benzo-condensed analogs (e.g., benzimidazolinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

The term "aryl" as used in the present invention refers to an aromatic monocyclic or polycyclic hydrocarbon ring system, consisting only of hydrogen and carbon, and containing 6 to 18 carbon atoms, wherein the ring system may be partially saturated. In certain embodiments, aryl is C ₆ -C ₁₄ aryl. In certain embodiments, aryl is C ₆ -C ₁₂ aryl. In certain embodiments, aryl is C ₆ -C ₁₀ aryl. In certain embodiments, illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, and fluorenyl. In certain embodiments, an aryl group can be optionally substituted, that is, substituted or unsubstituted.

The term "heteroaryl" used in the present invention refers to a 5 to 18-membered aromatic ring group containing 1 to 17 carbon atoms and 1 to 10 heteroatoms selected from nitrogen, oxygen and sulfur. For the purposes of the present invention, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused or bridged ring systems; and a nitrogen, carbon or sulfur atom in the heteroaryl group May be optionally oxidized; nitrogen atoms may be optionally quaternized. In certain embodiments, a heteroaryl group may contain 4 to 14 atoms in the ring. In certain embodiments, a heteroaryl group may contain 5 to 10 atoms in the ring. In certain embodiments, a heteroaryl group may contain 5 to 6 atoms in the ring. In certain embodiments, illustrative examples of heteroaryl include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolanyl, Benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxanyl , benzonaphthofuranyl, benzodioxolane, benzodioxenyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophene base, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, terazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, imidazopyridine base, imidazopyrazinyl, imidazopiridinyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl , isoindolyl, isoquinolinyl, indanyl, isoxazolyl, naphthyl, diazanaphthyl, diazolinyl, 2-oxoazepine, oxazolyl, ring Oxyethyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, 2,3-diazanaphthyl, pteridinyl, purinyl, pyrrolyl, pyridyl Azolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, Thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl. In certain embodiments, heteroaryl groups can be optionally substituted, that is, substituted or unsubstituted.

The term "physiologically acceptable" as used herein defines carriers, diluents or excipients which do not eliminate the biological activity and properties of the compound.

As used herein, the term "vector" refers to a substance that effects the incorporation of a compound into cells or tissues.

The term "excipient" used in the present invention refers to those added to the pharmaceutical composition to provide (without limitation) volume, consistency, stability, binding ability, lubricity, disintegration ability, etc. to the composition. Inert substances.

The term "diluent" as used herein refers to an ingredient in a pharmaceutical composition that is not pharmaceutically active but may be necessary or desirable for pharmaceutical use.

The term "mammal" as used in the present invention refers to animals including, for example, dogs, cats, cattle, sheep, horses, humans, and the like. In certain embodiments, mammals include humans.

The term "patient" as used herein refers to animals (eg, humans), companion animals (eg, dogs, cats, or horses), and livestock (eg, cattle, pigs, and sheep). In certain embodiments, the patient is a mammal including both male and female. In certain embodiments, the patient is a human.

The term "pharmaceutically acceptable" or "pharmaceutically acceptable" as used herein refers to a carrier, carrier, diluent, excipient and/or salt which must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or condition may or may not occur, and that the description includes the occurrence or absence of the event or condition.

The "pharmaceutically acceptable carrier, diluent or excipient" used in the present invention includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration and can be used in humans or animals. Glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers Various forms of carriers that have no side effects on the composition of pharmaceutical compositions.

The term "pharmaceutically acceptable salts" as used in the present invention includes "acceptable acid addition salts" and "acceptable base addition salts".

"Acceptable acid addition salts" refer to those salts which retain the biological effectiveness and properties of the free base, are biologically or otherwise suitable and are formed using inorganic or organic acids , the inorganic acid such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., the organic acid such as but not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, ascorbic acid, etc. Partic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane Alkylaminosulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucose Heptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lacturonic acid, lauric acid Acid, maleic acid, malic acid, malonic acid, mandelic acid, methane sulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, tobacco Acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, butyric acid Diacid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

"Acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and salts of basic ion exchange resins such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, Caffeine, procaine, hypamine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, Purine, pipiazine, pipidine, N-ethylpipidine, polyamine resin, etc. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Typically, crystallization results in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more molecules of a solvent. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist in hydrated forms, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as in corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases the compounds of the present invention may retain only the occasional water or be a mixture of water plus a portion of the occasional solvent.

As used herein, the term "pharmaceutical composition" refers to a formulation of a compound described in the present invention and a vehicle generally accepted in the art for delivering the bioactive compound to a mammal such as a human. Such media include all pharmaceutically acceptable carriers, diluents or excipients.

As used herein, a "therapeutically effective amount" refers to a compound or compounds that ameliorates, attenuates, or eliminates a specified disease or condition and symptoms of a specified disease or condition, or avoids or delays the onset of a specified disease or condition, or symptoms of a specified disease or condition. Amount of combination. The amount of a compound described in the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the state of the disease and its severity, and the age, weight, etc. of the mammal to be treated, but those skilled in the art will vary according to their own The amount of compounds described in the present invention can be routinely determined based on the knowledge and knowledge of the present invention.

As used herein, "treating" or "treating" encompasses the treatment of a relevant disease or condition in a mammal, such as a human, suffering from the relevant disease or condition, and includes: (i) prevent the occurrence of a disease or disease state in a mammal, in particular where the mammal is susceptible to said disease state but has not yet been diagnosed with such disease state; (ii) inhibit a disease or disease state, that is, prevent its occurrence; or (iii) Alleviation of a disease or disease state, i.e., regression or non-progression of a disease or disease state.

As used herein, the terms "disease" and "disease state" may be used interchangeably, or may be different, since a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology). ), it is therefore not recognized as a disease, but rather as an undesirable disease state or condition in which clinicians have identified a more or less specific set of symptoms.

The compounds described in the present invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers, and thus may produce enantiomers, diastereoisomers, and other stereoisomeric forms, which may be Absolute stereochemistry defines it as I- or (S)-, or (D)- or (L)- for amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), I- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or using conventional techniques such as HPLC using chiral columns. When a compound described in the present invention contains an olefinic double bond or other center of geometric asymmetry, it is meant that the compound includes E and Z geometric isomers unless otherwise stated. Likewise, all tautomeric forms are also intended to be included.

"Stereoisomers" refer to compounds that are composed of the same atoms bound by the same bonds, but have different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof.

"Cis-trans isomers" refer to molecules with the same molecular formula. Due to factors such as double bonds or rings, the free rotation of the bonds is hindered, resulting in spatial configurations with different relative distances between adjacent atoms or atomic groups.

"Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the compounds described.

The term "prodrug" as used herein is intended to mean a compound that can be converted to a bioactive compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs can be inactive when administered to an individual in need thereof, but are converted in the body to the active compounds of the invention. Prodrugs are typically converted rapidly in vivo to the parent compound of the invention, for example by hydrolysis in the blood. Prodrug compounds often offer solubility, histocompatibility, or delayed release advantages in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 , (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al, “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design Bioreversible Carriers), Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

The term "prodrug" as used herein is also intended to include any covalently bound carrier that releases the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the invention can be prepared by modifying the functional groups present on the compounds of the invention in such a manner that these modified substances are cleaved to the parent compound of the invention during routine manipulation or in vivo. Prodrugs include compounds of the present invention in which a hydroxyl, amino or thiol group is bound to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, free amino or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds of the present invention, or amide derivatives of amine functional groups, and the like.

The present invention also encompasses in vivo metabolites of the disclosed compounds. These products are obtained by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the given compounds, mainly due to enzymatic processes. Accordingly, the present invention includes compounds produced by a process that involves contacting a compound of the invention with a mammal for a period of time sufficient to produce its metabolites. Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention and administering them parenterally to animals, such as rats, mice, guinea pigs, at detectable doses (e.g., greater than about 0.5 mg/kg). Monkeys, or humans, are allowed sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and for isolation of its transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes present in the metabolites). Metabolite structures are determined in a conventional manner, for example, by MS, LC/MS or NMR analysis. Generally, analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise undetectable in vivo, they may be used in assays for the administration of therapeutic doses of the compounds of the invention.

In one aspect, the invention relates to a compound of formula II, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula III, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the invention relates to a compound of formula IV, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula V, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula VI, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula VII, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula VIII, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula IX, or a pharmaceutically acceptable salt thereof: Wherein R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -(CO )C ₅ -C ₁₀ aryl optionally substituted by one or more halogens.

In another aspect, the present invention relates to a compound of formula X, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH.

In another aspect, the present invention relates to a compound of formula XI, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens.

In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof: Wherein, R ₁ or R ₂ is independently selected from H, heteroaryl, -(CO)C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ Aryl, -(CO)C ₅ -C ₁₀ heteroaryl, -(CO)OC ₅ -C ₁₀ aryl, -(CO)OC ₅ -C ₁₀ heteroaryl, -(CO)NHC ₁ -C ₆ Alkyl, (CO)NHC ₅ -C ₁₀ aryl or (CO)NHC ₅ -C ₁₀ heteroaryl, the heteroaryl, -(CO)C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ aryl, -(CO)C ₅ -C ₁₀ heteroaryl, -(CO)OC ₅ -C ₁₀ aryl, -(CO)OC ₅ - C ₁₀ heteroaryl, -(CO)NHC ₁ -C ₆ alkyl, (CO)NHC ₅ -C ₁₀ aryl or (CO)NHC ₅ -C ₁₀ heteroaryl is optionally replaced by one or more halogens, OH, -OC ₁ -C ₆ alkyl, NR ₆ R ₅ , C ₁ -C ₆ alkyl, C ₅ -C ₁₀ aryl and heteroaryl substitution; R ₃ or R ₄ are independently selected from H, D, Halogen or C ₁ -C ₃ alkyl, the alkyl group is optionally substituted by one or more halogens; R ₅ or R ₆ is independently selected from H, OH, C ₁ -C ₆ alkyl, -(CO) C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ aryl, -(CO)C ₅ -C ₁₀ heteroaryl, C ₅ -C ₁₀ Aryl or C ₅ -C ₁₀ heteroaryl; link is independently selected from the following groups: , wherein R ₇ or R ₈ is independently selected from H and C ₁ -C ₆ alkyl, and R ₇ and R ₈ can be fused to each other to form a ring.

In some embodiments, R ₃ or R ₄ is independently selected from H, D, F, Cl, Br, CH ₃ or CF ₃ .

In some embodiments, R ₅ or R ₆ is independently selected from H, OH, C ₁ -C ₆ alkyl, -(CO)C ₁ -C ₆ alkyl, or -(CO)OC ₁ -C ₆ alkyl .

On the other hand, the present invention relates to the following compounds and pharmaceutically acceptable salts thereof: .

pharmaceutical composition

In another aspect, the invention relates to pharmaceutical compositions comprising compounds contemplated by the invention.

In certain embodiments, pharmaceutical compositions include a compound contemplated by the invention and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical compositions of the present invention include physiologically acceptable surfactants, carriers, diluents, excipients, lubricants, suspensions, film-forming substances, coating auxiliaries, or combinations thereof, As well as compounds of the invention, pharmaceutically acceptable salts, isomers, prodrugs or metabolites thereof. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, ^18th Ed., Mack Publishing Co., Easton, PA (1990). Description, the entire contents of which are incorporated herein by reference.

Preservatives, stabilizers, dyes, sweeteners, fragrances, flavors, and the like may be provided in the pharmaceutical compositions. For example, sodium benzoate, ascorbic acid and esters of parahydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used.

In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, Magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used As a lubricant; coconut oil, olive oil, sesame oil, peanut oil, soybean oil can be used as a suspension or lubricant; cellulose acetate as a derivative of sugars such as cellulose or sugar, or as a derivative of polyethylene Methyl acetate-methacrylate copolymers can be used as suspension agents; and plasticizers such as phthalates can be used as suspension agents.

Suitable routes of administration may include, for example, oral, rectal, transmembrane, topical or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary and intrathecal Injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection. The compounds can also be extended and/or timed at a predetermined rate in sustained or controlled release dosage forms including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc. , pulse administration.

The pharmaceutical composition of the present invention can be produced by known methods, for example, by conventional mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, entrapping or tableting operations.

The pharmaceutical compositions used according to the invention can therefore be formulated in conventional manner using one or more physiologically acceptable carriers containing excipients and auxiliaries which facilitate processing of the active compounds into pharmaceutically usable form. preparations. Suitable formulation depends on the route of administration chosen. Any well-known techniques, carriers and excipients may be used as appropriate and understood in the art.

Injectables can be prepared in the conventional forms: as solutions or suspensions, in solid dosage forms suitable for solution or suspension prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, if necessary, the injection pharmaceutical composition may contain a small amount of non-toxic auxiliaries, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing formulations (eg liposomes) can be used.

For transmembrane administration, penetrants suitable for permeating the barrier may be used in the formulation.

Pharmaceutical preparations for parenteral administration, eg by bolus injection or continuous infusion, include aqueous solutions of the active compound in a water-soluble form. Alternatively, suspensions of the active compounds may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil, or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or lipids. body. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compounds for the preparation of highly concentrated formulations. Formulations for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle such as sterile pyrogen-free water before use.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral administration can be obtained by mixing the active compounds with solid excipients, optionally grinding the resulting mixture and processing the granular mixture, after adding suitable auxiliaries, if necessary, to obtain tablets or lozenge cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulosic preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, formazan, etc. Cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate can be added if desired. Apply a suitable coating to the tablet core. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, arbopol gel, polyethylene glycol and/or titanium dioxide, shellac lacquer solution and a suitable organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, shellac solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations capable of oral administration include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredients mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredients can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All preparations for oral administration should be formulated at dosages suitable for such administration.

For oral administration, the compositions may be formulated in the form of tablets or lozenges in conventional manner.

For administration by inhalation, compounds of the present invention are administered from a pressurized bag or nebulizer by use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Conveniently delivered in spray form. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, such as gelatin, for use in inhalers or insufflators may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

The present invention also discloses various pharmaceutical compositions that are well known in the pharmaceutical field and are used for intraocular, intranasal and intraaural delivery. Penetrants suitable for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in water-soluble form, such as eye drops, or in the form of gellan gum or hydrogels; ophthalmic ointments; ophthalmic suspensions, such as microgranules, These include small polymer particles, lipid-soluble formulations, and microspheres suspended in a liquid carrier medium; and ophthalmic inserts. These suitable pharmaceutical preparations are most often and preferably formulated as sterile, isotonic and buffered pharmaceutical preparations for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, which are typically formulated to mimic nasal secretions in many respects to ensure that normal ciliary action is maintained. As is well known to those skilled in the art, suitable formulations are most often and preferably isotonic, lightly buffered to maintain a pH of 5.5 to 6.5, and which most often and preferably include an antimicrobial preservative and a suitable Drug stabilizers. Pharmaceutical formulations for intraaural delivery include suspensions and ointments for topical application within the ear. Common solvents used in such otic preparations include glycerol and water.

The compounds may also be formulated into rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerolipids.

In addition to the aforementioned formulations, the compounds may also be formulated as depot formulations. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated using suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives such as a sparingly soluble salt.

For hydrophobic compounds, a suitable pharmaceutical carrier may be a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The common co-solvent system used is the VPD co-solvent system, which is 3% w/v benzyl alcohol, 8% w/v non-polar surfactant polysorbate (POLYSORBATE) 80TM and 65% w/v polyethylene. Diol 300 and make up the volume with absolute ethanol. Of course, the proportions of the cosolvent system can be varied considerably without destroying its solubility and toxicity characteristics. In addition, the co-solvent composition can be changed: for example, other low-toxicity non-polar surfactants can be used instead of polysorbate 80TM; the fragment size of polyethylene glycol can be changed; other biocompatible polymers such as polyvinylpyrrolidone, etc. Polyethylene glycol can be replaced by polyethylene glycol; and glucose can be replaced by other sugars or polysaccharides.

Alternatively, other delivery systems for hydrophobic drug compounds may be employed. Well-known examples of delivery vehicles or carriers for hydrophobic drugs are liposomes and emulsions. Certain organic solvents, such as dimethylsulfoxide, can also be used, although usually at the expense of higher toxicity. Additionally, compounds can be delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. Many sustained release materials are known and established to those skilled in the art. Depending on their chemical properties, extended-release capsules can release the compounds over a period of weeks to 100 days.

Agents for intracellular administration are administered using techniques well known to those of ordinary skill in the art. For example, such agents can be encapsulated into liposomes. When liposomes are formed, all molecules present in the aqueous solution are incorporated into the aqueous interior. The contents of the liposomes are not only not affected by the external microenvironment, but also are effectively transported to the cytoplasm due to the fusion of the liposomes with the cell membrane. Liposomes can be coated with tissue-specific antibodies. The liposomes will be targeted to and selectively absorbed by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly intracellularly.

Treatment methods and uses

In another aspect, the present invention relates to methods of preventing, treating or ameliorating symptoms of viral infection in a subject using a pharmaceutical composition of a compound disclosed herein.

In certain embodiments, the methods include the step of administering an effective amount of a compound of the present application to a subject in need thereof.

In some embodiments, the viral infection is a SARS-CoV-2 infection.

In certain embodiments, illustrative examples of viruses that can be used in the present invention include, but are not limited to, Middle East syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus (SARS-CoV), influenza A Influenza virus, influenza B virus, novel coronavirus pneumonia (COVID-19), Spanish influenza virus, arenavirus, bunya virus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, E. Bora virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, Japanese encephalitis virus, West Nile virus viruses, Newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackie virus, rotavirus or tobacco mosaic virus.

In certain embodiments, illustrative examples of individuals that can be used in the present invention include, but are not limited to, mammals.

In certain embodiments, individuals useful in the present invention are humans.

In certain embodiments, the triazine derivatives represented by the general formula I of the present invention, their pharmaceutically acceptable salts, solvates, isomers, deuterates, prodrugs or metabolites are effective against coronavirus infectious diseases. Has excellent therapeutic effect.

Dosing method

The compound or pharmaceutical composition may be administered to the patient by any suitable method. Non-limiting examples of administration methods include (a) administration by the oral route, including administration in the form of capsules, tablets, granules, sprays, syrups, or other such forms; (b) by Administration by non-oral routes, such as rectal, vaginal, intraurethral, intraocular, intranasal or intraaural, including aqueous suspensions, oily preparations, etc., or drops, sprays, suppositories, ointments, ointments (c) Administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracystic injection, intraspinal injection, intrasternal injection, etc., including Infusion pump delivery; (d) localized administration such as injection directly in the renal region or cardiac region, for example by depot implantation; and I topically administered; as one skilled in the art A suitable mode of administration is considered to be contact of the compounds of the invention with living tissue.

The most appropriate approach depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients, and other matters related to delivering the compound to an object in need thereof.

Pharmaceutical compositions suitable for administration include those containing an effective amount of the active ingredient to achieve its intended effect. The dosage required to obtain a therapeutically effective amount of the pharmaceutical compositions disclosed herein depends on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal in question. Dosage may be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medications, and other factors recognized by those skilled in the medical field. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prevent, reduce, or ameliorate the symptoms of a disease, or to extend the lifespan of an individual treated. Therapeutically effective amounts are well within the purview of those skilled in the art, particularly in light of the detailed disclosure provided herein.

As will be apparent to those skilled in the art, dosages and specific modes of administration for in vivo administration will vary depending on the age, weight, and species of mammal being treated, the specific compounds used, and the nature of those compounds used. specific uses. Those skilled in the art can use conventional pharmacological methods to achieve the purpose of determining effective dosage levels, that is, the dosage levels necessary to determine the desired effect. Typically, human clinical applications of compounds are initiated at lower dosage levels, with dosage levels being increased until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective dosages and routes of administration for the compositions identified by this method.

In non-human animal studies, the application of a potential compound is initiated at higher dose levels and the dose is reduced until the desired effect is no longer achieved or undesirable side effects disappear. Depending on the desired effect and indication for treatment, the dosage range may be wider. Generally, the dosage may be about 10 μg/kg body weight to 500 mg/kg body weight, preferably about 100 μg/kg body weight to 200 mg/kg body weight. Alternatively, as will be understood by those skilled in the art, the dosage may be based on and calculated based on the patient's surface area.

Each physician will be able to select the exact formulation, route of administration and dosage of the pharmaceutical composition of the present invention based on the patient's condition. Generally, the dosage of the composition administered to a patient may range from about 0.5 mg/kg to 1000 mg/kg of the patient's body weight. Doses may be given as a single dose or as two or more doses over the course of one or more days, depending on the patient's needs. Where human dosages of a compound are established for at least certain conditions, the present invention will employ those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosages, with a more preferred dosage range of 25 % to 250% of the established human dose. In cases where no established human dosage is available, as in the case of newly discovered pharmaceutical compounds, the appropriate human dosage can be inferred from the ED ₅₀ or ID ₅₀ value, or other appropriate value from in vitro or in vivo studies, as in Toxicity studies and efficacy studies in animals are quantified.

It should be noted that the attending physician will know how and when to terminate, interrupt, or adjust dosing due to toxicity and organ dysfunction. Conversely, if the clinical response is inadequate (to rule out toxicity), the attending physician will also know to adjust treatment to a higher level. The magnitude of the dosage administered in the treatment of the condition of interest will vary with the severity of the disease state being treated and the route of administration. The severity of the disease state may be assessed, for example, in part by standard prognostic assessment methods. In addition, the dosage and possible dosage frequency will also vary depending on the age, weight, and response of the individual patient. Schemes equivalent to those discussed above may be used in veterinary medicine.

Although exact dosages can be determined on a drug-by-drug basis, in most cases some generalizations can be made about the agents. The daily dosage regimen for adult patients is, for example, an oral dosage of 0.1 mg to 2000 mg of each active ingredient, preferably 1 mg to 1000 mg of each active ingredient, such as 5 to 500 mg of each active ingredient. In other embodiments, each active ingredient is used in an intravenous, subcutaneous or intramuscular dose of 0.01 mg to 1000 mg, preferably 0.1 mg to 800 mg, such as 1 to 200 mg. Where a pharmaceutically acceptable salt is administered, the dosage may be calculated as the free base. In certain embodiments, the composition is administered from 1 to 4 times daily. Alternatively, the compositions of the invention may be administered by continuous intravenous infusion, preferably at a daily dose of up to 1000 mg of each active ingredient. As will be understood by those skilled in the art, in certain circumstances, in order to effectively and rapidly treat a rapidly developing disease or infection, it is necessary to administer a compound disclosed in the present invention in an amount that exceeds or far exceeds the above-mentioned preferred dosage range. necessary. In certain embodiments, the compound is administered over a continuous period of treatment, such as one or several weeks, or months or years.

Dosage and dosing intervals can be individually adjusted to provide plasma levels of the active moiety sufficient to maintain the modified effect or minimum effective concentration (MEC). The MEC is different for each compound, but the MEC can be estimated from in vitro data. The dosage required to achieve the MEC depends on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC assays or bioassays.

Dosing intervals can also be determined using MEC values. The composition should be administered using a treatment regimen that maintains plasma levels above the MEC 10-90% of the time, preferably 30-90% of the time, and more preferably 50-90% of the time.

In the case of local administration or selective absorption, the effective local concentration of the drug is independent of the plasma concentration.

The amount of composition administered will, of course, depend on the individual to be treated, upon the individual's weight, severity of pain, mode of administration, and the judgment of the prescribing physician.

The potency and toxicity of the compounds disclosed herein can be assessed using known methods. For example, the toxicology of a specific compound, or a subset of such compounds that share certain chemical moieties, can be established by assaying toxicity in cell lines, such as mammalian cell lines and preferably human cell lines, in vitro. The results of such studies often predict toxicity in animals such as mammals or, more specifically, in humans. Alternatively, the toxicity of a particular compound can be determined in animal models such as mice, rats, rabbits or monkeys using known methods. The potency of a specific compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every disease state, including, but not limited to, cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents for treating these disease states. When selecting a model to determine efficacy, the skilled artisan will be able to select appropriate models, dosage and routes of administration, and treatment regimens under the guidance of the state of the art. Of course, human clinical trials can also be used to measure the effectiveness of compounds in humans.

If desired, the composition can be placed in a package or dispensing device, which can contain one or more unit dosage forms containing the active ingredient. The packaging may, for example, comprise metal or plastic foil, such as a blister pack. The packaging or dispensing device may carry instructions for administration. The packaging or dispensing device may also bear precautions associated with the container that are prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, the precautions reflecting that the drug form has been approved by that agency. Approved for human or veterinary administration. Such notices may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs, or approved product inserts. Compositions comprising a compound of the invention can also be prepared in a suitable container, formulated in a compatible pharmaceutical carrier, and labeled for the treatment of a specified disease state.

The compounds of the present invention can be prepared using the methods disclosed herein and conventional modifications thereof. It is obvious that in addition to the methods disclosed herein and well known in the art, conventional and well-known synthetic methods can also be used.

The synthesis of typical compounds of formula (I) or pharmaceutically acceptable salts thereof, such as compounds having structures described by one or more of formula (I), or compounds of other formulas disclosed herein, can be described in the following examples. method to complete.

Typical embodiments of compounds according to the invention may be synthesized using the general reaction schemes and/or examples described below. In view of the description herein, it is apparent that correspondingly different products can be produced by replacing the starting materials with materials of similar structure. The synthetic descriptions that follow provide many examples of how the starting materials can be varied to provide the corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for the synthesis of the compounds that are examples of the present invention. Group labels (e.g., R1, R2) used in the reaction schemes of this article are for illustrative purposes only.

Synthesis reaction parameters

Compounds of the present invention can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given; unless otherwise stated, other process conditions may also be used. Optimum reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by routine process optimization by those skilled in the art.

Additionally, for those skilled in the art, traditional protecting groups may be necessary to prevent certain functional groups from undergoing side reactions. Suitable protecting groups for various functional groups and suitable conditions for protection and deprotection of specific functional groups are well known in the art, for example, T.W. Greene and G.M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd ed., Wiley, New York , and the references cited therein describe many protecting groups.

Furthermore, the compounds of the present invention may contain one or more chiral centers.

Thus, if desired, these compounds can be prepared or isolated as pure stereoisomers, ie as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art or these compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc. racemic mixture.

The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, WI, USA). Others can be prepared by processes or obvious modifications thereof, described in standard references, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 5th Edition, 2001), and Larock's General Organic Transformation (VCH Publishers Inc., 1989).

The term "solvent", "inert organic solvent" or "inert solvent" refers to a solvent that is inert under the reaction conditions described in connection therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethyl methylformamide ("DMF"), chloroform, methylene chloride (or methylene chloride), ether, methanol, pyridine, etc.). Unless otherwise specified, the solvent used in the reaction of the present invention is an inert organic solvent, and the reaction is carried out under an inert gas, preferably nitrogen.

The term "q.s." means adding an amount sufficient to perform the stated function, e.g., to bring the solution to the desired volume (i.e., 100%). The compounds provided herein can be synthesized according to the general schemes provided below. In the schemes below, it will be understood that each compound shown therein can have the desired protecting group in any step. Standard protecting groups are well within the capabilities of those skilled in the art

On the other hand, the present invention provides a method for preparing the compound of formula (I), its pharmaceutically acceptable salt, ester or stereoisomer, which method includes five general routes (Route A, Route B, Route C, Route D and route E):

Route A:

Route B:

Route C:

Route D:

Route E:

steps

Synthesis 1: ((3aR, 4R, 6R, 6aR)-6-((Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2H)-yl)- Preparation of 2-oxotetrahydrofura[3,4-d][1,3]dioxol-4-yl)methylisobutyrate (1)

Monupiravir (4 g, 1.0 equivalent), dichloromethane (DCM) (15 ml), 1,1'-carbonyldiimidazole (CDI) (2.16 g, 1.1 equivalent) were stirred at room temperature overnight; H ₂ O (15 mL) was added, and the organic layer was separated; the organic layer was concentrated and crystallized from ethyl acetate to obtain compound 1, 3.04 g, yield: 70.5%.

Synthesis 2: (3aR, 4R, 6R, 6aR)-6-(4-((benzyloxy)amino)-2-oxopyrimidin-1(2H)-yl)-2-oxotetrahydrofura[ Preparation of 3,4-d][1,3]dioxol-4-yl) methyl isobutyrate (2)

Benzyl chloride (4.35 g, 1.1 equivalents) was slowly dropped into a solution of compound 1 (10 g, 1.0 equivalents) and triethylamine (4.27 g, 1.5 equivalents) in dichloromethane (100 ml) at room temperature. Stir at room temperature for 1 hour. H ₂ O (100 mL) was added, and the organic layer was separated. The organic layer was concentrated and crystallized from ethyl acetate to obtain compound 2, 6.5 g, with a yield of 50.3%.

Synthesis 3: (3aR, 4R, 6R, 6aR)-6-(4-(hydroxyamino)-2-oxopyrimidine-1(2H)-yl)-2-oxotetrahydrofurano[3,4-d] Preparation of [1,3]dioxol-4-yl) methyl benzoate (3)

At room temperature, slowly drop benzyl chloride (59.4 g, 2.2 equivalents) into a solution of compound NHC (50 g, 1.0 equivalents) and triethylamine (48.7 g, 2.5 equivalents) in dichloromethane (300 ml). Stir at room temperature for 1 hour. H ₂ O (300 mL) was added and the organic layer was separated. The organic layer was concentrated and crystallized from ethyl acetate to obtain compound 3-1, 30.0 g, with a yield of 33.3%. LCMS: [M+H] ⁺ :468.13. ¹ H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.16-8.18 (m, 2H), 7.93-7.97 (m, 4H), 7.61-7.68 (m, 2H), 7.47-7.52 ( m, 3H), 7.198-7.22 (d, 1H, J =8.4Hz), 5.74-5.76 (m, 2H), 5.65-5.67 (m, 2H), 5.46-5.50 (m, 1H), 5.31-5.32( d, 1H, J =5.2Hz), 4.54-4.50 (m, 1H), 4.39-4.44 (m, 1H).

A solution of compound 3-1 (15 g, 1.0 equiv) and 1,1'-carbonyldiimidazole (6.76 g, 1.3 equiv) in dichloromethane (100 ml) was stirred at room temperature overnight. H ₂ O (40 mL) was added and the organic layer was separated. The organic layer was concentrated and crystallized with ethyl acetate/petroleum ether (v/v: 20%) to obtain compound 3-2, 15 g, with a yield of 94.5%. LCMS: [M+H] ⁺ : 494.11. ¹ H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.16-8.18 (m, 2H), 7.93-7.97 (m, 4H), 7.61- 7.68(m, 2H), 7.47-7.52(m, 3H), 7.198-7.22(d, 1H, J =8.4Hz), 5.74-5.76(m, 1H), 5.61-5.56(m, 1H), 5.55- 5.50(m, 1H), 5.40-5.35(m, 1H), 4.57-4.50(m, 1H), 4.49-4.43(m, 1H).

To a solution of compound 3-2 (30.0 g, 1.0 equiv) in methanol (90 ml) and N,N-dimethylacetamide (90 ml) was added 37% concentrated hydrochloric acid (37.5 ml) at room temperature. Raise the temperature to 55°C and stir for 8 hours. After cooling, H ₂ O (400 mL) was added, then the pH was adjusted to 8 with NaHCO ₃ solution, and the organic layer was extracted. The organic layer was concentrated and crystallized from ethyl acetate to obtain compound 3 (4.8 g, 40.5%).

Synthesis 4: ((3aR, 4R, 6R, 6aR)-6-((Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2H)-yl-5 , Preparation of 6-d2)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (4)

According to step 1, the raw material monopiravir is replaced with 5,6-D ₂ -molnupiravir to obtain target compound 4. LCMS:[M+H] ⁺ :358.10. ¹ H NMR (400 MHz, DMSO-d6) δ10.08 (s, 1H), 9.84 (d, J =2.1Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32(m, 1H), 4.32-4.23(m, 1H), 4.22-4.13(m, 1H), 2.56-2.48(m, 1H), 1.06(d, J =1.3Hz, 3H), 1.04( d, J =1.3Hz, 3H).

Synthesis 5: ((7R, 9R, 9aS, Z)-9-((E)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2H)-yl)- 2,5-dioxo-2,5,6a,7,9,9a-hexahydrofuro[3,4-b][1,4]dioxoct-7-yl)methylisobutyric acid Preparation of ester (5)

At 0°C, maleyl dichloride (21.23 g, 1.20 equiv) was slowly added dropwise to monopivir (4.0 g, 1.0 equiv), Et ₃ N (3.07 g, 2.5 equiv) in dichloromethane (20 mL ) solution and then stirred for 4 hours. H ₂ O (20 mL) was added and the organic layer was separated. The organic layer was concentrated and purified by column chromatography to obtain compound 5, 450 mg, yield: 9%.

Synthesis 6: ((7R, 9R, 9aS, Z)-9-((E)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2H)-yl)- 2,5-dioxo-2,5,6a,7,9,9a-hexahydrofuro[3,4-b][1,4]dioxoct-7-yl)methylisobutyric acid Preparation of ester (6)

At 0°C, slowly add phthaloyl chloride (21.23 g, 1.20 equiv) into 3-1 (5.0 g, 1.0 equiv), Et ₃ N (2.71 g, 2.5 equiv) in dichloromethane (20 ml ) solution and stir for 4 hours. H ₂ O (20 mL) was added and the organic layer was separated. The organic layer was concentrated and purified by column chromatography to obtain compound 6, 900 mg, yield: 14%.

Synthesis 7: ((3aR, 4R, 6R, 6aR)-6-((Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidine-1(2H)-yl)- Preparation of 2,2-dimethyltetrahydrofura[3,4-d][1,3]dioxol-4-yl)methylisobutyrate (7)

Concentrated sulfuric acid (98%, 0.5 ml) was slowly added to monopivir (10 g, 1.0 equiv), 2,2-dimethoxypropane (3.48 g, 1.1 equiv) in MeOH (100 ml) at room temperature. ) solution, stir at room temperature overnight. _H2O (100 ml) was added slowly and a solid precipitated. After filtration, solid compound 7 was obtained, 8.50 g, yield 75.8%.

Synthesis 8: 1-((3aR, 4R, 6R, 6aR)-6-(hydroxymethyl)-2-oxotetrahydrofurano[3,4-d][1,3]dioxol-4 Preparation of -yl)-4-((isobutoxy)amino)pyrimidine-2(1H)-one (8)

Isobutyryl chloride (0.37, 0.9 equivalent) was slowly added to a solution of NHC (1.0 g, 1.0 equivalent), Et3N (0.43 g, 1.1 equivalent) in dichloromethane (10 ml) at -25~-20°C. , stir for 4 hours. H ₂ O (20 mL) was added and the organic layer was separated. The organic layer was concentrated and purified by column chromatography to obtain compound 8-1, 0.45 g, yield 35.42%. LCMS: [M+H] ⁺ :330.1.

A solution of compound 8-1 (0.45 g, 1.0 equiv) and 1,1'-carbonyldiimidazole (0.29 g, 1.3 equiv) in dichloromethane (10 ml) was stirred at room temperature overnight. _H2O (10 ml) was added and the organic layer was separated. The organic layer was concentrated and purified by column chromatography to obtain compound 8, 0.32 g, yield 65.9%.

Synthesis 9: ((3aR, 4R, 6R, 6aR)-6-(4-(hydroxyamino)-2-oxopyrimidine-1(2H)-yl)-2-oxotetrahydrofurano[3,4-d Preparation of ][1,3]dioxol-4-yl)methyl L-alanine (9)

Under nitrogen protection at 0°C, add DMF-DMA (9.8 mg, 82 mmol) to the solution of cytidine (5.0 g, 20.5 mmol) and pyridine (10 ml) in DCM (50 ml). Stir at room temperature overnight. Add H ₂ O (50 mL), separate the organic layer, and concentrate the organic phase to obtain crude product 9-1, which can be used directly in the next reaction without purification.

Solution of compound 9-1, (tert-butoxycarbonyl)-L-alanine (7.78g, 2eq), HATU (23.45g, 3eq), DIPEA (13.3g, 5eq) and DMAP (100mg) in DCM (50ml) , stir at room temperature for 3 hours. Then add ethanol (100 mL) and heat to reflux for 1 hour. Cool to room temperature and concentrate to obtain crude product 9-2. The crude product was subjected to column chromatography to obtain product 9-2, 4.3 g. LCMS: [M+H] ⁺ : 470.2.

Hydroxylamine sulfate (1.4g, 4eq) was added to the aqueous solution (5ml) of compound 9-2 (1.0g, 1eq), and the temperature was raised to 78°C and stirred for 18h. After cooling, the solid was filtered out, added to HCl/EA (1 mol/L, 10 ml), and stirred at room temperature for 2 hours. After filtration, 0.5g of the target substance was obtained, with a yield of 71.07%.

According to step 1, 1,1’-carbonyldiimidazole was used for cyclization to obtain target compound 9.

Synthesis 10: ((3aR, 4R, 6R, 6aR)-6-(4-(hydroxyamino)-2-oxopyrimidine-1(2H)-yl)-2-oxotetrahydrofurano[3,4-d Preparation of ][1,3]dioxol-4-yl)methyl L-serine (10)

Following step 9, compound 10-3 was obtained by substituting (tert-butoxycarbonyl)-L-alanine with O-benzyl-N-(tert-butoxycarbonyl)-L-serine.

Pd/C (12 mg, wt 10%) was added to a solution of compound 10-3 (120 mg, 1 eq) in methanol (5 mL), and then stirred at room temperature overnight under hydrogen protection. Filter, concentrate the filtrate, and purify using preparative HPLC (0.1% trifluoroacetic acid aqueous solution/acetonitrile) to obtain 10.35 mg of the compound, with a yield of 36.23%.

Following the procedures described herein (shown in Step Table 1), the following compounds can be prepared using appropriate starting materials and appropriate protecting groups as desired. The key reaction is the cyclization reaction: CDI or 2,2-dimethoxypropane forms a five-membered ring; oxalic acid chloride forms a six-membered ring; maleic acid dichloride or phthalic acid chloride forms an eight-membered ring.

Table 1 No. Structural formula ES/MS (m/z, M+H ⁺ ) ¹ H NMR synthesis 1 356.30 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 2.1 Hz , 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.56 -2.48 (m, 1H), 1.06 (d, J = 1.3 Hz, 3H), 1.04 (d, J = 1.3 Hz, 3H). 1 2 460.41 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.02 – 7.96 (m, 2H), 7.99 – 7.91 (m, 1H), 7.61 – 7.54 (m, 1H), 7.51 – 7.44 (m, 2H), 6.27 – 6.22 (m, 1H), 5.96 (d, J = 7.5 Hz, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.31 – 4.21 ( m, 2H), 2.61 – 2.50 (m, 1H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H). 2 3 390.32 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 8.05 – 7.99 (m, 2H), 7.98 – 7.92 (m , 1H), 7.58 – 7.51 (m, 1H), 7.49 – 7.42 (m, 2H), 6.27 – 6.22 (m, 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.62 – 5.57 (m, 1H ), 5.34 – 5.28 (m, 1H), 4.63 – 4.49 (m, 3H). 3 4 440.38 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.31 ( d, J = 8.5 Hz, 1H), 8.06 – 8.00 (m, 1H), 8.03 – 7.92 (m, 2H), 7.91 – 7.83 (m, 1H), 7.57 – 7.47 (m, 2H), 6.27 – 6.22 ( m, 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.62 – 5.57 (m, 1H), 5.34 – 5.28 (m, 1H), 4.63 – 4.49 (m, 3H). 3 5 356.30 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 7.98 – 7.92 (m, 1H), 6.27 – 6.22 (m , 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.56 – 4.49 (m, 1H), 4.23 – 4.11 (m, 2H ), 2.33 (t, J = 7.1 Hz, 2H), 1.71 – 1.57 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 3 6 384.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 7.95 – 7.92 (m, J = 7.21 Hz, 1H), 6.27 – 6.22 (m, 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.56 – 4.49 (m, 1H), 4.23 – 4.11 (m, 2H), 2.36 – 2.29 (m, 2H), 1.64 – 1.54 (m, 2H), 1.43 – 1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 3 7 370.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 7.98 – 7.92 (m, 1H), 6.27 – 6.22 (m , 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.56 – 4.49 (m, 1H), 4.23 – 4.11 (m, 2H ), 2.33 (t, J = 7.1 Hz, 2H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H). 9 8 368.31 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 7.98 – 7.92 (m, 1H), 6.27 – 6.22 (m , 1H), 5.94 (d, J = 7.3 Hz, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.56 – 4.49 (m, 1H), 4.23 – 4.11 (m, 2H ), 2.33 (t, J = 7.1 Hz, 2H), 1.28 (m, 2 H), 1.20 (m, 2H). 9 9 370.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 7.98 – 7.92 (m, 1H), 6.27 – 6.22 (m , 1H), 5.97 – 5.91 (m, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.32 – 4.22 (m, 2H), 2.46 – 2.35 (m, 1H), 1.56 – 1.43 (m, 2H), 1.16 (d, J = 8.2 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H). 9 10 370.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.32 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.3 Hz, 1H), 7.98 – 7.92 (m, 1H), 6.27 – 6.22 (m , 1H), 5.97 – 5.91 (m, 1H), 5.62 – 5.57 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.32 – 4.22 (m, 2H), 2.46 – 2.35 (m, 1H), 1.56 – 1.43 (m, 2H), 1.16 (d, J = 8.2 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H). 9 11 418.37 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 7.31 – 7.27 (m, 3H), 7.34 – 7.23 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.58 – 4.51 (m, 1H), 4.29 (d, J = 5.1 Hz, 2H), 3.72 – 3.64 (m, 1H), 1.43 (s, 3H). 9 12 418.37 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 7.31 – 7.27 (m, 3H), 7.34 – 7.23 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.58 – 4.51 (m, 1H), 4.29 (d, J = 5.1 Hz, 2H), 3.72 – 3.64 (m, 1H), 1.43 (s, 3H). 9 13 354.29 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.35 – 4.24 (m, 2H), 1.96 – 1.89 (m, 1H), 1.14 – 1.01 (m, 2H), 1.01 – 0.89 (m, 2H). 9 14 368.31 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.35 – 4.24 (m, 2H), 2.44 – 2.36 (m, 1H), 2.10 – 1.92 (m, 4H), 1.92 – 1.69 (m, 2H). 9 15 396.3 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.35 – 4.28 (m, 1H), 4.29 (d, J = 3.8 Hz, 1H), 2.42 – 2.33 (m, 1H), 1.88 – 1.77 (m, 2H), 1.69 – 1.48 (m, 4H), 1.48 – 1.37 (m, 3H). 9 16 464.25 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.38 – 4.28 (m, 2H), 4.01 – 3.90 (m, 1H). 9 17 382.22 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.22 (m, 1H), 4.58 – 4.52 (m, 1H), 4.45 – 4.36 (m, 2H). 9 18 380.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.58 – 4.51 (m, 1H), 4.33 – 4.23 (m, 2H), 2.16 – 2.10 (m, 3H), 2.10 – 2.04 (m, 1H), 1.94 – 1.87 (m, 3H). 9 19 408.38 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.35 – 4.24 (m, 2H), 2.46 – 2.38 (m, 1H), 2.02 – 1.94 (m, 2H), 1.86 – 1.78 (m, 2H), 1.69 – 1.43 (m, 6H). 9 20 422.41 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.58 – 4.51 (m, 1H), 4.33 – 4.23 (m, 2H), 2.00 – 1.91 (m, 3H), 1.80 – 1.67 (m, 7H), 1.52 – 1.40 (m, 3H). 9 twenty one 357.29 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.33 – 4.22 (m, 2H), 3.86 – 3.76 (m, 1H), 3.44 – 3.37 (m, 1H), 3.27 – 3.20 (m, 1H), 1.40 (m, 3H). 9 twenty two 371.31 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.33 – 4.22 (m, 2H), 3.86 – 3.76 (m, 1H), 3.44 – 3.37 (m, 1H), 3.27 – 3.20 (m, 1H), 1.40 (m, 2H), 1.28(t, J = 7.3 Hz, 3H). 9 twenty three 385.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.33 – 4.22 (m, 2H), 3.86 – 3.76 (m, 1H), 3.44 – 3.37 (m, 1H), 3.27 – 3.20 (m, 1H), 1.40 (m, 2H), 1.28(m, 3H), 1.24(m, 3H). 9 twenty four 447.42 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 7.27 – 7.20 (m, 5H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.32 – 4.22 (m, 2H), 3.92 – 3.84 (m, 1H), 3.29 – 3.20 (m, 1H), 3.08 (d, J = 7.1 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H). 9 25 343.26 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.72 – 6.65 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.56 – 4.50 (m, 1H), 4.25 (d, J = 5.1 Hz, 2H), 2.72 (d , J = 5.5 Hz, 3H). 9 26 357.28 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.72 – 6.65 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.56 – 4.50 (m, 1H), 4.25 (d, J = 5.1 Hz, 2H), 2.74 (d , J = 5.5 Hz, 3H), 2.70 (d, J = 5.5 Hz, 3H). 9 27 399.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.37 – 4.31 (m, 1H), 4.31 – 4.25 (m, 1H), 3.73 – 3.67 (m, 4H), 3.65 – 3.59 (m, 2H), 3.58 – 3.52 (m, 2H). 9 28 397.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.37 – 4.31 (m, 1H), 4.31 – 4.25 (m, 1H), 3.55 – 3.47 (m, 2H), 3.46 – 3.38 (m, 2H), 1.76 – 1.68 (m, 4H), 1.67 – 1.58 (m, 2H). 9 29 344.25 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.39 (m, 1H), 4.37 – 4.30 (m, 1H), 3.04 (s, 3H) . 9 30 372.30 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.06 – 4.97 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 1.33 (d, J = 5.9 Hz, 3H), 1.28 (d, J = 5.7 Hz, 3H). 9 31 386.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.06 – 4.97 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 1.33 (d, J = 5.9 Hz, 3H), 1.28 (m, 2H), 1.09 (t, J = 5.9 Hz, 3H). 9 32 386.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.06 – 4.97 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 1.33 (d, J = 5.9 Hz, 3H), 1.28 (m, 2H), 1.09 (t, J = 5.9 Hz, 3H). 9 33 358.28 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.06 – 4.97 (m, 1H), 4.62 – 4.55 (m, 2H), 4.46 – 4.33 (m, 2H), 1.33 (d, J = 5.9 Hz, 3H). 9 34 412.25 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.82 – 4.73 (m, 3H), 4.62 – 4.55 (m, 1H), 4.44 – 4.37 (m, 1H), 4.37 – 4.30 (m, 1H). 9 35 386.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.06 – 4.97 (m, 1H), 4.62 – 4.55 (m, 2H), 4.46 – 4.33 (m, 2H), 1.33 (m, 1H) , 1.12 (d, J = 5.9 Hz, 3H), 1.09 (d, J = 5.9 Hz, 3H). 9 36 414.38 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.06 – 4.97 (m, 1H), 4.62 – 4.55 (m, 2H), 4.46 – 4.33 (m, 2H), 1.33 (m, 1H) , 1.18 (m, 2H), 1.15 (m, 2H), 1.05 (d, J = 5.9 Hz, 3H), 1.01 (d, J = 5.9 Hz, 3H). 9 37 400.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.40 – 6.35 (m, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 ( m, 1H), 5.26 – 5.21 (m, 1H), 4.84 – 4.75 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 1.68 – 1.50 (m, 4H), 0.95 (t, J = 7.4 Hz, 6H). 9 38 400.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.40 – 6.35 (m, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 ( m, 1H), 5.26 – 5.21 (m, 1H), 4.84 – 4.75 (m, 1H), 4.62 – 4.55 (m, 2H), 4.46 – 4.33 (m, 2H), 1.55 (3, 9H). 9 39 398.34 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.62 – 4.55 (m, 1H), 4.43 – 4.37 (m, 1H), 4.37 – 4.30 (m, 1H), 4.12 (s, 2H) , 1.19 – 1.08 (m, 2H), 0.99 (s, 3H), 0.68 – 0.61 (m, 1H), 0.63 – 0.56 (m, 1H). 9 40 384.31 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.91 – 4.84 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 2.09 – 1.94 (m, 2H), 1.87 – 1.75 (m, 4H). 9 41 402.33 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 2H), 5.19 (d, J = 3.3 Hz, 1H), 4.62 – 4.55 (m, 1H), 4.43 – 4.37 (m, 1H), 4.37 – 4.30 (m, 1H), 3.98 – 3.90 (m, 1H), 1.24 (d, J = 5.5 Hz, 3H), 1.19 (d, J = 5.5 Hz, 3H). 9 42 420.35 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 7.34 (d, J = 4.2 Hz, 4H), 7.34 – 7.25 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 5.18 (s, 2H), 4.62 – 4.55 (m , 1H), 4.43 – 4.37 (m, 1H), 4.37 – 4.30 (m, 1H). 9 43 434.37 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 7.40 – 7.34 (m, 2H), 7.33 – 7.22 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.95 – 5.87 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.39 (m, 1H), 4.39 – 4.32 (m, 1H), 1.62 (s, 3H). 9 44 416.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.17 (m, 1H), 6.17 – 6.11 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 4.14 – 4.05 (m, 1H), 1.48 (s, 3H), 1.21 (d, J = 5.3 Hz, 6H). 9 45 430.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.17 (m, 1H), 6.17 – 6.11 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.33 (m, 2H), 4.14 – 4.05 (m, 1H), 1.48 (s, 6H), 1.21 (d, J = 5.3 Hz, 6H). 9 46 400.31 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 2H), 5.19 (d, J = 3.3 Hz, 1H), 4.62 – 4.55 (m, 1H), 4.43 – 4.37 (m, 1H), 4.37 – 4.30 (m, 1H), 3.98 – 3.90 (m, 1H), 1.24 (m, 2H), 1.19 (m, 2H). 9 47 398.22 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.26 – 5.21 (m, 1H), 4.62 – 4.55 (m, 1H), 4.45 – 4.38 (m, 1H), 4.37 – 4.30 (m, 1H). 9 48 406.32 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.85 – 7.79 (m, 1H), 7.55 – 7.49 (m, 1H), 7.49 – 7.42 (m, 1H), 7.01 – 6.93 ( m, 2H), 6.94 (d, J = 1.3 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.34 – 5.28 (m, 1H), 4.60 – 4.53 (m, 1H), 4.53 – 4.47 (m, 1H), 4.47 – 4.41 (m, 1H). 9 49 413.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.77 – 6.71 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.21 – 6.16 (m, 1H) , 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.31 – 4.21 (m, 2H), 2.75 (d, J = 4.9 Hz, 3H), 2.61 – 2.50 (m, 1H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 2 50 427.36 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.77 – 6.71 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.21 – 6.16 (m, 1H) , 5.42 – 5.37 (m, 1H), 5.27 – 5.21 (m, 1H), 4.57 – 4.50 (m, 1H), 4.31 – 4.21 (m, 2H), 2.75 (d, J = 4.9 Hz, 3H), 2.61 – 2.50 (m, 1H), 1.18 (d, J = 7.3 Hz, 6H), 1.13 (d, J = 7.4 Hz, 3H). 2 51 426.114 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.19-6.01 (m, 1H), 5.40-5.30 (m, 1H), 5.24-5.11 (m, 1H), 4.54 (dt, J = 5.7, 5.0 Hz, 1H), 4.39 – 3.98 (m, 2H), 2.67-2.60 (m, 1H), 2.54-2.41 (m, 1H), 1.18 (d, J = 7.1 Hz, 6H), 1.13 (d, J = 7.1 Hz, 6H). 2 52 452.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.32 – 5.97 (m, 1H), 5.67 – 5.33 (m, 1H), 5.36 – 5.00 (m, 1H), 4.78 – 4.45 (m, 1H), 4.39 – 3.99 (m, 2H), 2.88 – 2.23 (m, 1H), 1.15 (dd, J = 25.1, 7.3 Hz, 6H). 2 53 441.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.83 – 6.67 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.26 – 6.13 (m, 1H), 5.54 – 5.33 (m, 1H), 5.32 – 5.21 (m, 1H), 4.65 – 4.48 (m, 1H), 4.38 – 4.18 (m, 2H), 2.75 (d, J = 4.9 Hz , 3H), 2.43 – 2.24 (m, 1H), 1.68 – 1.47 (m, 4H), 0.91 (t, J = 7.1 Hz, 6H). 9, 2 54 482.21 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.25 – 6.00 (m, 1H), 5.56 – 5.34 (m, 1H), 5.31 – 5.03 (m, 1H), 4.66 – 4.41 (m, 1H), 4.43 – 4.17 (m, 2H), 2.56 – 2.10 (m, 2H), 1.63 – 1.51 (m, 9H) , 1.09 – 0.75 (m, 12H). 9, 2 55 454.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.27 – 6.10 (m, 1H), 5.49 – 5.32 (m, 1H), 5.34 – 5.12 (m, 1H), 4.66 – 4.43 (m, 1H), 4.37 – 3.99 (m, 2H), 2.76 – 2.24 (m, 3H), 1.77 – 1.25 (m, 6H) , 1.25 – 0.81 (m, 9H). 9, 2 56 468.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.29 – 6.14 (m, 1H), 5.55 – 5.34 (m, 1H), 5.30 – 5.19 (m, 1H), 4.68 – 4.45 (m, 1H), 4.37 – 4.11 (m, 2H), 2.57 – 2.29 (m, 3H), 1.70 – 1.45 (m, 4H) , 1.46 – 1.07 (m, 7H), 0.91 (dt, J = 15.1, 6.9 Hz, 6H). 9, 2 57 468.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.27 – 6.07 (m, 1H), 5.55 – 5.35 (m, 1H), 5.32 – 5.17 (m, 1H), 4.69 – 4.44 (m, 1H), 4.42 – 4.05 (m, 2H), 2.69 – 2.24 (m, 3H), 1.82 – 1.45 (m, 4H) , 1.42 – 1.11 (m, 7H), 0.91 (dt, J = 15.1, 6.9 Hz, 6H). 9, 2 58 455.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.29 – 6.02 (m, 1H), 5.48 – 5.15 (m, 2H), 4.64 – 4.43 (m, 1H), 4.39 – 4.16 (m, 2H), 3.99 – 3.69 (m, 1H), 3.56 – 3.10 (m, 2H), 2.51 (t, J = 7.5 Hz , 2H), 1.74 – 1.26 (m, 9H), 1.07 – 0.74 (m, 3H). 9, 2 59 455.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.26 – 6.13 (m, 1H), 5.55 – 5.33 (m, 1H), 5.32 – 5.15 (m, 1H), 4.67 – 4.17 (m, 3H), 3.96 – 3.67 (m, 1H), 3.41 (dd, J = 7.1, 6.4 Hz, 1H), 3.23 (dd , J = 7.2, 6.5 Hz, 1H), 2.51 (t, J = 7.5 Hz, 2H), 1.88 – 1.23 (m, 9H), 1.04 – 0.78 (m, 3H). 9, 2 60 471.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.26 – 6.10 (m, 1H), 5.58 – 5.11 (m, 2H), 4.62 – 4.12 (m, 3H), 3.93 – 3.62 (m, 3H), 3.58 – 3.17 (m, 3H), 2.51 (t, J = 7.5 Hz, 2H), 1.79 – 1.28 (m , 6H), 1.00 – 0.78 (m, 3H). 10,2 61 427.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.50 – 6.11 (m, 2H), 5.51 – 5.14 (m, 2H), 4.62 – 4.16 (m, 3H), 3.97 – 3.71 (m, 1H), 3.48 – 3.11 (m, 2H), 2.81 – 2.48 (m, 1H), 1.54 – 1.06 (m, 9H). 9, 2 62 427.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.50 – 6.11 (m, 2H), 5.51 – 5.14 (m, 2H), 4.62 – 4.16 (m, 3H), 3.97 – 3.71 (m, 1H), 3.48 – 3.11 (m, 2H), 2.81 – 2.48 (m, 1H), 1.54 – 1.06 (m, 9H). 9, 2 63 443.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.59 – 6.01 (m, 2H), 5.51 – 5.04 (m, 2H), 4.64 – 4.16 (m, 3H), 3.95 – 3.60 (m, 3H), 3.58 – 3.24 (m, 3H), 2.83 – 2.51 (m, 1H), 1.15 (dd, J = 24.9, 6.7 Hz, 6H). 10, 2 64 477.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.16 – 7.87 (m, 2H), 7.63 – 7.29 (m, 4H), 6.38 (d, J = 7.3 Hz, 1H), 6.24 – 6.09 (m, 1H) , 5.46 – 5.15 (m, 2H), 4.64 – 4.45 (m, 1H), 4.41 – 4.17 (m, 2H), 3.91 – 3.64 (m, 3H), 3.53 – 3.25 (m, 3H). 10, 2 65 489.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.10 – 7.97 (m, 2H), 7.69 – 7.37 (m, 4H), 6.38 (d, J = 7.3 Hz, 1H), 6.25 – 6.03 (m, 1H) , 5.52 – 5.01 (m, 4H), 4.64 – 4.15 (m, 3H), 3.71 – 3.41 (m, 1H), 2.39 – 1.98 (m, 1H), 0.98 (dd, J = 6.4, 1.7 Hz, 6H) . 9, 2 66 503.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.14 – 7.98 (m, 2H), 7.69 – 7.39 (m, 5H), 6.54 – 6.09 (m, 2H), 5.54 – 5.17 (m, 2H), 4.67 – 4.17 (m, 3H), 3.58 (dt, J = 7.3, 6.6 Hz, 1H), 3.09 (dt, J = 80.9, 6.9 Hz, 2H), 2.22 – 1.96 (m, 1H), 1.53 – 1.14 (m, 2H), 1.08 – 0.83 (m, 6H). 9, 2 67 441.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.65 – 7.27 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.30 – 6.15 (m, 1H), 5.50 – 5.34 (m, 1H) , 5.34 – 5.12 (m, 1H), 4.69 – 4.17 (m, 3H), 3.90 – 3.58 (m, 1H), 3.49 – 3.16 (m, 2H), 2.73 – 2.45 (m, 1H), 1.83 – 1.36 ( m, 5H), 1.30 – 0.86 (m, 6H). 9, 2 68 567.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.50 – 6.08 (m, 2H), 5.51 – 5.13 (m, 2H), 4.68 – 4.22 (m, 3H), 4.20 – 3.80 (m, 1H), 3.38 – 2.98 (m, 3H), 2.55 (qt, J = 7.4, 5.9 Hz, 1H), 1.94 – 1.50 (m, 6H), 1.24 – 0.86 (m, 6H). 9, 2 69 414.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.52 – 6.15 (m, 2H), 5.47 – 5.11 (m, 2H), 4.68 – 4.19 (m, 3H), 3.04 (s, 2H), 2.78 – 2.51 (m, 1H), 1.15 (dd, J = 24.9, 6.8 Hz, 6H). 9, 2 70 442.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.54 – 6.07 (m, 2H), 5.50 – 4.93 (m, 3H), 4.70 – 4.28 (m, 3H), 2.83 – 2.46 (m, 1H), 1.54 – 1.02 (m, 12H). 9, 2 71 472.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.52 – 6.11 (m, 2H), 5.53 – 5.11 (m, 4H), 4.70 – 4.23 (m, 3H), 4.07 – 3.67 (m, 1H), 2.97 – 2.45 (m, 1H), 1.46 – 0.53 (m, 12H). 9, 2 72 453.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.50 – 6.01 (m, 2H), 5.52 – 5.14 (m, 2H), 4.64 – 4.09 (m, 3H), 3.69 – 3.29 (m, 4H), 2.91 – 2.40 (m, 1H), 2.12 – 1.67 (m, 4H), 1.15 (dd, J = 24.9, 6.7 Hz, 6H). 9, 2 73 428.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.49 – 6.07 (m, 2H), 5.50 – 5.10 (m, 2H), 4.69 – 4.16 (m, 3H), 4.03 – 3.12 (m, 6H), 1.44 (dd, J = 32.0, 5.8 Hz, 6H). 8 74 484.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.68 – 7.31 (m, 1H), 6.49 – 6.00 (m, 2H), 5.44 – 5.03 (m, 4H), 4.57 – 4.21 (m, 3H), 3.80 – 3.51 (m, 2H), 3.45 – 3.21 (m, 2H), 2.40 – 1.91 (m, 2H), 1.15 – 0.86 (m, 11H). 8 75 391.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.00 – 8.63 (m, 2H), 8.21 – 7.80 (m, 2H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H) , 6.56 – 6.03 (m, 2H), 5.45 – 5.17 (m, 2H), 4.85 – 4.47 (m, 3H). 3 76 391.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.00 – 8.63 (m, 2H), 8.21 – 7.80 (m, 2H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H) , 6.56 – 6.03 (m, 2H), 5.45 – 5.17 (m, 2H), 4.85 – 4.47 (m, 3H). 3 77 391.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.00 – 8.63 (m, 2H), 8.21 – 7.80 (m, 2H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H) , 6.56 – 6.03 (m, 2H), 5.45 – 5.17 (m, 2H), 4.85 – 4.47 (m, 3H). 3 78 446.06 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.15 – 7.90 (m,2H), 7.60 – 7.26 (m, 3H), 6.44 – 6.13 (m, 2H), 5.45 – 5.27 (m, 2H), 4.69 – 4.47 (m, 3H). 3 79 447.05 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 8.09 – 7.94 (m,2H), 7.58 – 7.34 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.27 – 6.16 (m, 1H), 5.44 – 5.28 (m, 2H), 4.64 – 4.48 (m, 3H). 3 80 431.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 8.09 – 7.94 (m,2H), 7.58 – 7.34 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.27 – 6.16 (m, 1H), 5.44 – 5.28 (m, 2H), 4.64 – 4.48 (m, 3H). 9 81 392.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (d, J = 1.6 Hz, 1H), 8.79 – 8.63 (m, 2H), 7.52 (dd, J = 7.2, 1.7 Hz , 1H), 6.43 – 6.12 (m, 2H), 5.46 – 5.26 (m, 2H), 4.66 – 4.46 (m, 3H). 3 82 404.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 8.02 – 7.77 (m, 2H), 7.60 – 7.17 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.22 – 6.08 (m, 1H), 5.51 – 5.17 (m, 2H), 4.66 – 4.36 (m, 3H), 2.39 (d, J = 0.9 Hz, 3H). 3 83 420.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.86 – 7.72 (m, 2H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 7.10 – 6.82 (m, 2H) , 6.44 – 6.09 (m, 2H), 5.50 – 5.24 (m, 2H), 4.71 – 4.35 (m, 3H), 3.83 (s, 3H). 3 84 474.07 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 8.00 – 7.90 (m, 2H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 7.31 – 7.15 (m, 2H) , 6.45 – 6.12 (m, 2H), 5.51 – 5.26 (m, 2H), 4.73 – 4.36 (m, 3H). 3 85 462.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.91 – 8.68 (m, 2H), 8.06 – 7.89 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.48 – 6.15 (m, 2H), 5.50 – 5.23 (m, 2H), 4.71 – 4.27 (m, 3H), 3.97 – 3.78 (m, 1H), 3.60 – 3.29 (m, 2H), 1.47 (d, J = 5.5 Hz, 3H) . 9, 2 86 475.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.08 – 7.81 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.34 – 7.14 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.26 – 6.03 (m, 1H), 5.46 – 5.28 (m, 2H), 4.72 – 4.41 (m, 3H), 4.01 – 3.82 (m, 1H), 3.63 – 3.33 (m, 2H) , 2.39 (d, J = 1.0 Hz, 3H), 1.47 (d, J = 5.5 Hz, 3H). 9, 2 87 491.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.79 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.15 – 6.79 (m, 2H), 6.48 – 6.10 (m, 2H), 5.50 – 5.26 (m, 2H), 4.71 – 4.43 (m, 3H), 4.03 – 3.77 (m, 4H), 3.47 (ddd, J = 57.5, 7.3, 5.9 Hz, 2H), 1.47 (d, J = 5.5 Hz, 3H). 9, 2 88 545.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.05 – 7.80 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.29 – 6.98 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.25 – 6.08 (m, 1H), 5.45 – 5.17 (m, 2H), 4.79 – 4.41 (m, 3H), 4.01 – 3.82 (m, 1H), 3.58 – 3.30 (m, 2H) , 1.47 (d, J = 5.5 Hz, 3H). 9, 2 89 489.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.08 – 7.93 (m, 2H), 7.67 – 7.39 (m, 4H), 6.41 (d, J = 7.5 Hz, 1H), 6.23 – 6.09 (m, 1H) , 5.45 – 5.25 (m, 2H), 4.69 – 4.42 (m, 3H), 3.78 – 3.17 (m, 3H), 2.26 – 1.93 (m, 1H), 0.97 (dd, J = 6.6, 0.9 Hz, 6H) . 9, 2 90 491.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.07 – 7.94 (m, 2H), 7.64 – 7.35 (m, 4H), 6.41 (d, J = 7.5 Hz, 1H), 6.25 – 6.14 (m, 1H) , 5.47 – 5.25 (m, 2H), 4.69 – 4.45 (m, 3H), 4.18 – 3.91 (m, 2H), 3.61 – 3.25 (m, 3H), 1.22 (d, J = 6.2 Hz, 3H). 9, 2 91 575.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.96 – 7.78 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.38 – 7.10 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.23 – 6.11 (m, 1H), 5.42 – 5.24 (m, 2H), 4.70 – 4.34 (m, 3H), 4.12 – 3.91 (m, 2H), 3.55 (dd, J = 7.2, 6.5 Hz, 1H), 3.40 – 3.23 (m, 2H), 1.22 (d, J = 6.2 Hz, 3H). 10, 2 92 573.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.00 – 7.88 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.27 – 7.16 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.23 – 6.13 (m, 1H), 5.48 – 5.25 (m, 2H), 4.75 – 4.35 (m, 3H), 3.85 – 3.63 (m, 1H), 3.50 – 3.14 (m, 2H) , 2.57 – 1.74 (m, 1H), 0.97 (dd, J = 6.6, 0.9 Hz, 6H). 9, 2 93 455.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.25 – 6.14 (m, 1H), 5.49 – 5.17 (m, 2H), 4.70 – 4.14 (m, 3H), 3.79 – 3.63 (m, 1H), 3.49 – 3.19 (m, 2H), 2.67 – 2.38 (m, 1H), 2.27 – 2.00 (m, 1H) , 1.32 – 0.80 (m, 12H). 2 94 427.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.19 (ddt, J = 4.2, 1.6, 0.8 Hz , 1H), 5.44 – 5.20 (m, 2H), 4.62 – 4.15 (m, 3H), 3.88 (h, J = 5.6 Hz, 1H), 3.47 (ddd, J = 57.4, 7.3, 5.9 Hz, 2H), 2.55 (dt, J = 14.7, 7.3 Hz, 1H), 1.47 (d, J = 5.5 Hz, 3H), 1.15 (dd, J = 25.1, 7.3 Hz, 6H). 2 95 443.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.19 (ddt, J = 4.2, 1.6, 0.8 Hz , 1H), 5.48 – 5.10 (m, 2H), 4.62 – 4.20 (m, 3H), 4.07 – 3.71 (m, 3H), 3.67 – 3.35 (m, 3H), 2.55 (dt, J = 14.7, 7.3 Hz , 1H), 1.15 (dd, J = 25.1, 7.3 Hz, 6H). 2 96 457.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.25 – 6.07 (m, 1H), 5.50 – 5.19 (m, 2H), 4.60 – 4.19 (m, 3H), 4.14 – 3.89 (m, 2H), 3.55 (dd, J = 7.2, 6.5 Hz, 1H), 3.46 – 3.28 (m, 2H), 2.73 – 2.42 (m, 1H), 1.26 – 0.98 (m, 9H). 2 97 443.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.27 – 6.02 (m, 1H), 5.48 – 5.19 (m, 2H), 4.68 – 4.31 (m, 3H), 3.79 – 3.59 (m, 1H), 3.48 – 3.20 (m, 2H), 3.04 (s, 2H), 2.26 – 1.99 (m, 1H), 0.97 (dd, J = 6.6, 0.9 Hz, 6H). 9, 2 98 471,16 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.19 (ddt, J = 4.2, 1.6, 0.8 Hz , 1H), 5.53 – 4.90 (m, 3H), 4.70 – 4.33 (m, 3H), 3.78 – 3.19 (m, 3H), 2.14 (dq, J = 12.9, 6.5 Hz, 1H), 1.31 (dd, J = 25.0, 5.8 Hz, 6H), 0.97 (dd, J = 6.6, 0.9 Hz, 6H). 9, 2 99 443.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.10 (m, 1H), 5.56 – 5.18 (m, 2H), 5.17 – 4.92 (m, 1H), 4.63 – 4.24 (m, 3H), 4.01 – 3.82 (m, 1H), 3.63 – 3.17 (m, 2H), 1.61 – 1.18 (m, 9H) . 9, 2 100 473.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.26 – 6.02 (m, 1H), 5.50 – 5.16 (m, 2H), 5.14 – 4.90 (m, 1H), 4.70 – 4.30 (m, 3H), 4.18 – 3.92 (m, 2H), 3.70 – 3.22 (m, 3H), 1.51 – 1.14 (m, 9H) . 9, 2 101 404.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.70 – 7.64 (m, 1H), 7.33 – 7.19 (m, 5H), 6.23 – 6.18 (m, 1H), 6.02 (d , J = 12.8 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.56 – 4.49 (m, 1H), 4.30 – 4.21 (m, 2H), 3.47 – 3.35 (m , 2H). 3 102 444.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.41 (s), 8.77 (s), 7.66 (dd, J = 12.6, 1.8 Hz, 1H), 7.19 – 7.11 (m, 3H), 6.35 (d, J = 12.8 Hz, 1H), 6.29 – 6.24 (m, 1H), 5.49 – 5.44 (m, 1H), 5.28 – 5.23 (m, 1H), 4.56 – 4.49 (m, 1H), 4.30 – 4.20 (m, 2H), 3.67 – 3.57 (m, 2H), 2.89 – 2.78 (m, 4H), 2.12 – 2.04 (m, 2H). 3 103 396.06 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.41 (s, 1H), 8.77 (s, 1H), 7.95 (dd, J = 7.3, 1.8 Hz, 1H), 6.28 – 6.25 (m, 1H), 5.97 (d, J = 7.3 Hz, 1H), 5.48 – 5.44 (m, 1H), 5.28 – 5.23 (m, 1H), 4.56 – 4.49 (m, 1H), 4.27 – 4.14 (m, 2H), 3.21 – 3.13 (m, 2H). 3 104 467.09 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 8.02 – 7.86 (m, 1H), 6.33 – 6.21 (m, 1H), 5.97 (d, J = 7.5 Hz, 1H), 5.52 – 5.41 (m, 1H), 5.32 – 5.22 (m, 1H), 4.60 – 4.46 (m, 1H), 4.26 – 4.21 (m, 1H), 4.21 – 4.13 (m, 1H), 3.94 (dd, J = 7.3, 6.1 Hz, 1H), 3.87 (dd, J = 7.3, 6.2 Hz, 1H), 3.80 (p, J = 5.9 Hz, 1H), 3.20 – 3.13 (m, 2H), 1.44 (d, J = 5.7 Hz, 3H). 9, 2 105 356.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 2.73 – 2.62 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). 8 106 340.07 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 8.77 (s, 1H), 7.67 (dd, J = 12.6, 1.8 Hz, 1H), 6.23 – 6.18 (m, 1H), 6.16 – 6.02 (m, 2H), 6.05 – 5.96 (m, 2H), 5.42 – 5.37 (m, 1H), 5.29 – 5.23 (m, 1H), 4.56 – 4.49 (m, 1H), 4.37 – 4.25 (m , 2H). 9 107 354.09 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.67 (dd, J = 12.6, 1.8 Hz, 1H), 6.66 – 6.57 (m, 1H), 6.23 – 6.18 (m, 1H ), 6.02 (d, J = 12.8 Hz, 1H), 5.85 – 5.79 (m, 1H), 5.42 – 5.37 (m, 1H), 5.29 – 5.23 (m, 1H), 4.56 – 4.49 (m, 1H), 4.37 – 4.25 (m, 2H), 1.94 – 1.89 (m, 3H). 9 108 352.07 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 8.77 (s, 1H), 7.67 (dd, J = 12.6, 1.8 Hz, 1H), 6.23 – 6.18 (m, 1H), 6.02 (d, J = 12.8 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.27 – 5.22 (m, 1H), 4.60 – 4.53 (m, 1H), 4.38 – 4.31 (m, 2H), 1.97 ( s, 3H). 9 109 358.06 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.67 (dd, J = 12.6, 1.8 Hz, 1H), 6.66 – 6.57 (m, 1H), 6.23 – 6.18 (m, 1H ), 6.02 (d, J = 12.8 Hz, 1H), 5.85 – 5.79 (m, 1H), 5.42 – 5.37 (m, 1H), 5.29 – 5.23 (m, 1H), 4.37 – 4.25 (m, 2H) 9 110 353.07 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 8.77 (s, 1H), 7.67 (dd, J = 12.6, 1.8 Hz, 1H), 6.66 – 6.57 (m, 1H), 6.23 – 6.18 (m, 1H), 6.02 (d, J = 12.8 Hz, 1H), 5.85 – 5.79 (m, 1H), 5.42 – 5.37 (m, 1H), 5.29 – 5.23 (m, 1H), 3.56 ( s, 2H) 9 111 424.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 8.02 – 7.86 (m, 1H), 6.33 – 6.21 (m, 1H), 5.97 (d, J = 7.5 Hz, 1H), 5.52 – 5.41 (m, 1H), 5.32 – 5.22 (m, 1H), 4.60 – 4.46 (m, 1H), 4.26 – 4.21 (m, 1H), 4.21 – 4.13 (m, 1H), 3.94 (dd, J = 7.3, 6.1 Hz, 1H), 3.87 (dd, J = 7.3, 6.2 Hz, 1H), 3.80 (p, J = 5.9 Hz, 1H), 3.56 (s, 2H), 1.44 (d, J = 5.7 Hz , 3H). 9, 2 112 433.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 8.77 (s, 1H), 7.53 (dd, J = 7.2, 1.7 Hz, 1H), 7.30 – 7.18 (m, 5H), 6.23 – 6.18 (m, 1H), 6.02 (d, J = 7.1 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.57 – 4.50 (m, 1H), 4.25 ( dd, J = 5.0, 1.4 Hz, 2H), 3.95 – 3.87 (m, 1H), 3.66 (t, J = 7.1 Hz, 1H), 3.42 (t, J = 7.1 Hz, 1H), 3.09 – 3.02 (m , 1H), 3.02 – 2.94 (m, 1H). 9 113 472.14 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.67 (dd, J = 12.6, 1.8 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.15 – 7.08 (m, 2H ), 6.50 (d, J = 2.1 Hz, 1H), 6.23 – 6.18 (m, 1H), 6.02 (d, J = 12.8 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.57 – 4.50 (m, 1H), 4.25 (dd, J = 5.0, 1.4 Hz, 2H), 4.10 (t, J = 7.1 Hz, 1H), 3.91 – 3.83 (m, 1H), 3.73 – 3.67 (m, 1H), 3.06 – 2.92 (m, 2H). 9 114 387.11 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 8.77 (s, 1H), 7.55 – 7.50 (m, 1H), 6.23 – 6.18 (m, 1H), 6.02 (d, J = 7.1 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.57 – 4.50 (m, 1H), 4.25 (dd, J = 5.0, 1.4 Hz, 2H), 4.22 ( t, J = 7.2 Hz, 1H), 4.07 (t, J = 7.1 Hz, 1H), 3.93 – 3.80 (m, 3H), 1.16 (d, J = 6.1 Hz, 3H). 10 115 423.12 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.67 – 7.65 (m, 2H), 7.07 – 7.04 (m, 1H), 6.23 – 6.19 (m, 1H), 6.04 – 5.99 (m, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.57 – 4.49 (m, 1H), 4.30 – 4.21 (m , 2H), 4.07 – 3.99 (m, 1H), 3.80 (d, J = 14.8 Hz, 1H), 3.56 (t, J = 7.3 Hz, 1H), 3.14 – 3.07 (m, 1H), 3.01 – 2.93 ( m, 1H). 9 116 399.14 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.55 – 7.50 (m, 1H), 6.23 – 6.18 (m, 1H), 6.02 (d, J = 7.1 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.57 – 4.50 (m, 1H), 4.25 (dd, J = 5.0, 1.4 Hz, 2H), 3.71 – 3.62 (m, 1H), 3.51 (dd, J = 7.3, 6.4 Hz, 1H), 3.43 (dd, J = 7.2, 6.3 Hz, 1H), 1.76 – 1.59 (m, 3H), 0.93 – 0.87 (m, 6H). 9 117 390.09 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H) ,8.08 – 8.02 (m, 2H), 7.64 – 7.56 (m, 2H), 7.50 – 7.43 (m, 2H), 6.22 – 6.17 (m, 1H), 6.03 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.45 – 4.39 (m, 1H), 4.33 – 4.27 (m , 1H), 3.71 – 3.58 (m, 2H). 8 118 343.08 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 7.65 – 7.49 (m, 1H), 7.39 – 7.19 (m, 1H), 6.31 – 6.13 (m, 1H), 6.07 (d , J = 7.5 Hz, 1H), 5.48 – 5.37 (m, 1H), 5.36 – 5.28 (m, 1H), 4.45 – 4.39 (m, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m , 2H), 2.71 (d, J = 4.9 Hz, 3H). 8 119 357.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 7.65 – 7.49 (m, 1H), 6.31 – 6.13 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.48 – 5.37 (m, 1H), 5.36 – 5.28 (m, 1H), 4.45 – 4.39 (m, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 2.71-2.56 (m ,6H). 8 120 372.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 5.14 – 5.03 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 1.28 (d, J = 5.9 Hz, 6H). 8 121 356.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.78 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 2.73 – 2.62 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). 8 122 328.07 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.78 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.45 – 4.39 (m, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 2.28 (s, 3H) 8 123 384.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.78 (s, 1H), 7.60 – 7.57 (m, 1H), 6.21 – 6.18 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.42 – 5.39 (m, 1H), 5.33 – 5.30 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.32 – 4.28 (m, 1H), 3.71 – 3.59 (m, 2H), 2.50 ( t, J = 7.6 Hz, 2H), 1.65 – 1.54 (m, 2H), 1.39 – 1.27 (m, 4H), 0.92 – 0.85 (m, 3H). 8 124 370.12 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 2.61 – 2.50 (m, 1H), 1.64 – 1.52 (m, 2H), 1.14 (d, J = 7.5 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H). 8 125 370.12 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.23 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.43 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 2.62 – 2.50 (m, 1H), 1.64 – 1.52 (m, 2H), 1.14 (d, J = 7.5 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H). 8 126 357.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.17 – 4.11 (m, 1H), 4.10 – 4.04 (m, 1H), 3.95 – 3.87 (m, 1H), 3.71 – 3.58 (m, 2H), 1.47 (d, J = 5.5 Hz, 3H). 8 127 357.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.17 – 4.11 (m, 1H), 4.10 – 4.04 (m, 1H), 3.95 – 3.87 (m, 1H), 3.71 – 3.58 (m, 2H), 1.47 (d, J = 5.5 Hz, 3H). 8 128 371.11 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.74 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.10 – 6.05 (m, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.80 – 3.72 (m, 1H), 3.71 – 3.58 (m , 2H), 3.51 – 3.45 (m, 1H), 3.42 – 3.35 (m, 1H), 1.89 – 1.77 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H). 8 129 371.11 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.74 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.10 – 6.05 (m, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.80 – 3.72 (m, 1H), 3.71 – 3.58 (m , 2H), 3.51 – 3.45 (m, 1H), 3.42 – 3.35 (m, 1H), 1.89 – 1.77 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H). 8 130 373.09 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.73 – 7.45 (m, 1H), 6.27 – 6.14 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.37 (t, J = 5.5 Hz, 1H), 4.33 – 4.27 (m, 1H) , 4.17 (d, J = 6.5 Hz, 2H), 4.05 – 3.98 (m, 1H), 3.79 – 3.70 (m, 2H), 3.70 – 3.58 (m, 2H). 8 131 373.09 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.73 – 7.45 (m, 1H), 6.27 – 6.14 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.37 (t, J = 5.5 Hz, 1H), 4.33 – 4.27 (m, 1H) , 4.17 (d, J = 6.5 Hz, 2H), 4.05 – 3.98 (m, 1H), 3.79 – 3.70 (m, 2H), 3.70 – 3.58 (m, 2H). 8 132 344.08 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.45 – 4.39 (m, 1H), 4.33 – 4.27 (m, 1H), 3.77 (s, 3H), 3.71 – 3.58 (m, 2H ). 8 133 354.09 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.61 – 7.56 (m, 1H), 6.85 – 6.75 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H ), 5.98 – 5.91 (m, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 1.87 (dd, J = 5.9, 1.5 Hz, 3H). 8 134 368.10 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.09 – 6.04 (m, 1H), 5.67 – 5.62 (m, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m , 2H), 2.03 – 1.99 (m, 3H), 1.99 – 1.94 (m, 3H). 8 135 358.06 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.09 – 6.04 (m, 1H), 5.44 (d , J = 3.8 Hz, 0H), 5.43 – 5.38 (m, 1H), 5.40 – 5.35 (m, 1H), 5.34 (s, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.72 – 3.64 (m, 1H), 3.64 – 3.57 (m, 1H). 8 136 352.07 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 1.96 ( s, 3H). 8 137 385.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.19 (s, 1H), 3.93 – 3.86 ( m, 1H), 3.71 – 3.58 (m, 2H), 2.21 – 2.09 (m, J = 6.4 Hz, 1H), 1.01 – 0.96 (m, 6H). 8 138 385.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H ), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.19 (s, 1H), 3.93 – 3.86 (m, 1H), 3.71 – 3.58 (m, 2H), 2.21 – 2.09 (m, J = 6.4 Hz, 1H), 1.01 – 0.96 (m, 6H). 8 139 382.04 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H ), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H). 8 140 406.08 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 7.44 – 7.37 (m, 2H), 7.28 – 7.22 (m, 2H), 7.26 – 7.19 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H). 8 141 386.06 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H), 3.42 – 3.20 (m, 2H). 8 142 464.05 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.38 – 4.29 (m, 1H), 4.32 – 4.26 (m, 1H), 3.71 – 3.58 (m, 2H). 8 143 387.11 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.50 – 4.45 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.25 (m, 2H), 4.01 – 3.87 (m, 3H), 3.71 – 3.58 (m, 2H), 1.19 (d, J = 5.9 Hz, 3H). 8 144 387.11 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.50 – 4.45 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.25 (m, 2H), 4.01 – 3.87 (m, 3H), 3.71 – 3.58 (m, 2H), 1.19 (d, J = 5.9 Hz, 3H). 8 145 433.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 7.30 – 7.22 (m, 4H), 7.25 – 7.18 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.05 – 3.98 (m, 1H), 3.85 – 3.79 (m, 1H), 3.71 – 3.58 (m, 3H), 3.06 – 2.98 (m, 1H), 2.98 – 2.90 (m, 1H ). 8 146 433.13 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 7.30 – 7.22 (m, 4H), 7.25 – 7.18 (m, 1H), 6.22 – 6.17 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 4.05 – 3.98 (m, 1H), 3.85 – 3.79 (m, 1H), 3.71 – 3.58 (m, 3H), 3.06 – 2.98 (m, 1H), 2.98 – 2.90 (m, 1H ). 8 147 391.08 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.86 – 8.81 (m, 2H), 8.03 – 7.99 (m, 2H), 7.61 – 7.56 (m, 1H), 6.22 – 6.17 (m, 1H), 6.03 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H). 8 148 391.08 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.78 – 8.73 (m, 1H), 8.23 – 8.17 (m, 1H), 7.89 – 7.82 (m, 1H), 7.61 – 7.53 (m, 2H), 6.22 – 6.17 (m, 1H), 6.03 (d, J = 7.5 Hz, 1H), 5.43 – 5.38 (m, 1H), 5.35 – 5.29 (m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.71 – 3.58 (m, 2H). 8 149 481.11 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.80 – 7.38 (m, 1H), 6.23 – 6.18 (m, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.42 – 5.37 (m, 1H), 5.32 – 5.19 (m, 1H), 4.57 – 4.51 (m, 1H), 4.40 (t, J = 3.8 Hz, 2H), 4.18 (d, J = 6.6 Hz, 2H) , 3.96 – 3.88 (m, 1H), 2.21 – 2.09 (m, J = 6.4 Hz, 1H), 1.01 – 0.96 (m, 6H). 8 150 532.21 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ8.76 (s, 1H), 7.61 – 7.56 (m, 1H), 7.30 – 7.18 (m, 5H), 6.24 – 6.17 (m, 2H), 6.13 – 6.05 (m, 2H), 5.42 – 5.37 (m, 1H), 5.28 – 5.23 (m, 1H), 4.57 – 4.50 (m, 1H), 4.30 – 4.20 (m, 2H), 4.07 – 3.99 (m, 1H ), 3.85 – 3.79 (m, 1H), 3.67 – 3.55 (m, 2H), 3.06 – 2.98 (m, 1H), 2.98 – 2.90 (m, 1H), 2.25 – 2.12 (m, J = 6.5 Hz, 1H ), 1.02 – 0.97 (m, 6H). 8 151 286.06 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.17 (m, 1H ), 5.40 (m, 1H), 5.31 (m, 1H), 4.36 – 4.29 (m, 1H), 3.79 – 3.67 (m, 3H). 1 152 503.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.94 (dd, J = 7.5, 1.8 Hz, 1H), 6.24 (m, 1H), 5.98 (d, J = 7.5 Hz, 1H), 5.59 (td, J = 3.5, 0.8 Hz, 1H), 5.25 (m, 1H), 4.57 – 4.50 (m, 1H), 4.33 – 4.22 (m, 2H), 3.84 (m, 1H), 3.41 (dd, J = 7.1, 6.4 Hz, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 1.40 (s, 1H). 9, 2 153 432.04 ¹ H NMR (500 MHz, Chloroform- d ) δ11.01(s,1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.19 (m, 1H), 5.40 (m, J = 4.2, 3.5, 0.8 Hz, 1H), 5.25 (m, 1H), 4.57 – 4.51 (m, 1H), 4.28 (dd, J = 11.7, 4.0 Hz, 1H), 4.20 (dd, J = 11.8, 3.9 Hz, 1H). 9 154 448.01 ¹ H NMR (500 MHz, Chloroform- d ) δ 11.01(s,1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.25 – 6.09 (m, 1H), 5.61 – 5.34 (m, 1H), 5.30 – 5.16 (m, 1H), 4.61 – 4.50 (m, 1H), 4.28 (dd, J = 11.7, 4.0 Hz, 1H ), 4.20 (dd, J = 11.8, 3.9 Hz, 1H). 9 155 463.98 ¹ H NMR (500 MHz, Chloroform- d ) δ 11.01(s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.21 – 6.16 (m, 1H), 5.42 – 5.37 (m, 1H), 5.28 – 5.22 (m, 1H), 4.57 – 4.51 (m, 1H), 4.42 – 4.31 (m, 2H). 9 156 534.02 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12(s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.26 – 6.13 (m , 1H), 5.44 – 5.34 (m, 1H), 5.31 – 5.19 (m, 1H), 4.65 – 4.46 (m, 1H), 4.44 – 4.27 (m, 2H), 2.77 – 2.56 (m, 1H), 1.15 (dd, J = 24.9, 6.7 Hz, 6H). 9 157 373.09 ¹ H NMR (500 MHz, Chloroform- d ) δ11.01(s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.27 – 6.11 (m, 1H), 5.45 – 5.36 (m, 1H), 5.31 – 5.19 (m, 1H), 4.63 – 4.48 (m, 1H), 4.42 – 4.17 (m, 2H), 3.86 – 3.64 (m, 3H), 3.48 (t, J = 5.5 Hz, 1H), 3.41 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H). 9 158 373.09 ¹ H NMR (500 MHz, Chloroform- d ) δ11.01(s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.27 – 6.11 (m, 1H), 5.45 – 5.36 (m, 1H), 5.31 – 5.19 (m, 1H), 4.63 – 4.48 (m, 1H), 4.42 – 4.17 (m, 2H), 3.86 – 3.64 (m, 3H), 3.48 (t, J = 5.5 Hz, 1H), 3.41 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H). 10 159 387.11 ¹ H NMR (500 MHz, Chloroform- d ) δ11.01(s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.28 – 6.12 (m, 1H), 5.53 – 5.31 (m, 1H), 5.29 – 5.17 (m, 1H), 4.74 – 4.45 (m, 1H), 4.41 – 4.21 (m, 2H), 4.10 – 3.94 (m, 1H), 3.99 – 3.85 (m, 1H), 3.42 – 3.09 (m, 3H), 1.22 (d, J = 6.2 Hz, 3H). 10 160 387.11 ¹ H NMR (500 MHz, Chloroform- d ) δ11.01(s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.2, 1.7 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.28 – 6.12 (m, 1H), 5.53 – 5.31 (m, 1H), 5.29 – 5.17 (m, 1H), 4.74 – 4.45 (m, 1H), 4.41 – 4.21 (m, 2H), 4.10 – 3.94 (m, 1H), 3.99 – 3.85 (m, 1H), 3.42 – 3.09 (m, 3H), 1.22 (d, J = 6.2 Hz, 3H). 10 161 458.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H)7.96 – 7.90 (m, 2H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.26 ( m, 2H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.54 – 4.44 (m, 2H), 2.39 (s, 3H). 9, 6 162 445.09 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 9.06 (dd, J = 2.0, 1.0 Hz, 1H), 8.77 – 8.72 (m, 1H), 8.29 – 8.23 (m, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.46 (dd, J = 8.0, 4.9 Hz, 1H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H ), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.53 (dd, J = 12.5, 4.8 Hz, 1H), 4.47 ( dd, J = 12.5, 4.6 Hz, 1H). 9, 6 163 445.09 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 8.76 (dd, J = 4.3, 1.7 Hz, 1H), 7.96 (dd, J = 7.6, 1.5 Hz , 1H), 7.88 (td, J = 7.4, 1.6 Hz, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.44 – 7.38 (m, 1H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.61 – 4.50 (m, 2H). 9, 6 164 474.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.82 – 7.76 (m, 2H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.99 – 6.93 (m, 2H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.30 – 5.24 (m, 1H), 4.71 – 4.64 (m, 1H) , 4.54 – 4.44 (m, 2H), 3.83 (s, 3H). 9, 6 165 408.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.99 – 5.94 (m, 1H), 5.77 – 5.71 (m, 1H), 5.68 – 5.63 (m, 1H), 5.26 (dd, J = 6.5, 5.8 Hz, 1H), 4.77 – 4.70 (m, 1H), 4.37 (dd, J = 12.1, 4.8 Hz, 1H), 4.30 (dd, J = 12.1, 4.8 Hz, 1H), 1.93 (d, J = 2.9 Hz, 3H). 9, 6 166 436.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.29 – 5.23 (m, 1H), 4.50 – 4.43 (m, 1H), 4.31 – 4.18 (m, 2H), 2.50 – 2.42 (m, 1H) , 1.90 – 1.80 (m, 1H), 1.15 (dd, J = 6.1, 1.5 Hz, 3H), 0.43 (d, J = 6.4 Hz, 4H). 9, 6 167 422.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.26 (dd, J = 6.5, 5.8 Hz, 1H), 4.56 – 4.50 (m, 1H), 4.30 (dd, J = 11.8, 3.9 Hz, 1H ), 4.25 (dd, J = 11.7, 3.8 Hz, 1H), 1.65 – 1.56 (m, 2H), 1.44 – 1.33 (m, 2H), 1.21 (s, 3H). 9, 6 168 436.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 3H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 3H), 6.40 – 6.34 (m, 6H), 6.31 (s, 6H), 5.77 – 5.71 (m, 3H), 5.26 (dd, J = 6.5, 5.8 Hz, 3H), 4.56 – 4.50 (m, 3H), 4.32 (dd, J = 11.8, 3.9 Hz, 3H ), 4.26 (dd, J = 11.8, 3.9 Hz, 3H), 1.80 – 1.72 (m, 6H), 1.72 – 1.62 (m, 3H), 1.62 – 1.52 (m, 3H), 1.38 – 1.31 (m, 5H ), 1.30 (d, J = 8.8 Hz, 1H), 0.88 (t, J = 6.2 Hz, 9H). 9, 6 169 528.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.97 – 7.91 (m, 2H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.25 – 7.19 (m, 2H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.54 – 4.44 (m, 2H). 9, 6 170 484.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.80 – 7.74 (m, 2H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.37 – 7.31 (m, 2H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.54 – 4.44 (m, 2H), 2.50 – 2.42 (m, 1H), 1.01 – 0.88 (m, 2H), 0.84 – 0.71 (m, 2H). 9, 6 171 486.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.84 – 7.78 (m, 2H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.28 – 7.22 (m, 2H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.54 – 4.44 (m, 2H), 2.96 – 2.85 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H). 9, 6 172 510.09 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.96 – 7.90 (m, 2H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.20 – 7.14 (m, 2H), 6.40 – 6.34 (m, 2H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.27 (dd, J = 6.5, 5.8 Hz, 1H), 4.71 – 4.64 (m, 1H), 4.51 (dd, J = 12.5, 4.8 Hz, 1H), 4.45 (dd, J = 12.5, 4.6 Hz, 1H). 9, 6 173 410.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.37 – 6.32 (m , 1H), 6.31 (s, 2H), 5.75 – 5.69 (m, 1H), 5.27 (t, J = 6.4 Hz, 1H), 4.29 – 4.22 (m, 1H), 3.82 – 3.67 (m, 3H), 2.73 – 2.61 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 8, 6 174 438.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.37 – 6.32 (m , 1H), 6.31 (s, 2H), 5.75 – 5.69 (m, 1H), 5.27 (t, J = 6.4 Hz, 1H), 4.29 – 4.22 (m, 1H), 3.82 – 3.67 (m, 3H), 2.39 (p, J = 6.5 Hz, 1H), 1.63 – 1.49 (m, 4H), 0.90 (t, J = 7.1 Hz, 6H). 8, 6 175 480.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.38 – 6.34 (m , 1H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.26 (dd, J = 6.5, 5.8 Hz, 1H), 4.50 – 4.43 (m, 1H), 4.23 (d, J = 5.0 Hz, 2H), 2.73 – 2.61 (m, 1H), 2.61 – 2.49 (m, 1H), 1.15 (dd, J = 25.0, 7.0 Hz, 12H). 8, 6 176 481.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.38 – 6.34 (m , 1H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.26 (dd, J = 6.5, 5.8 Hz, 1H), 4.52 – 4.45 (m, 1H), 4.33 – 4.23 (m, 2H ), 3.86 – 3.76 (m, 1H), 3.41 (dd, J = 7.1, 6.4 Hz, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.73 – 2.61 (m, 1H), 1.40 ( s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 3, 6 177 497.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.39 (m, 1H), 4.32 (dd, J = 11.9, 5.1 Hz, 1H), 4.26 (dd, J = 11.8 , 5.0 Hz, 1H), 3.85 – 3.72 (m, 2H), 3.70 – 3.61 (m, 1H), 3.48 (t, J = 5.6 Hz, 1H), 3.41 (t, J = 7.2 Hz, 1H), 3.30 (t, J = 7.2 Hz, 1H), 2.73 – 2.61 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 178 481.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.38 (m, 1H), 4.32 – 4.22 (m, 2H), 3.86 – 3.76 (m, 1H), 3.41 (dd , J = 7.1, 6.4 Hz, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.73 – 2.61 (m, 1H), 1.40 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 179 481.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.38 – 6.34 (m , 1H), 6.31 (s, 2H), 5.77 – 5.71 (m, 1H), 5.26 (dd, J = 6.5, 5.8 Hz, 1H), 4.52 – 4.45 (m, 1H), 4.33 – 4.23 (m, 2H ), 3.86 – 3.76 (m, 1H), 3.41 (dd, J = 7.1, 6.4 Hz, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.73 – 2.61 (m, 1H), 1.40 ( s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 180 509.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 5.10 (d, J = 7.2 Hz, 2H), 4.46 – 4.38 (m, 1H), 4.32 (dd, J = 11.9, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.64 – 3.56 (m, 1H), 2.73 – 2.61 (m, 1H), 2.18 (dt, J = 13.0, 6.5 Hz, 1H) , 1.18 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H), 0.98 (dd, J = 6.4, 1.7 Hz, 6H). 9, 2, 6 181 511.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.38 (m, 1H), 4.35 – 4.23 (m, 2H), 3.81 – 3.72 (m, 1H), 3.71 – 3.61 (m, 2H), 3.57 (dd, J = 7.3, 6.6 Hz, 1H), 3.50 – 3.42 (m, 2H), 2.73 – 2.61 (m, 1H), 2.06 – 1.92 (m, 2H), 1.18 (d , J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 10, 2, 6 182 464.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 6.15 – 6.05 (m, 2H), 5.99 (dd, J = 11.2, 3.1 Hz, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.35 (m, 2H ), 4.30 (dd, J = 11.7, 4.8 Hz, 1H), 2.73 – 2.61 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 183 482.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.44 (m, 3H), 5.37 (dd, J = 52.4, 3.8 Hz, 1H), 4.50 – 4.43 (m, 1H), 4.43 – 4.40 (m, 2H ), 2.73 – 2.61 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 184 462.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 2H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.50 – 4.43 (m, 1H), 4.37 (d, J = 4.6 Hz, 2H), 3.36 (s, 1H), 2.73 – 2.61 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 185 476.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.31 (s, 1H ), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.50 – 4.43 (m, 1H), 4.41 – 4.32 (m, 2H), 2.73 – 2.61 (m, 1H), 1.18 (d , J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 2, 6 186 406.08 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.26 – 6.20 (m, 1H), 5.56 – 5.43 (m, 2H), 4.52 – 4.43 (m, 1H), 4.41 – 4.31 (m, 2H), 1.97 (s, 3H ). 9, 6 187 412.07 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.53 – 5.44 (m, 3H), 5.37 (dd, J = 52.4, 3.8 Hz, 1H), 4.50 – 4.43 (m, 1H), 4.43 – 4.40 (m, 2H). 9, 6 188 427.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.39 (m, 1H), 4.32 (dd, J = 11.9, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.85 – 3.72 (m, 2H), 3.70 – 3.61 (m, 1H), 3.48 (t, J = 5.6 Hz, 1H), 3.41 (t, J = 7.2 Hz, 1H), 3.30 (t, J = 7.2 Hz, 1H). 10, 6 189 410.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.22 (d, J = 5.1 Hz, 2H), 2.61 – 2.50 (m, 1H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 9, 6 190 438.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.29 (dd, J = 11.7, 5.1 Hz, 1H), 4.22 (dd, J = 11.8, 5.0 Hz, 1H), 2.30 (p, J = 7.2 Hz, 1H), 1.59 – 1.51 (m, 4H), 0.91 (t, J = 7.1 Hz, 6H). 9, 6 191 410.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.20 (dd, J = 11.8, 4.9 Hz, 1H), 4.14 (dd, J = 11.9, 4.8 Hz, 1H), 2.33 (t, J = 7.1 Hz, 2H), 1.71 – 1.57 (m, 2H), 0.97 – 0.90 (m, 3H). 9, 6 192 438.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.22 – 4.11 (m, 2H), 2.30 (t, J = 8.1 Hz, 2H), 1.62 – 1.52 (m, 2H), 1.39 – 1.27 (m, 4H), 0.94 – 0.84 (m, 3H). 9, 6 193 424.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.24 – 4.12 (m, 2H), 2.30 – 2.18 (m , 2H), 2.10 – 2.00 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 9, 6 194 439.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 5.10 (d, J = 7.2 Hz, 2H), 4.46 – 4.38 (m, 1H), 4.32 ( dd, J = 11.9, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.65 – 3.57 (m, 1H), 2.23 – 2.12 (m, 1H), 0.98 (dd, J = 6.4, 1.7 Hz, 6H). 9, 6 195 396.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.22 – 4.11 (m, 2H), 2.42 – 2.34 (m , 2H), 1.14 (t, J = 8.0 Hz, 3H). 9, 6 196 439.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 5.10 (d, J = 7.2 Hz, 2H), 4.46 – 4.38 (m, 1H), 4.32 ( dd, J = 11.9, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.64 – 3.56 (m, 1H), 2.23 – 2.12 (m, 1H), 0.98 (dd, J = 6.4, 1.7 Hz, 6H). 9, 6 197 441.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.38 (m, 1H), 4.32 (dd, J = 11.9, 5.2 Hz, 1H), 4.26 (dd, J = 11.9, 4.9 Hz, 1H), 4.04 – 3.95 (m, 1H), 3.95 – 3.88 (m, 1H), 3.35 (t, J = 7.2 Hz, 1H), 3.28 (d, J = 4.9 Hz, 1H), 3.24 (t, J = 7.2 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H). 10, 6 198 441.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.38 (m, 1H), 4.32 (dd, J = 11.9, 5.2 Hz, 1H), 4.26 (dd, J = 11.9, 4.9 Hz, 1H), 4.04 – 3.95 (m, 1H), 3.95 – 3.88 (m, 1H), 3.35 (t, J = 7.2 Hz, 1H), 3.28 (d, J = 4.9 Hz, 1H), 3.24 (t, J = 7.2 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H). 10, 6 199 425.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.46 – 4.38 (m, 1H), 4.33 (dd, J = 11.9, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.71 – 3.62 (m, 1H), 3.04 (t, J = 7.1 Hz, 1H), 2.95 (t, J = 7.1 Hz, 1H), 1.92 – 1.75 (m, 2H), 0.95 (t, J = 7.1 Hz, 3H). 9, 6 200 424.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 9.12 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 6.31 (s, 2H), 6.25 – 6.20 (m, 1H), 5.52 – 5.43 (m, 2H), 4.45 – 4.38 (m, 1H), 4.29 (dd, J = 11.9, 5.1 Hz, 1H), 4.22 (dd, J = 11.8, 5.0 Hz, 1H), 2.46 – 2.34 (m, 1H), 1.60 – 1.47 (m, 2H), 1.16 (d, J = 8.2 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H). 9, 6 201 424.13 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J = 6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H), 5.82 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42- 4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.56-2.48 (m, 1H), 1.37 (d, J = 3.4 Hz, 2H), 1.06 (d, J = 1.3 Hz, 3H), 1.04 (d, J = 1.3 Hz, 3H). 9, 6 202 422.11 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J = 6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H), 5.82 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42- 4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.77-2.73 (m, 1H), 2.56-2.48 (m, 1H), 1.72 (d, J = 1.8 Hz, 2H), 1.60 (d, J = 2.1 Hz, 2H), 1.47 (d, J = 2.3 Hz, 2H). 9, 6 203 436.13 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J = 6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H), 5.82 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42- 4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.77-2.73 (m, 1H), 2.56-2.48 (m, 1H), 2.17 (d, J = 1.3 Hz, 2H), 1.72 (d, J = 1.8 Hz, 2H), 1.60 (d, J = 2.1 Hz, 2H), 1.47 (d, J = 2.3 Hz, 2H). 9, 6 204 422.11 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J = 6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H), 5.82 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42- 4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.77-2.73 (m, 1H), 2.56-2.48 (m, 1H), 2.17 (d, J = 1.3 Hz, 2H), 1.70 (d, J = 1.8 Hz, 2H), 1.45 (d, J = 2.3 Hz, 2H). 9, 6 205 458.11 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 7.69-7.57 (m, 2H), 7.47-7.52(m, 2H), 7.198-7.22(d, J =8.4Hz, 1H,) , 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J =6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H) , 5.82 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22 -4.13 (m, 1H), 3.71 (d, J = 2.3 Hz, 2H), 2.56-2.48 (m, 1H). 9, 6 206 498.14 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 7.69-7.57 (m, 2H), 7.198-7.22(d, J =8.4 Hz, 1H,) , 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J =6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H), 5.82 (d, J = 2.1 Hz , 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.91 -2.85(m, 4H), 2.56-2.48 (m, 1H), 2.07-2.04(m, 2H). 9, 6 207 444.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 7.69-7.57 (m, 2H), 7.47-7.52(m, 2H), 7.198-7.22(d, J =8.4Hz, 1H,) , 6.91 (d, J = 8.2 Hz, 1H), 6.39(d, J =6.8Hz, 1H), 6.30(d, J =6.8Hz, 1H) , 5.82 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22 -4.13 (m, 1H), 2.56-2.48 (m, 1H). 9, 6 208 445.09 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 8.58-8.53 (m, 2H), 7.47-7.52(m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.39 (d, J =6.8Hz, 1H), 6.30 (d, J =6.8Hz, 1H), 5.82 (d, J = 2.1 Hz, 1H), 5.58- 5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.56-2.48 (m, 1H ). 9, 6 209 384.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.37(d, J = 7.3 Hz, 1H ), 6.24-6.18 (m, 1H), 5.38 (m, 1H), 5.09 (m, 1H), 4.47 – 4.39 (m, 1H), 4.22 (d, J = 5.1 Hz, 2H), 2.55-2.45 ( m, 1H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 9, 6 210 412.13 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.52– 7.46 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24 –6.14(m, 1H), 5.38–5.26 (m, 1H), 5.09–4.98(m, 1H), 4.47 – 4.40 (m, 1H), 4.29–4.25(m, 1H), 4.23–4.15 (m, 1H), 2.30 (d, J = 4.2 Hz, 1H), 1.55 (d, J =2.1 Hz, 4H), 0.91 (d, J = 1.3 Hz, 6H). 9, 6 211 384.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.53– 7.42 (m, 1H), 6.25– 6.17 (m, 1H), 6.02 (d, J = 7.3 Hz, 1H), 5.38– 5.28 (m, 1H), 5.10– 5.02 (m, 1H), 4.41– 4.31 (m, 1H), 4.19– 4.15 (m, 1H), 4.10– 3.93 (m, 1H), 2.32 (d, J = 14.2 Hz, 1H), 1.70 – 1.56 (m, 2H), 0.93 (d, J = 1.7 Hz, 3H). 9, 6 212 412.13 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.53 (d, J = 7.3, 1H), 6.25-6.21 (m, 1H), 6.02 ( d, J = 7.3 Hz, 1H), 5.38-5.35 (m, 1H), 5.10-5.07 (m, 1H), 4.42-4.36 (m, 1H), 4.19-4.13 (m, 1H), 4.10-4.04 ( m, 1H), 2.30 (d, J = 16.3 Hz, 1H), 1.62 – 1.50 (m, 2H), 1.40 – 1.25 (m, 4H), 0.96 – 0.83 (m, 2H). 9, 6 213 370.08 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.53-7.43 (m, 1H), 6.25 (m, 1H), 6.02 (d, J = 7.3 Hz, 1H), 5.38 -5.21(m, 1H), 5.10 (m, 1H), 4.42-4.30 (m, 1H), 4.24 – 4.09 (m, 2H), 2.42 – 2.30 (m, 2H), 1.11 (t, J = 8.0 Hz, 3H). 9, 6 214 398.11 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.53-7.45 (m, 1H), 6.25-6.18 (m, 1H), 6.02 (d, J = 7.3 Hz, 1H), 5.38-5.31 (m, 1H), 5.10-5.03 (m, 1H), 4.42-4.32 (m, 1H), 4.21-4.09 (m, 1H), 4.14 – 4.02 (m, 1H), 2.32 – 2.17 (m, 2H), 2.04– 1.92 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 9, 6 215 413.12 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.53–7.44 (m, 1H), 6.25–6.16 (m, 1H), 6.02 (d, J = 7.3 Hz, 1H), 5.38–5.31 (m, 1H), 5.10–5.01 (m, 1H), 4.42–4.31 (m, 1H), 4.26–4.21 (m, 2H), 3.59 (d, J = 6.6 Hz, 1H), 2.19–2.11 (m, 1H), 0.99–0.91 (m, 6H). 9, 6 216 413.12 ¹ H NMR (400 MHz, DMSO -d ₆ ) δ10.08 (s, 1H), 9.57 (s, 1H), 7.53–7.44 (m, 1H), 6.25–6.16 (m, 1H), 6.02 (d, J = 7.3 Hz, 1H), 5.38–5.31 (m, 1H), 5.10–5.01 (m, 1H), 4.42–4.31 (m, 1H), 4.26–4.21 (m, 2H), 3.59 (d, J = 6.6 Hz, 1H), 2.19–2.11 (m, 1H), 0.99–0.91 (m, 6H). 9, 6 217 415.10 ¹ H NMR (400 MHz, Chloroform -d ) δ7.52–7.46 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24–6.16 (m, 1H), .5.38–5.31 (m 1H ), 5.09–5.02 (m, 1H), 4.43–4.33 (m, 1H), 4.36 – 4.21 (m, 2H), 4.04-3.96 (m, 1H), 3.92 (d, J = 5.9 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H). 9, 6 218 415.10 ¹ H NMR (400 MHz, Chloroform -d ) δ 7.52–7.46 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24–6.16 (m, 1H), 5.38–5.31 (m 1H), 5.09–5.02 (m, 1H), 4.43–4.33 (m, 1H), 4.36 – 4.21 (m, 2H), 4.04–3.95 (m, 1H), 3.92 (d, J = 5.9 Hz, 1H), 1.22 ( d, J = 6.2 Hz, 3H). 10, 6 219 399.11 ¹ H NMR (400 MHz, Chloroform -d ) δ 7.52–7.42 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24–6.16 (m, 1H), 5.38–5.31 (m, 1H) , 5.09-5.02 (m, 1H), 4.43-4.36 (m, 1H), 4.29-4.21 (m, 2H), 3.66 (t, J = 5.2 Hz, 1H), 1.94 – 1.73 (m, 2H), 0.95 (d, J = 2.1 Hz, 3H). 9, 6 220 398.11 ¹ H NMR (400 MHz, Chloroform- d ) δ 7.52 – 7.45 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24 – 6.14 (m, 1H), 5.38 – 5.32 (m, 1H) , 5.09-4.99 (m, 1H), 4.43 – 4.33 (m, 1H), 4.29-4.21 (m, 1H), 4.21 – 4.11 (m, 1H), 2.40 – 2.32 (m, 1H), 1.61 – 1.47 ( m, 2H), 1.16 (d, J = 8.0 Hz, 3H), 0.92 (d, J = 2.0 Hz, 3H). 9, 6 221 398.11 ¹ H NMR (400 MHz, Chloroform- d ) δ 7.52 – 7.45 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24 – 6.14 (m, 1H), 5.38 – 5.32 (m, 1H) , 5.09-4.99 (m, 1H), 4.43 – 4.33 (m, 1H), 4.29-4.21 (m, 1H), 4.21 – 4.11 (m, 1H), 2.40 – 2.32 (m, 1H), 1.61 – 1.47 ( m, 2H), 1.16 (d, J = 8.0 Hz, 3H), 0.92 (d, J = 2.0 Hz, 3H). 9, 6 222 396.10 ¹ H NMR (400 MHz, Chloroform- d ) δ 7.52 – 7.42(m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24 – 6.14 (m, 1H), 5.38 –5.31(m, 1H) , 5.09 –5.02 (m, 1H), 4.43 – 4.33 (m, 1H), 4.33 – 4.18 (m, 2H), 2.40 (d, J = 1.9 Hz, 1H), 2.11 – 1.68 (m, 6H). 9, 6 223 410.11 ¹ H NMR (400 MHz, Chloroform- d ) δ 7.52–7.42 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24– 6.15 (m, 1H), 5.38– 5.31 (m, 1H) , 5.09– 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.25 – 4.11 (m, 2H), 2.39– 2.32 (m, 1H), 2.29– 2.21 (m, 1H), 2.13– 2.06 ( m, 1H), 1.85 – 1.59 (m, 5H). 9, 6 224 396.10 ¹ H NMR (400 MHz, Chloroform -d ) δ 7.52–7.42 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.24–6.16 (m, 1H), 5.38–5.32 (m, 1H) , 5.09–5.01 (m, 1H), 4.42–4.32 (m, 1H), 4.25 – 4.11 (m, 2H), 2.36–2.31 (m, 1H), 2.27–2.21 (m, 1H), 1.62–1.54 ( m, 1H), 0.50 – 0.34 (m, 4H). 9, 6 225 432.10 ¹ H NMR (400 MHz, Chloroform- d ) δ 7.52–7.42 (m, 1H), 7.34 – 7.20 (m, 4H), 6.37 (d, J = 7.3 Hz, 1H), 6.24–6.15 (m, 1H) , 5.38 –5.28 (m, 1H), 5.09–4.99 (m, 1H), 4.42–4.32 (m, 1H), 4.36 – 4.24 (m, 2H), 3.40 –3..28 (m, 2H). 9, 6 226 472.13 ¹ H NMR (400 MHz, Chloroform- d ) δ 7.52–7.42 (m, 1H), 7.18 – 7.10 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.24–6.14 (m, 1H) , 5.38–5.32 (m, 1H), 5.09–5.01 (m, 1H), 4.42–4.32 (m, 1H), 4.36 – 4.24 (m, 2H), 3.61–3.51 (m, 2H), 2.89 – 2.78 ( m, 5H), 2.14 – 2.05 (m, 2H). 9, 6 227 418.08 ¹ H NMR (400 MHz, Chloroform -d ) δ 8.05 – 7.98 (m, 2H), 7.59 – 7.51 (m, 1H), 7.55 – 7.49 (m, 1H), 7.49 – 7.41 (m, 2H), 6.37 ( d, J = 7.3 Hz, 1H), 6.24– 6.14 (m, 1H), 5.38– 5.32 (m, 1H), 5.30– 5.22 (m, 1H), 4.62 – 4.52 (m, 2H), 4.50 – 4.42 ( m, 1H). 9, 6 228 419.08 ¹ H NMR (400 MHz, Chloroform- d ) δ 8.80 – 8.74 (m, 2H), 7.97 – 7.91 (m, 2H), 7.52– 7.45 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H) , 6.24– 6.15 (m, 1H), 5.38– 5.32 (m, 1H), 5.30– 5.20 (m, 1H), 4.62 – 4.54 (m, 2H), 4.50 – 4.42 (m, 1H). 9, 6 229 384.10 ¹ H NMR (400 MHz, Chloroform -d ) δ 7.58– 7.49 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.20– 6.13 (m, 1H), 5.39– 5.32 (m, 1H) , 5.30 – 5.20 (m, 1H), 4.14– 4.05 (m, 1H), 3.72– 3.62 (m, 2H), 2.67– 2.63 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 8, 6 230 385.09 ¹ H NMR (400 MHz, Chloroform-d) δ 7.58 – 7.51 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.20 – 6.10 (m, 1H), 5.39 – 5.26 (m, 1H) , 5.30 – 5.20 (m, 1H), 4.14 – 4.04 (m, 1H), 3.72 – 3.62 (m, 2H), 2.82 (s, 7H). 8, 6 231 371.08 ¹ H NMR (400 MHz, Chloroform -d ) δ 7.58– 7.51 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.20– 6.10 (m, 1H), 5.39– 5.31 (m, 1H) , 5.30– 5.20 (m, 1H), 4.14– 4.04 (m, 1H), 3.72– 3.62 (m, 2H), 2.75 (s, 3H). 8, 6 232 418.08 ¹ H NMR (400 MHz, Chloroform -d ) δ 8.09 – 8.01 (m, 2H), 7.62 – 7.53 (m, 2H), 7.51 – 7.41 (m, 2H), 6.38 (d, J = 7.5 Hz, 1H) , 6.20 – 6.10 (m, 1H), 5.39 – 5.31 (m, 1H), 5.30 – 5.20 (m, 1H), 4.14 – 4.02 (m, 1H), 3.72 – 3.61 (m, 2H). 8, 6 233 426.11 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.47 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.32 (m, 1H ), 5.09 (m, 1H), 4.43 – 4.32 (m, 1H), 4.22 (d, J = 5.0 Hz, 2H), 2.55 – 2.45 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H) , 1.13 (d, J = 7.4 Hz, 3H). 9, 2, 6 234 516.15 ¹ H NMR (400 MHz, Chloroform -d ) δ 8.09 – 8.01 (m, 2H), 7.62 – 7.53 (m, 2H), 7.51 – 7.41 (m, 2H), 6.38 (d, J = 7.5 Hz, 1H) , 6.24 – 6.14 (m, 1H), 5.38 – 5.31 (m, 1H), 5.09 – 4.99 (m, 1H), 4.43 – 4.32 (m, 1H), 4.33 – 4.18 (m, 2H), 2.30 (d, J = 3.2 Hz, 1H), 1.55 (d, J = 2.1 Hz, 4H), 0.91 (d, J = 2.2 Hz, 6H). 9, 2, 6 235 441.12 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.16 – 4.08 (m, 2H), 2.75 (s, 3H), 2.33 (d, J = 7.1 Hz, 2H), 1.72 – 1.55 (m, 2H), 0.93 (d, J = 2.7 Hz, 3H). 9, 2, 6 236 482.17 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.16 – 4.08 (m, 2H), 2.67 (d, J = 3.8 Hz, 1H), 2.30 (d, J = 4.1 Hz, 2H), 1.63 – 1.50 (m, 2H), 1.41 – 1.26 (m, 4H), 1.15 – 1.02 (m, 6H), 0.95 – 0.83 (m, 3H). 9, 2, 6 237 385.09 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.20 – 6.12 (m, 1H), 5.39 – 5.31 (m, 1H ), 5.30 – 5.20 (m, 1H), 4.14 – 4.02 (m, 1H), 3.91 (d, J = 5.5 Hz, 1H), 3.72 – 3.61 (m, 2H), 1.46 (s, 2H). 8, 6 238 385.09 1H NMR (400 MHz, Chloroform-d) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.20 – 6.12 (m, 1H), 5.39 – 5.31 (m, 1H) , 5.30 – 5.20 (m, 1H), 4.14 – 4.02 (m, 1H), 3.88 (d, J = 5.5 Hz, 1H), 3.72 – 3.61 (m, 2H), 1.46 (s, 2H). 8, 6 239 455.13 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.22 (d, J = 5.0 Hz, 2H), 3.91 (d, J = 2.5 Hz, 1H), 2.54 – 2.43 (m, 1H), 1.46 (s, 2H), 1.18 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 9, 2, 6 240 483.16 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.22 (d, J = 5.0 Hz, 2H), 3.71 (d, J = 5.9 Hz, 1H), 2.55 (d, J = 2.4 Hz, 1H), 2.20 – 2.06 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H), 0.97 – 0.93 (m, 6H). 9, 2, 6 241 401.09 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.20 – 6.12 (m, 1H), 5.39 – 5.31 (m, 1H ), 5.30 – 5.20 (m, 1H), 4.14 – 4.02 (m, 1H), 4.04 (d, J = 3.9 Hz, 1H), 3.78 – 3.72 (m, 3H), 3.69– 3.61 (m, 1H). 10, 2, 6 242 485.14 ¹ H NMR (400 MHz, Chloroform- d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.22 (d, J = 5.0 Hz, 2H), 4.09 – 4.02 (m, 1H), 3.98 (d, J = 5.2 Hz, 1H), 2.55 (d, J = 7.4 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H) . 10, 2, 6 243 485.14 ¹ H NMR (400 MHz, Chloroform -d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.22 (d, J = 5.0 Hz, 2H), 3.71 (d, J = 5.9 Hz, 1H), 2.55 (d, J = 7.4 Hz, 1H), 2.20 – 2.06 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H), 0.97 – 0.93 (m, 6H). 9, 2, 6 244 485.14 ¹ H NMR (400 MHz, Chloroform- d ) δ7.58 – 7.51 (m, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H ), 5.09 – 4.99 (m, 1H), 4.42 – 4.32 (m, 1H), 4.22 (d, J = 5.0 Hz, 2H), 4.09 – 4.02 (m, 1H), 3.98 (d, J = 5.2 Hz, 1H), 2.55 (d, J = 7.4 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H) . 10, 2, 6 245 489.12 ¹ H NMR (400 MHz, Chloroform -d ) δ 8.05 – 7.98 (m, 2H), 7.61 – 7.50 (m, 2H), 7.50 – 7.41 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H), 5.30 – 5.20 (m, 1H), 4.62 – 4.48 (m, 2H), 4.50 – 4.42 (m, 1H), 3.91 (d, J = 5.5 Hz, 1H), 1.46 (s, 1H). 9, 2, 6 246 489.12 ¹ H NMR (400 MHz, Chloroform- d ) δ 8.05 – 7.98 (m, 2H), 7.61 – 7.50 (m, 2H), 7.50 – 7.41 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H), 5.30 – 5.20 (m, 1H), 4.62 – 4.48 (m, 2H), 4.50 – 4.42 (m, 1H), 3.88 (d, J = 5.5 Hz, 1H), 1.46 (s, 1H). 9, 2, 6 247 517.15 ¹ H NMR (400 MHz, Chloroform -d ) δ 8.05 – 7.98 (m, 2H), 7.61 – 7.50 (m, 2H), 7.50 – 7.41 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H), 5.30 – 5.20 (m, 1H), 4.62 – 4.48 (m, 2H), 4.50 – 4.42 (m, 1H), 3.71 (d, J = 6.0 Hz, 1H), 2.14– 2.04 (m, 1H), 0.97 – 0.93 (m, 6H). 9, 2, 6 248 517.15 ¹ H NMR (400 MHz, Chloroform -d ) δ 8.05 – 7.98 (m, 2H), 7.61 – 7.50 (m, 2H), 7.50 – 7.41 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.24 – 6.15 (m, 1H), 5.38 – 5.31 (m, 1H), 5.30 – 5.20 (m, 1H), 4.62 – 4.48 (m, 2H), 4.50 – 4.42 (m, 1H), 3.71 (d, J = 6.0 Hz, 1H), 2.14– 2.04 (m, 1H), 0.97 – 0.93 (m, 6H). 9, 2, 6 249 370.15 ¹ H NMR (400 MHz, Chloroform- d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.41 – 4.31 (m, 1H), 4.27 – 4.15 (m, 2H), 2.55 (d, J = 5.4 Hz, 1H), 1.38 (s, 3H), 1.18 ( d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 7 250 474.18 ¹ H NMR (400 MHz, Chloroform- d ) δ 8.03 – 7.96 (m, 2H), 7.94 – 7.87 (m, 1H), 7.62 – 7.53 (m, 1H), 7.52 – 7.43 (m, 2H), 6.15 – 6.06 (m, 1H), 5.96 (d, J = 7.5 Hz, 1H), 4.76 – 4.68 (m, 1H), 4.56 – 4.48 (m, 1H), 4.41– 4.31 (m, 1H), 4.27 – 4.15 ( m, 2H), 2.55 (d, J = 5.4 Hz, 1H), 1.38 (s, 3H), 1.18 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 7, 2 251 404.14 ¹ H NMR (400 MHz, Chloroform- d ) δ 8.05 – 7.98 (m, 2H), 7.59 – 7.51 (m, 1H), 7.55 – 7.49 (m, 1H), 7.49 – 7.41 (m, 2H), 6.37 ( d, J = 7.3 Hz, 1H), 5.92 – 5.86 (m, 1H), 4.92 – 4.83 (m, 1H), 4.56 – 4.48 (m, 1H), 4.50 – 4.39 (m, 3H), 1.38 (s, 3H). 9, 7 252 453.15 ¹ H NMR (400 MHz, Chloroform- d ) δ 8.46 – 8.39 (m, 1H), 8.31 – 8.22 (m, 1H), 8.07 – 7.94 (m, 2H), 7.90 – 7.83 (m, 1H), 7.58 – 7.47 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 5.92 – 5.86 (m, 1H), 4.92 – 4.83 (m, 1H), 4.56 – 4.48 (m, 1H), 4.51 – 4.39 ( m, 3H), 1.38 (s, 3H). 9, 7 253 384.17 ¹ H NMR (400 MHz, Chloroform- d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.41 – 4.32 (m, 1H), 4.31 – 4.17 (m, 2H), 2.40–2.33 (m, 1H), 1.63 – 1.47 (m, 2H), 1.38 (s , 3H), 1.16 (d, J = 8.1 Hz, 3H), 0.92 (d, J = 3.0 Hz, 3H). 9, 7 254 384.17 ¹ H NMR (400 MHz, Chloroform- d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.41 – 4.32 (m, 1H), 4.31 – 4.17 (m, 2H), 2.40–2.33 (m, 1H), 1.63 – 1.47 (m, 2H), 1.38 (s , 3H), 1.16 (d, J = 8.1 Hz, 3H), 0.92 (d, J = 3.0 Hz, 3H). 9, 7 255 370.15 ¹ H NMR (400 MHz, Chloroform -d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.43 – 4.35 (m, 1H), 4.28 – 4.23 (m, 1H), 4.21 – 4.15 (m, 1H), 2.33 (d, J = 4.1 Hz, 2H), 1.72 – 1.55 (m, 2H), 1.38 (s, 3H), 0.93 (d, J = 4.7 Hz, 3H). 9, 7 256 398.18 ¹ H NMR (400 MHz, Chloroform- d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.43 – 4.35 (m, 1H), 4.28 – 4.23 (m, 1H), 4.21 – 4.15 (m, 1H), 2.30 (d, J = 4.2 Hz, 2H), 1.63 – 1.50 (m, 1H), 1.43 (s, 3H), 1.40 – 1.26 (m, 7H), 0.95 – 0.83 (m, 3H). 9, 7 257 432.17 ¹ H NMR (400 MHz, Chloroform -d ) δ7.52 – 7.43 (m, 1H), 7.35 – 7.22 (m, 5H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H ), 4.92 – 4.83 (m, 1H), 4.56 – 4.48 (m, 1H), 4.41 – 4.35 (m, 1H), 4.28 – 4.23 (m, 1H), 4.21 – 4.15 (m, 1H), 3.68 – 3.58 (m, 1H), 1.45 (s, 2H), 1.38 (s, 3H). 9, 7 258 432.17 ¹ H NMR (400 MHz, Chloroform -d ) δ7.52 – 7.43 (m, 1H), 7.35 – 7.22 (m, 5H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H ), 4.92 – 4.83 (m, 1H), 4.56 – 4.48 (m, 1H), 4.41 – 4.35 (m, 1H), 4.28 – 4.23 (m, 1H), 4.21 – 4.15 (m, 1H), 3.68 – 3.58 (m, 1H), 1.45 (s, 2H), 1.38 (s, 3H). 9, 7 259 384.17 ¹ H NMR (400 MHz, Chloroform- d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.43 – 4.35 (m, 1H), 4.27 – 4.23 (m, 1H), 4.21 – 4.15 (m, 1H), 2.25 – 2.17 (m, 2H), 2.05 – 1.97 (m, 1H), 1.38 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 9, 7 260 398.18 ¹ H NMR (400 MHz, Chloroform- d ) δ7.52 – 7.43 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.89 – 5.79 (m, 1H), 4.92 – 4.83 (m, 1H ), 4.56 – 4.48 (m, 1H), 4.43 – 4.35 (m, 1H), 4.27 – 4.23 (m, 1H), 4.21 – 4.15 (m, 1H), 2.28 – 2.21 (m, 2H), 1.97 – 1.91 (m, 1H), 1.41 (d, J = 20.0 Hz, 7H), 1.38 – 1.23 (m, 1H), 0.95 (d, J = 7.8 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H) . 9, 7 261 368.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.29 – 4.18 (m, 2H), 1.97 – 1.89 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.14 – 1.01 (m, 2H), 1.01 – 0.89 (m, 2H). 9, 7 262 382.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.29 – 4.18 (m, 2H), 2.44 – 2.36 (m, 1H), 2.10 – 1.92 (m, 4H), 1.92 – 1.69 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 263 410.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.29 – 4.18 (m, 2H), 2.42 – 2.33 (m, 1H), 1.88 – 1.77 (m, 2H), 1.69 – 1.48 (m, 4H), 1.48 – 1.38 (m, 3H), 1.38 (s, 3H). 9, 7 264 478.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.36 – 4.28 (m, 2H), 4.01 – 3.90 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H) 9, 7 265 396.09 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.46 – 4.37 (m, 2H), 4.34 (dd, J = 11.7, 3.5 Hz, 1H ), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 266 436.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.45 – 4.39 (m, 1H), 4.31 (dd, J = 11.7, 3.5 Hz, 1H ), 4.23 (dd, J = 11.7, 3.5 Hz, 1H), 2.00 – 1.91 (m, 3H), 1.80 – 1.67 (m, 8H), 1.52 – 1.41 (m, 3H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 267 422.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.29 – 4.18 (m, 2H), 2.46 – 2.38 (m, 1H), 1.98 (dd, J = 12.4, 5.9 Hz, 2H), 1.82 (dd, J = 12.4, 5.9 Hz, 2H), 1.69 – 1.43 (m, 6H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 268 394.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.89 (m, 1H), 4.92 (td, J = 3.7, 0.8 Hz, 1H), 4.56 (m, 1H), 4.44 – 4.40 (m, 1H), 4.31 (dd, J = 11.7, 3.5 Hz, 1H), 4.23 (dd, J = 11.7, 3.5 Hz, 1H), 2.14 (d, J = 4.0 Hz, 2H), 2.11 (d, J = 3.8 Hz, 2H), 2.09 – 2.05 (m, 1H), 1.91 (d, J = 3.8 Hz, 1H), 1.89 (d, J = 3.8 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 269 371.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.27 – 4.16 (m, 2H), 3.86 – 3.76 (m, 1H), 3.41 (dd, J = 7.1, 6.4 Hz, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 1.45 – 1.36 (m, 7H). 9, 7 270 385.16 H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H) , 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.28 – 4.16 (m, 2H), 3.71 – 3.62 ( m, 1H), 3.07 – 3.01 (m, 1H), 2.98 – 2.92 (m, 1H), 1.92 – 1.74 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 0.98 – 0.92 ( m, 3H) 9, 7 271 399.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 5.10 (d, J = 7.2 Hz, 2H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.27 – 4.17 (m, 2H), 3.64 – 3.56 (m, 1H), 2.24 – 2.14 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 0.98 (dd, J = 6.4, 1.7 Hz, 6H). 9, 7 272 461.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 7.28 – 7.19 (m, 6H), 6.37 (d, J = 7.3 Hz, 1H), 5.94 – 5.83 (m, 1H), 4.98 – 4.88 (m, 1H), 4.61 – 4.51 (m, 1H), 4.43 – 4.38 (m, 1H), 4.22 (dd , J = 6.7, 4.5 Hz, 2H), 3.88 (d, J = 8.1 Hz, 1H), 3.08 (d, J = 7.1 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.36 (s, 1H), 1.35 (s, 1H) 9, 7 273 357.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.74 – 6.67 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.47 – 4.41 (m, 1H), 4.23 (dd , J = 4.5, 0.8 Hz, 2H), 2.72 (d, J = 5.5 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 274 371.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.49 – 4.42 (m, 1H), 4.25 (d, J = 4.5 Hz, 2H), 2.98 (s, 4H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 275 413.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.49 – 4.42 (m, 1H), 4.36 – 4.25 (m, 2H), 3.73 – 3.67 (m, 4H), 3.62 (dd, J = 6.3, 3.5 Hz, 2H), 3.55 (dd, J = 6.3, 3.5 Hz, 2H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 276 411.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.49 – 4.42 (m, 1H), 4.36 – 4.25 (m, 2H), 3.55 – 3.47 (m, 2H), 3.46 – 3.38 (m, 2H), 1.76 – 1.68 (m, 3H), 1.67 – 1.58 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 277 358.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.38 (dd, J = 12.0, 4.3 Hz, 1H ), 4.31 (dd, J = 12.1, 4.2 Hz, 1H), 3.04 (s, 2H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 278 386.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 5.06 – 4.97 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.32 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.33 (d, J = 5.9 Hz, 3H), 1.28 (d, J = 5.7 Hz, 3H). 9, 7 279 400.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.92 – 4.84 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.32 (m, 2H), 1.71 – 1.54 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.34 (d, J = 6.6 Hz, 3H), 0.95 (t, J = 8.1 Hz, 3H). 9, 7 280 400.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.92 – 4.84 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.45 – 4.32 (m, 2H), 1.72 – 1.53 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.34 (d, J = 6.6 Hz, 3H), 0.95 (t, J = 8.2 Hz, 3H). 9, 7 281 372.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.29 (m, 2H), 4.26 – 4.18 (m, 2H) , 1.43 (s, 3H), 1.38 (s, 3H), 1.33 (t, J = 6.4 Hz, 3H). 9, 7 282 426.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.82 – 4.73 (m, 2H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.29 (m, 2H) , 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 283 400.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.29 (m, 2H), 4.09 – 4.03 (m, 1H) , 4.03 – 3.97 (m, 1H), 2.06 – 1.95 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.00 (d, J = 7.3 Hz, 3H), 0.95 (d, J = 7.3 Hz, 3H). 9, 7 284 428.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.29 (m, 2H), 4.03 (d, J = 6.6 Hz , 2H), 1.72 – 1.60 (m, 1H), 1.45 – 1.36 (m, 9H), 0.88 (t, J = 6.8 Hz, 6H). 9, 7 285 414.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.84 – 4.75 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.32 (m, 2H) , 1.69 – 1.50 (m, 4H), 1.43 (s, 3H), 1.38 (s, 3H), 0.95 (t, J = 7.4 Hz, 6H). 9, 7 286 414.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.29 (m, 2H), 4.04 (d , J = 1.6 Hz, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.01 (s, 6H). 9, 7 287 412.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.41 – 4.29 (m, 2H), 4.12 (s, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.19 – 1.08 (m, 2H), 0.99 (s, 3H), 0.68 – 0.56 (m, 2H). 9, 7 288 398.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.94 (s, 1H), 9.57 (s, 1H), 7.55 – 7.49 (m, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.84 (m, 2H), 4.59 – 4.53 (m, 1H), 4.48 – 4.41 (m, 1H), 4.45 – 4.32 (m, 2H), 2.08 – 1.95 (m, 2H) , 1.86 – 1.75 (m, 4H), 1.43 (s, 3H), 1.38 (s, 3H). 9, 7 289 300.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.95 (s, 1H), 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H ), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H). 7 290 441.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.27 – 4.16 (m, 2H), 3.89 – 3.79 (m, 1H), 3.41 (dd, J = 7.1, 6.4 Hz, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.73 – 2.61 (m, 1H), 1.43 (s, 3H), 1.41 (s, 2H), 1.40 (s, 1H), 1.38 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 9, 7, 2 291 455.21 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 (m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.27 – 4.16 (m, 2H), 3.88 – 3.79 (m, 1H), 3.44 – 3.37 (m, 1H) , 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.48 (d, J = 6.8 Hz, 2H), 2.22 – 2.11 (m, 1H), 1.43 (s, 3H), 1.41 (s, 2H), 1.40 (s, 2H), 1.38 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 9, 7, 2 292 471.20 H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.91 – 5.86 (m, 1H), 4.95 – 4.89 ( m, 1H), 4.58 – 4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.28 – 4.16 (m, 2H), 3.82 – 3.69 (m, 2H), 3.69 – 3.61 (m, 1H), 3.48 (t, J = 5.5 Hz, 1H), 3.41 (t, J = 7.2 Hz, 1H), 3.30 (t, J = 7.2 Hz, 1H), 2.48 (d, J = 6.8 Hz, 2H), 2.23 – 2.11 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 9, 7, 2 293 342.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.14 (s, 3H), 1.43 (s , 3H), 1.38 (s, 3H). 8, 7 294 356.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.81 – 2.65 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.18 (t, J = 7.4 Hz, 3H). 8, 7 295 370.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.73 – 2.61 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). 8, 7 296 398.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.51 (t, J = 7.5 Hz, 2H ), 1.67 – 1.57 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.36 – 1.31 (m, 3H), 0.93 – 0.84 (m, 3H). 8, 7 297 357.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.77 – 6.71 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H) , 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.75 (d, J = 4.9 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H). 8, 7 298 371.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.82 (s, 6H), 1.43 (s , 3H), 1.38 (s, 3H). 8, 7 299 358.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.83 (s, 3H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 1.43 (s , 3H), 1.38 (s, 3H). 8, 7 300 386.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.42 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 5.14 – 5.03 (m, 1H) , 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.32 (d, J = 5.9 Hz, 3H), 1.27 (d, J = 5.9 Hz, 3H). 8, 7 301 371.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.95 – 3.86 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 3.56 – 3.50 (m, 1H), 3.44 – 3.38 (m, 1H), 1.47 (d, J = 5.5 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H). 8, 7 302 371.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.93 – 3.84 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m , 2H), 3.53 (dd, J = 7.3, 5.8 Hz, 1H), 3.41 (dd, J = 7.2, 5.8 Hz, 1H), 1.47 (d, J = 5.5 Hz, 3H), 1.43 (s, 3H) , 1.38 (s, 3H). 8, 7 303 399.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.75 – 3.68 (m, 1H), 3.68 – 3.59 (m , 2H), 3.42 – 3.35 (m, 1H), 3.27 (t, J = 6.8 Hz, 1H), 2.20 – 2.07 (m, J = 6.4 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 0.98 (d, J = 0.9 Hz, 3H), 0.97 (d, J = 0.9 Hz, 3H). 8, 7 304 399.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.75 – 3.68 (m, 1H), 3.68 – 3.59 (m, 2H), 3.42 – 3.35 (m, 1H), 3.27 (t, J = 6.8 Hz, 1H), 2.20 – 2.07 (m, J = 6.4 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 0.98 (d, J = 0.9 Hz, 3H), 0.97 (d, J = 0.9 Hz, 3H). 8, 7 305 387.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 4.04 – 3.96 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.79 – 3.73 (m, 2H), 3.70 – 3.60 (m, 2H), 3.58 (d, J = 6.4 Hz, 2H), 3.42 (t, J = 5.5 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H). 8, 7 306 401.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.03 (m, 2H), 3.99 – 3.92 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 3.58 – 3.51 (m, 1H), 3.36 – 3.30 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.22 (d, J = 6.2 Hz, 3H). 8, 7 307 401.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.03 (m, 2H), 3.99 – 3.92 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 3.58 – 3.51 (m, 1H), 3.36 – 3.30 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.22 (d, J = 6.2 Hz, 3H). 8, 7 308 387.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.60 – 7.55 (m, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H) , 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 4.04 – 3.96 (m, 1H), 3.86 – 3.75 (m, 3H), 3.70 – 3.60 (m, 2H), 3.58 (d, J = 6.4 Hz, 2H), 3.42 (t, J = 5.5 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H). 8, 7 309 404.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.08 – 8.02 (m, 2H), 7.61 – 7.54 (m, 2H), 7.50 – 7.42 (m, 2H), 6.37 (d, J = 7.5 Hz, 1H) , 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H). 8, 7 310 418.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.03 – 7.97 (m, 2H), 7.60 – 7.55 (m, 1H), 7.36 – 7.30 (m, 2H), 6.37 (d, J = 7.5 Hz, 1H) , 5.93 – 5.88 (m, 1H), 4.87 – 4.82 (m, 1H), 4.65 – 4.60 (m, 1H), 4.12 – 4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 2H), 2.39 (d, J = 0.9 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H). 8, 7 311 372.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 2H), 6.40 (d, J = 7.5 Hz, 2H), 5.90-5.87 (m, 2H), 5.44 (d , J = 3.8 Hz, 1H), 5.37 (d, J = 3.8 Hz, 1H), 5.33-5.32 (m, 2H), 4.84-4.80 (m, 2H), 4.63-4.61 (m, 2H), 4.12 – 4.05 (m, 2H), 3.78 (t, J = 5.9 Hz, 2H), 3.70 – 3.58 (m, 4H), 1.38 (s, 6H). 8, 7 312 433.16 1H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.46-7.45 (m, 2H), 7.37 (dd, J = 7.5, 1.0 Hz, 1H), 7.36 – 7.27 (m, 2H), 6.40 (d, J = 7.5 Hz, 1H), 5.91-5.89 (m, 1H), 5.08-5.05 (m, 1H), 4.84-4.83 (m, 1H), 4.64-4.62 ( m, 1H), 4.08-4.05 (m, 1H), 3.78 (t, J = 5.9 Hz, 1H), 3.70 – 3.59 (m, 4H), 1.38 (s, 3H). 8, 7 313 474.18 1H NMR (500 MHz, Chloroform-d) δ 8.08 – 8.02 (m, 2H), 7.61 – 7.54 (m, 2H), 7.50 – 7.42 (m, 2H), 6.37 (d, J = 7.5 Hz, 1H), 5.87-5.83 (m, 1H), 4.93-4.90 (m, 1H), 4.56-4.55 (m, 1H), 4.41-4.39 (m, 1H), 4.26 – 4.16 (m, 2H), 2.55-2.51 (m , 1H), 1.38 (s, 2H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 8, 7 314 440.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.87-5.85 (m, 1H), 4.92-4.90 (m, 1H), 4.56-4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.26 – 4.16 (m, 2H), 2.67-2.62 m, 1H), 2.55 -2.51(m, 1H), 1.38 (s, 3H), 1.15-1.10 (m, 12H). 8, 7 315 441.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.87-5.85 (m, 1H), 4.92-4.89 (m, 1H), 4.57-4.52 (m, 1H), 4.44 – 4.37 (m, 1H), 4.27 – 4.16 (m, 2H), 3.84-3.80 (m, 1H), 3.41-3.38 (m, 1H) , 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.67-2.63 (m, 1H), 1.43 – 1.36 (m, 5H), 1.15 (d, J = 6.8 Hz, 6H). 8, 7 316 442.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.87-5.84 (m, 1H), 4.92-4.90 (m, 1H), 4.56-4.51 (m, 1H), 4.44 – 4.37 (m, 1H), 4.27 – 4.16 (m, 2H), 3.90-3.88 (m, 1H), 3.85-3.83(m, 1H) , 3.53 (dd, J = 7.2, 5.8 Hz, 1H), 3.41-3.87 (m, 2H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 1.48 – 1.36 (m, 10H). 8, 7 317 441.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.89-5.85 (m, 1H), 4.92-4.90 (m, 1H), 4.56-4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.26 – 4.16 (m, 2H), 3.89-3.87 (m, J = 5.6 Hz, 1H), 3.53 (dd , J = 7.3, 5.8 Hz, 1H), 3.41 (dd, J = 7.2, 5.8 Hz, 1H), 2.55-2.51 (m,1H), 1.47 (d, J = 5.5 Hz, 3H), 1.38 (s, 2H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 8, 7 318 441.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.89-5.85 (m, 1H), 4.92-4.90 (m, 1H), 4.56-4.53 (m, 1H), 4.44 – 4.37 (m, 1H), 4.26 – 4.16 (m, 2H), 3.89-3.87 (m, J = 5.6 Hz, 1H), 3.53 (dd , J = 7.3, 5.8 Hz, 1H), 3.41 (dd, J = 7.2, 5.8 Hz, 1H), 2.55-2.51 (m,1H), 1.47 (d, J = 5.5 Hz, 3H), 1.38 (s, 2H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 8, 7 319 475.18 1H NMR (500 MHz, Chloroform-d) δ 8.05 – 7.99 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.49 – 7.42 (m, 2H ), 6.40 (d, J = 7.5 Hz, 1H), 5.87-5.84 (m, 1H), 4.92-4.90 (m, 1H), 4.57-4.55 (m, 1H), 4.49 – 4.39 (m, 3H), 3.88-3.85 (m, 1H), 3.53-3.50 (m, 1H), 3.43-3.41 (m, 1H), 1.47 (d, J = 5.5 Hz, 3H), 1.38 (s, 2H). 9, 7, 7 320 474.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.05 – 7.99 (m, 2H), 7.58-7.55 (m, 1H), 7.54-7.51 (m, 1H), 7.49 – 7.42 (m, 2H), 6.40 ( d, J = 7.5 Hz, 1H), 5.88-5.85 (m, 1H), 4.92-4.89 (m, 1H), 4.56 4.53(m, 1H), 4.49 – 4.39 (m, 3H), 2.67-2.63 (m , 1H), 1.38 (s, 2H), 1.15 (d, J = 6.8 Hz, 6H). 9, 7, 2 321 390.09 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.76 (m, 2H), 7.54-7.50 (m, 1H), 7.47 (dd, J = 6.1, 3.8 Hz, 2H) , 6.37 (d, J = 7.3 Hz, 1H), 6.16-6.13 (m, 1H), 5.73-5.70 (m, 1H), 5.53-5.50 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.66 (m, 3H). 1, 6 322 460.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.76 (m, 2H), 7.55-7.53 (m, 1H), 7.47-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.16 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.51 (m, 1H), 4.46-4.45 (m, 1H), 4.30 – 4.19 (m, 2H), 2.56-2.52 (m, 1H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H). 1, 6 323 488.16 1H NMR (500 MHz, Chloroform-d) δ 9.57 7.77-7.76 (m, 2H), 7.55-7.53 (m, 1H), 7.47-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H) , 6.17-6.16 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.51 (m, 1H), 4.46-4.45 (m, 1H), 4.30 – 4.19 (m, 2H, 4.25-4.24 (m , 1H), 2.33-2.28 (m, 1H), 1.55-1.52 (m, 4H), 0.91 (t, J = 7.1 Hz, 6H). 9, 6 324 494.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 8.05 – 7.99 (m, 2H), 7.77-7.75 (m, 2H), 7.58 – 7.50 (m, 2H), 7.50 – 7.42 ( m, 4H), 6.37 (d, J = 7.3 Hz, 1H), 6.19-6.17 (m, 1H), 5.74-5.70 (m, 1H), 5.53-5.50 (m, 1H), 4.55-4.52 (m, 1H), 4.54 – 4.42 (m, 2H). 9, 6 325 474.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.14 (m, 1H), 5.74-5.71 (m, 1H), 5.55-5.53 (m, 1H), 4.49 – 4.42 (m, 1H), 4.20-4.18 (m, 1H), 4.11-4.09 (m, 1H), 2.35-2.34 (m, 2H), 1.59-1.58 (m, 2H), 1.38-1.35 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) . 9, 6 326 474.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.43 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.14 (m, 1H), 5.74-5.72 (m, 1H), 5.52-5.49 (m, 1H), 4.46-44 (m, 1H), 4.33-4.30 (m, 1H), 4.26 -4.23(m, 1H), 2.40-2.36 (m, 1H), 1.55-1.53 (m, 2H), 1.16 (d, J = 8.2 Hz, 3H), 0.92 (t, J = 7.0 Hz , 3H). 9, 6 327 474.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.43 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.14 (m, 1H), 5.74-5.72 (m, 1H), 5.52-5.49 (m, 1H), 4.46-44 (m, 1H), 4.33-4.30 (m, 1H), 4.26 -4.23(m, 1H), 2.40-2.36 (m, 1H), 1.55-1.53 (m, 2H), 1.16 (d, J = 8.2 Hz, 3H), 0.92 (t, J = 7.0 Hz , 3H). 9, 6 328 474.14 1H NMR (500 MHz, Chloroform-d) δ 9.56 (s, 1H), 7.77-7.52 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74-5.73 (m, 1H), 5.52-5.50 (m, 1H), 4.45-4.43 (m, 1H), 4.26 – 4.16 (m, 2H ), 2.30 – 2.18 (m, 2H), 2.05-2.01 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 9, 6 329 522.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.51 (m, 1H), 7.48-7.46 (m, 2H), 7.29 (s, 2H), 7.34 – 7.23 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.75-5.74 (m, 1H), 5.52-5.48 (m, 1H) , 4.50 – 4.43 (m, 1H), 4.33 – 4.23 (m, 2H), 3.72 – 3.64 (m, 1H), 1.43 (s, 1H). 9, 6 330 522.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.51 (m, 1H), 7.48-7.46 (m, 2H), 7.29 (s, 2H), 7.34 – 7.23 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.75-5.74 (m, 1H), 5.52-5.48 (m, 1H) , 4.50 – 4.43 (m, 1H), 4.33 – 4.23 (m, 2H), 3.72 – 3.64 (m, 1H), 1.43 (s, 1H). 9, 6 331 500.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (dm, 1H), 7.47-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.46 (m, 1H), 4.46-4.44 (m, 1H), 4.31-4.36 (m, 1H), 4.25-4.22 (m, 1H), 2.38-2.37 (m, 1H), 1.83-1.56 (m, 2H), 1.69 – 1.48 (m, 4H), 1.43-1.37 (m, 2H). 9, 6 332 526.17 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.76 (m, 2H), 7.52-7.50 (m, 1H), 7.48-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.14 (m, 1H), 5.74-5.73 (m, 1H), 5.52-5.48 (m, 1H), 4.51 – 4.44 (m, 1H), 4.30 – 4.20 (m, 2H), 2.00 – 1.91 (m, 3H), 1.79 – 1.67 (m, 7H), 1.52 – 1.40 (m, 3H). 9, 6 333 483.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.76 (m, 2H), 7.52-7.50 (m, 1H), 7.48-7.46 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.14 (m, 1H), 5.74-5.73 (m, 1H), 5.52-5.48 (m, 1H), 4.48-4.45 (m, 1H), 4.30 – 4.20 (m, 2H), 2.12-2.07 (m, 3H), 2.06-2.04 (m, 1H), 1.90-1.83 (m, 3H). 9, 6 334 475.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.49 (m, 1H), 4.49 – 4.42 (m, 1H), 4.33-4.30 (m, 1H), 4.26-4.22 (m, 1H), 3.71-3.67 (m, 1H), 3.04 (t, J = 7.1 Hz, 1H), 2.95 (t, J = 7.1 Hz, 1H), 1.95 – 1.77 (m , 2H), 0.95 (t, J = 7.1 Hz, 3H). 9, 6 335 477.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.49 (m, 1H), 4.49 – 4.41 (m, 1H), 4.33-4.29 (m, 1H), 4.26 -4.23(m, 1H), 3.85 – 3.72 (m, 2H), 3.65-3.62 (m, 1H), 3.48 (t, J = 5.6 Hz, 1H), 3.41 (t, J = 7.2 Hz , 1H), 3.30 (t, J = 7.2 Hz, 1H). 10,6 336 489.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.49 (m, 1H), 5.10 (d, J = 7.2 Hz, 2H), 4.45-4.43 (m, 1H), 4.34-4.32 (m, 1H), 4.26-4.23 (m, 1H), 3.60-3.57 (m, 1H), 2.18-2.15 (m, 1H), 0.98-0.96 (m, 6H) . 9, 6 337 491.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.49 (m, 1H), 4.45-44 (m, 1H), 4.35-4.33 (m, 1H), 4.25-4.22 (m, 1H), 3.99-3.37 (m, 1H), 3.91-3.88 (m, 1H), 3.35 (t, J = 7.2 Hz, 1H), 3.28 (d, J = 4.9 Hz , 1H), 3.24 (t, J = 7.2 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H). 10, 6 338 461.12 ¹ H NMR (500 MHz, Chloroform- d ) δ9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d , J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.49 – 4.42 (m, 1H), 4.34 – 4.23 (m , 2H), 3.81-3.79 (m, 1H), 3.41-3.38 (m, 1H), 3.23-3.21 (m, 1H), 1.40 (s, 1H). 9, 6 339 461.12 ¹ H NMR (500 MHz, Chloroform- d ) δ9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d , J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.49 – 4.42 (m, 1H), 4.34 – 4.23 (m , 2H), 3.81-3.79 (m, 1H), 3.41-3.38 (m, 1H), 3.23-3.21 (m, 1H), 1.40 (s, 1H). 9, 6 340 477.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.49 (m, 1H), 4.49 – 4.41 (m, 1H), 4.33-4.29 (m, 1H), 4.26 -4.23(m, 1H), 3.85 – 3.72 (m, 2H), 3.65-3.62 (m, 1H), 3.48 (t, J = 5.6 Hz, 1H), 3.41 (t, J = 7.2 Hz , 1H), 3.30 (t, J = 7.2 Hz, 1H). 10, 6 341 461.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.49 (m, 1H), 4.47-4.45 (m, 1H), 4.33 – 4.23 (m, 2H), 2.98 (s, 6H). 9, 6 342 447.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.49 – 4.46 (m, 1H), 4.31 – 4.23 (m, 2H), 2.72 (d, J = 5.5 Hz, 3H). 9, 6 343 447.09 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.52 – 4.45 (m, 1H), 4.38-4.35 (m, 2H), 3.04 (s, 3H). 9, 6 344 476.12 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), δ7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 ( d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 5.02-4.97 (m, 1H), 4.52 – 4.45 ( m, 1H), 4.44 – 4.33 (m, 2H), 1.33 (d, J = 5.9 Hz, 3H), 1.28 (d, J = 5.7 Hz, 3H). 9, 6 345 432.10 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H ), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.71 (m, 2H), 3.70-3.66 (m, 1H), 2.13(s, 3H). 6, 8 346 432.10 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.71 (m, 2H), 3.70-3.66 (m, 1H), 2.04(s, 3H). 6, 8 347 460.13 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H ), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.71 (m, 2H), 3.71 – 3.66 (m, 1H), 2.67-2.62 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). 6, 8 348 488.16 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H ), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.71 (m, 2H), 3.70 – 3.66 (m, 1H), 2.39 -2.36(m, 1H), 1.63 – 1.49 (m, 4H), 0.90 (t, J = 7.1 Hz, 6H). 6, 8 349 461.12 ¹ H NMR (500 MHz, Chloroform-d) δ7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H ), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.21-4.14 (m, 1H), 3.91 -3.87(m, 1H), 3.81-3.66 (m, 3H), 3.53-3.50(m, 1H), 3.41-3.37 (m, 1H), 1.47 (s, 3H). 6, 8 350 461.12 ¹ H NMR (500 MHz, Chloroform-d) δ7.77-7.75 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 2H), 6.37 (d, J = 7.3 Hz, 1H ), 6.17-6.15 (m, 1H), 5.74 -5.71(m, 1H), 5.52-5.50 (m, 1H), 4.21-4.14 (m, 1H), 3.91 -3.87(m, 1H), 3.81-3.66 (m, 3H), 3.53-3.50(m, 1H), 3.41-3.37 (m, 1H), 1.47 (s, 3H). 6, 8 351 489.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.16-6.14 m, 1H), 5.73-5.72 (m, 1H), 5.51-5.48 (m, 1H), 4.21 – 4.14 (m, 1H) , 3.81-3.66 (m, 4H), 3.42-3.35 (m, 1H), 3.30-3.24 (m, 1H), 2.13-2.11 (m, 1H), 0.97-0.96 (m, 6H). 6, 8 352 489.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.16-6.14 m, 1H), 5.73-5.72 (m, 1H), 5.51-5.48 (m, 1H), 4.21 – 4.14 (m, 1H) , 3.81-3.66 (m, 4H), 3.42-3.35 (m, 1H), 3.30-3.24 (m, 1H), 2.13-2.11 (m, 1H), 0.97-0.96 (m, 6H). 6, 8 353 491.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77-7.76 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.16-6.13 (m, 1H), 5.73-5.70 (m, 1H), 5.51-5.49 (m, 1H), 4.21-4.14 (m, 1H), 4.12-4.03 (m, 1H), 3.98-3.96 ( m, 1H), 3.81 – 3.66 (m, 3H), 3.55-3.52 (m, 1H), 3.36 – 3.30 (m, 2H), 1.22 (d, J = 6.2 Hz, 3H). 6, 8 354 491.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77-7.76 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.16-6.13 (m, 1H), 5.73-5.70 (m, 1H), 5.51-5.49 (m, 1H), 4.21-4.14 (m, 1H), 4.12-4.03 (m, 1H), 3.98-3.96 ( m, 1H), 3.81 – 3.66 (m, 3H), 3.55-3.52 (m, 1H), 3.36 – 3.30 (m, 2H), 1.22 (d, J = 6.2 Hz, 3H). 6, 8 355 505.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77-7.73 (m, 2H), 7.58-7.55 (m, 1H), 7.47 -7.44(m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.16-6.13 (m, 1H), 5.73-5.69 (m, 1H), 5.51-5.56 (m, 1H), 4.21 – 4.12 (m, 2H), 4.09-4.07 (m, 1H), 3.81 – 3.66 ( m, 3H), 3.44 (d, J = 5.5 Hz, 1H), 3.37-3.36 (m, 1H), 3.17-3.15 (m, 1H), 1.64 – 1.53 (m, 1H), 1.48-1.43 (m, 1H), 0.94 (t, J = 7.7 Hz, 3H). 6, 8 356 491.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77-7.75 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.45 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H) , 6.16-6.13 (m, 1H), 5.73-5.72 (m, 1H), 5.51-5.48 (m, 1H), 4.21 – 4.14 (m, 1H), 3.84-3.82 (m, 1H), 3.80 – 3.57 ( m, 6H), 3.49 (t, J = 6.1 Hz, 1H), 3.41-3.37 (m, 1H), 2.10 – 1.96 (m, 2H). 6, 8 357 447.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77-7.74 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.74 -6.73(m, 1H), 6.42 ( d, J = 7.5 Hz, 1H), 6.16-6.13 (m, 1H), 5.73-5.71 (m, 1H), 5.51-5.47 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.66 ( m, 3H), 2.75 (d, J = 4.9 Hz, 3H). 6, 8 358 461.12 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.74 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.42 (d, J = 7.5 Hz, 1H ), 6.16-6.12 (m, 1H), 5.73-5.71 (m, 1H), 5.51-5.47 (m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.66 (m, 3H), 2.82 (s , 6H). 6, 8 359 448.09 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.74 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.42 (d, J = 7.5 Hz, 1H ), 6.16-6.12 (m, 1H), 5.73-5.71 (m, 1H), 5.51-5.47 (m, 1H), 4.21 – 4.14 (m, 1H), 3.83 (s, 3H), 3.81 – 3.71 (m , 2H), 3.71 – 3.66 (m, 1H). 6, 8 360 476.12 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.74 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.42 (d, J = 7.5 Hz, 1H ), 6.16-6.12 (m, 1H), 5.73-5.71 (m, 1H), 5.51-5.47 (m, 1H), 5.09-5.05 m, 1H), 4.21 – 4.14 (m, 1H), 3.81 – 3.71 ( m, 2H), 3.71 – 3.66 (m, 1H), 1.29 (d, J = 5.9 Hz, 6H). 6, 8 361 532.16 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.74 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H ), 6.17-6.13 (m, 1H), 5.74-5.72 (m, 1H), 5.52-5.50 (m, 1H), 4.49 – 4.42 (m, 1H), 4.34 – 4.23 (m, 2H), 3.88-3.86 (m, 1H), 3.81-3.78 (m, 1H), 3.53-3.50 (m, 1H), 3.41-3.37 (m, 2H), 3.23-3.20 (m, 1H), 1.47 (s, 3H), 1.41 (d, J = 6.0 Hz, 3H). 3,6 362 532.16 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.74 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.46 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H ), 6.17-6.13 (m, 1H), 5.74-5.72 (m, 1H), 5.52-5.50 (m, 1H), 4.49 – 4.42 (m, 1H), 4.34 – 4.23 (m, 2H), 3.88-3.86 (m, 1H), 3.81-3.78 (m, 1H), 3.53-3.50 (m, 1H), 3.41-3.37 (m, 2H), 3.23-3.20 (m, 1H), 1.47 (s, 3H), 1.41 (d, J = 6.0 Hz, 3H). 3, 6 363 565.15 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.05 – 7.99 (m, 4H), 7.77-7.75 (m, 4H), 7.58 (d, J = 1.8 Hz, 1H), 7.58 – 7.51 (m, 3H) , 7.51 – 7.42 (m, 8H), 6.41 (d, J = 7.5 Hz, 2H), 6.17-6.10 (m, 2H), 5.74-5.68 (m, 2H), 5.51-5.47 (m, 2H), 4.59 – 4.52 (m, 2H), 4.52 – 4.42 (m, 4H), 3.91-3.85 (m, 2H), 3.53-3.49 (m, 2H), 3.41 (dd, J = 7.2, 5.8 Hz, 2H), 1.47 (s, 6H). 9, 6 364 581.14 ¹ H NMR (500 MHz, Chloroform- d ) δ 8.05 – 7.99 (m, 2H), 7.77-7.75 (m, 2H), 7.60 – 7.51 (m, 2H), 7.51 – 7.42 (m, 4H), 6.41 ( d, J = 7.5 Hz, 1H), 6.17-6.12 (m, 1H), 5.74-5.70 (m, 1H), 5.51-5.47 (m, 1H), 4.59 – 4.52 (m, 1H), 4.52 – 4.42 ( m, 2H), 4.00-3.95 (m, 1H), 3.76 (dd, J = 5.6, 3.8 Hz, 2H), 3.58 (d, J = 6.4 Hz, 2H), 3.42 (t, J = 5.5 Hz, 1H ). 9,6,2 365 558.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-70 (m, 1H), 5.52 -5.47(m, 1H), 4.46-4.43 (m, 1H ), 4.30 – 4.19 (m, 2H), 2.53-2.47 (m, 3H), 1.67 – 1.57 (m, 2H), 1.40 – 1.27 (m, 4H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H), 0.92 – 0.85 (m, 3H). 9,6,2 366 559.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.71 (m, 1H), 5.52-5.48 (m, 1H), 4.49 – 4.42 (m, 1H ), 4.34 – 4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.41-3.37 (m, 1H), 3.23-3.29 (m, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.67 – 1.57 (m, 2H), 1.43 – 1.36 (m, 4H), 1.36 – 1.27 (m, 4H), 0.92 – 0.84 (m, 3H). 9,6,2 367 559.20 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.71 (m, 1H), 5.52-5.48 (m, 1H), 4.49 – 4.42 (m, 1H ), 4.34 – 4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.41-3.37 (m, 1H), 3.23-3.29 (m, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.67 – 1.57 (m, 2H), 1.43 – 1.36 (m, 4H), 1.36 – 1.27 (m, 4H), 0.92 – 0.84 (m, 3H). 9,6,2 368 545.18 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.71 (m, 1H), 5.52-5.48 (m, 1H), 4.49 – 4.42 (m, 1H), 4.34 – 4.23 (m, 2H), 3.84-3.78 (m, 1H), 3.41 -3.38(m, 1H), 3.23 (dd, J = 7.2, 6.5 Hz, 1H), 2.48 (d, J = 7.0 Hz, 2H), 2.17-2.15 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 0.97 (d, J = 6.6 Hz, 6H). 9,6,2 369 589.21 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77-7.75 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.48 (m, 1H), 4.45-4.40 (m, 1H), 4.35-4.33 (m, 1H), 4.25 (dd, J = 11.8, 5.0 Hz, 1H), 4.04-3.99 (m, 1H), 3.91-3.87 (m, 1H), 3.35 (t, J = 7.2 Hz, 1H), 3.28 (d, J = 4.9 Hz, 1H), 3.24 (t, J = 7.2 Hz, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.67 – 1.57 (m, 2H), 1.40 – 1.27 (m , 4H), 1.22 (d, J = 6.2 Hz, 3H), 0.92 – 0.84 (m, 3H). 9,6,2 370 575.19 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.75 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.48 (m, 1H), 4.45-4.40 (m, 1H), 4.35- 4.33 (m, 1H), 4.33 (dd, J = 11.8, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.82 – 3.65 (m, 3H), 3.48 (t, J = 5.5 Hz, 1H), 3.41 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.67 – 1.57 (m, 2H) , 1.40 – 1.27 (m, 4H), 0.92 – 0.84 (m, 3H). 9,6,2 371 575.19 ¹ H NMR (500 MHz, Chloroform- d ) δ7.77-7.75 (m, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz, 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.48 (m, 1H), 4.45-4.40 (m, 1H), 4.35- 4.33 (m, 1H), 4.33 (dd, J = 11.8, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.82 – 3.65 (m, 3H), 3.48 (t, J = 5.5 Hz, 1H), 3.41 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.67 – 1.57 (m, 2H) , 1.40 – 1.27 (m, 4H), 0.92 – 0.84 (m, 3H). 9,6,2 372 575.19 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.14 (m, 1H), 5.74-5.70 (m, 1H), 5.52-5.48 (m, 1H), 4.49 – 4.42 (m, 1H ), 4.32 (dd, J = 11.8, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.77 – 3.67 (m, 1H), 3.67 – 3.61 (m, 2H), 3.57 ( dd, J = 7.3, 6.6 Hz, 1H), 3.50 – 3.42 (m, 2H), 2.48 (d, J = 7.0 Hz, 2H), 2.17-2.12 (m, 1H), 2.06 – 1.92 (m, 2H) , 0.97 (d, J = 6.6 Hz, 6H). 9,6,2 373 561.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.14 (m, 1H), 5.74 -5.68(m, 1H), 5.52-5.47 (m, 1H), 4.45-4.40 (m, 1H ), 4.35 (dd, J = 11.8, 5.1 Hz, 1H), 4.25 (dd, J = 11.8, 5.0 Hz, 1H), 4.04-3.91 (m, 1H), 3.91-3.87 (m, 1H), 3.35 ( t, J = 7.2 Hz, 1H), 3.28 (d, J = 4.9 Hz, 1H), 3.24 (t, J = 7.2 Hz, 1H), 2.67-2.62 (m, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.15 (d, J = 6.8 Hz, 6H). 9,6,2 374 547.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.10 (m, 1H), 5.74-5.70 (m, 1H), 5.52 -5.48(m, 1H), 4.49 – 4.41 (m, 1H ), 4.33 (dd, J = 11.8, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.82 – 3.65 (m, 3H), 3.48 (t, J = 5.5 Hz, 1H) , 3.41 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H), 2.67-2.61 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). 9,6,2 375 547.16 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.10 (m, 1H), 5.74-5.70 (m, 1H), 5.52 -5.48(m, 1H), 4.49 – 4.41 (m, 1H ), 4.33 (dd, J = 11.8, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.82 – 3.65 (m, 3H), 3.48 (t, J = 5.5 Hz, 1H) , 3.41 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H), 2.67-2.61 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). 9,6,2 376 561.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 7.77 (dd, J = 6.1, 3.7 Hz, 2H), 7.58 (dd, J = 7.5, 1.8 Hz, 1H), 7.47 (dd, J = 6.1, 3.8 Hz , 2H), 6.41 (d, J = 7.5 Hz, 1H), 6.17-6.13 (m, 1H), 5.74 -5.69(m, 1H), 5.52-5.48 (m, 1H), 4.49 – 4.42 (m, 1H ), 4.32 (dd, J = 11.8, 5.1 Hz, 1H), 4.26 (dd, J = 11.8, 5.0 Hz, 1H), 3.77-3.70 (m, 1H), 3.71 – 3.61 (m, 2H), 3.57 ( dd, J = 7.3, 6.6 Hz, 1H), 3.50 – 3.42 (m, 2H), 2.67-2.62 (m, 1H), 2.06 – 1.93 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H) . 9,6,2 377 410.18 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.55 (s, 1H), 7.60 (dd, J = 12.7, 1.7 Hz, 1H), 5.95 – 5.88 (m, 2H), 4.65-4.60 m, 1H), 4.53-4.50 (m, 1H), 4.44 – 4.37 (m, 1H), 4.26 – 4.16 (m, 2H), 2.54-2.51 (m, 1H), 1.85 – 1.80 (m, 1H), 1.80 – 1.76 (m , 1H), 1.76 – 1.42 (m, 8H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H). 7 378 398.11 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.15-6.10 (m , 1H), 5.69-5.55 (m, 1H), 5.33-5.31 (m, 1H), 4.46 – 4.39 (m, 1H), 4.22 (d, J = 5.2 Hz, 2H), 3.58 (d, J = 12.5 Hz, 1H), 3.43 (d, J = 12.5 Hz, 1H), 2.56 (dq, J = 14.7, 7.4 Hz, 1H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.4 Hz, 3H). 6, 8 379 424.13 ¹ H NMR (500 MHz, Chloroform- d ) δ 9.57 (s, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 6.14 -6.10(m , 1H), 5.71-5.65 (m, 1H), 5.33 -5.28(m, 1H), 4.47 – 4.40 (m, 1H), 4.22 (d, J = 5.1 Hz, 2H), 2.55-2.51 (m, 1H ), 2.07 – 1.96 (m, 2H), 1.94 – 1.84 (m, 2H), 1.18 (d, J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H). 6, 8

Example 2: Permeability of Compounds in Caco-2 Assay

Caco-2 cell culture

Caco-2 cells purchased from ATCC were inoculated onto the polyethylene membrane (PET) of a 96-well insert plate at a rate of 1x10 ⁵ cells/cm ² , and the medium was updated every 4 to 5 days until days 21 to 28. Form a cell monolayer.

Transshipment method

The migration buffer in the study was HBSS (10.0 mm HEPES) at a pH of 7.40±0.05. Test compounds were tested in duplicate at 2.00 μM in both directions. Digoxin was tested at 10.0 μM in both directions, in duplicate, and nadolol and metoprolol were tested at 2.00 μM in the A to B direction, in duplicate. The final DMSO concentration was adjusted to less than 1%. Incubate in a CO ₂ incubator at 37±1°C, 5% CO ₂ and saturated humidity for 2 hours without shaking. All samples were mixed with acetonitrile containing internal standard and centrifuged at 3200 rpm for 10 minutes. For nadolol and metoprolol, 200 μl of the supernatant was diluted with 600 μl of ultrapure water and used for LC-MS/MS analysis. For digoxin and test compounds, 200 μl of the supernatant was diluted with 200 μl of ultrapure water and used for LC-MS/MS analysis. The concentrations of test and control compounds in starting, donor, and acceptor solutions were quantified by the LC-MS/MS method using the analyte/internal standard peak area ratio.

After the transport experiment, a luciferin yellow exclusion assay was used to determine the integrity of the Caco-2 cell monolayer.

data analysis

The calculation formula of apparent permeability coefficient Papp (cm/s) is as follows: Papp = (dCr/dt) x Vr / (A x C0) where (dCr/dt) is the relationship between the cumulative concentration of the compound in the receiving chamber and time (uM /s); Vr is the solution volume in the receiving chamber (0.075 mL at the top, 0.25 mL at the basal side); A is the transmission surface area, that is, the single layer area is 0.0804 cm ² ; C0 is the initial concentration of the donor chamber (uM).

The calculation of the outflow rate Efflux Ratio is as follows: Efflux Ratio =Papp(BA)/Papp(AB)

The recovery rate is calculated using the following formula: Solution recovery rate %= 100 ×[(Vr × Cr) + (Vd ×Cd)] / (Vd ×C0) where Vd is the volume of the donor chamber (0.075 mL at the apical side and 0.25 mL at the basal side), and Cd and Cr are the final concentrations of the transported compounds in the donor and receiving chambers, respectively.

result:

Table 2. Permeability of compounds in Caco-2 test Compound number Average P _app ( ×10 ^{-6 cm/s} ) Efflux Ratio P _app A to B B to A Compound 1 0.565 2.04 3.61 middle Compound 3 0.632 2.31 3.66 middle Compound 6 0.412 1.03 2.50 middle Compound 7 0.553 1.98 3.58 middle Compound 51 1.320 0.87 0.66 Low Compound 61 0.870 2.76 3.17 middle Compound 89 0.782 1.55 1.98 Low Compound 103 0.342 2.11 6.17 middle Compound 105 0.763 1.96 2.57 middle Compound 117 0.682 2.19 3.21 middle Compound 119 <0.293 0.87 ＞2.97 middle Compound 142 0.883 1.57 1.78 Low Compound 154 0.541 3.65 6.75 middle Compound 151 <0.293 0.43 >1.46 Low Compound 161 0.352 0.54 1.53 Low Compound 189 0.395 0.45 1.14 Low Compound 249 0.582 13.55 23.28 high Compound 251 0.460 12.34 26.83 high Compound 264 0.764 12.87 16.85 high Compound 309 0.581 1.85 3.18 middle Compound 322 <0.293 0.93 ＞3.17 middle Monupivir <0.293 0.527 >1.80 Low

Standard*: Low permeability: Papp ≤ 2×10 ^-6 cm/s, medium permeability 2＜Papp＜20(×10 ^-6 cm/s), high permeability: Papp≥20(×10 ^-6 cm/s );

Example 3. Pharmacokinetic study

Individual plasma concentrations of compound NHC following a single oral administration of compound and monopiravir (100 mg/kg) to monkeys were used to calculate the mean pharmacokinetic parameters summarized in Table 3.

Table 3. Summary of pharmacokinetic parameters in male monkeys Compound number T _1/2 (hour) C _max (ng/mL) AUC _0-24h (hr*ng/mL) Compound 1 2.20 4062 8006 Compound 3 2.50 3110 7839 Compound 6 5.20 1350 6530 Compound 9 3.35 758 5820 Compound 16 2.35 3899 9500 Compound 21 1.75 2034 4355 Compound 30 1.90 3766 7905 Compound 58 6.43 675 10450 Compound 61 1.50 3023 5540 Compound 121 2.00 3518 4555 Compound 151 3.06 2988 3900 Compound 161 3.65 450 3030 Compound 227 3.41 543 4031 Compound 249 2.56 7856 15610 Compound 251 2.34 6500 11240 Compound 290 1.54 345 2457 Compound 322 3.43 16 98

All patents, patent application publications, patent applications, and non-patent publications cited in this specification are hereby incorporated by reference in their entirety.

It will be understood from the foregoing that, although specific embodiments of the invention are described herein for illustrative purposes, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the scope of the invention should be limited only by the appended claims.

without

without.

without.

Claims (10)

A compound of formula IV, or a pharmaceutically acceptable salt thereof, Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH; Preferably, it has the structure of formula V, Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens. A compound of formula VI, or a pharmaceutically acceptable salt thereof, Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl group, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH; Preferably, it has the structure of formula VII, Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens. A compound of formula VIII, or a pharmaceutically acceptable salt thereof, Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl radical, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH; Preferably, it has a structure of formula IX, Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens. A compound of formula X, or a pharmaceutically acceptable salt thereof, Wherein, R ₁ or R ₂ is independently selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, said -(CO)C ₁ -C ₆ alkyl group, or -(CO)C ₅ -C ₁₀ aryl optionally substituted by one or more halogens and OH; Preferably, it has the structure of formula XI, Wherein, R ₁ is selected from H, -(CO)C ₁ -C ₆ alkyl, or -(CO)C ₅ -C ₁₀ aryl, the -(CO)C ₁ -C ₆ alkyl, or -( CO)C ₅ -C ₁₀ aryl is optionally substituted with one or more halogens. A compound of formula I, or a pharmaceutically acceptable salt thereof, Wherein, R ₁ or R ₂ is independently selected from H, heteroaryl, -(CO)C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ Aryl, -(CO)C ₅ -C ₁₀ heteroaryl, -(CO)OC ₅ -C ₁₀ aryl, -(CO)OC ₅ -C ₁₀ heteroaryl, -(CO)NHC ₁ -C ₆ Alkyl, (CO)NHC ₅ -C ₁₀ aryl or (CO)NHC ₅ -C ₁₀ heteroaryl, the heteroaryl, -(CO)C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ aryl, -(CO)C ₅ -C ₁₀ heteroaryl, -(CO)OC ₅ -C ₁₀ aryl, -(CO)OC ₅ - C ₁₀ heteroaryl, -(CO)NHC ₁ -C ₆ alkyl, (CO)NHC ₅ -C ₁₀ aryl or (CO)NHC ₅ -C ₁₀ heteroaryl is optionally replaced by one or more halogens, OH, -OC ₁ -C ₆ alkyl, NR ₆ R ₅ , C ₁ -C ₆ alkyl, C ₅ -C ₁₀ aryl and heteroaryl substitution; R ₃ or R ₄ are independently selected from H, D, Halogen or C ₁ -C ₃ alkyl, the alkyl group is optionally substituted by one or more halogens; R ₅ or R ₆ is independently selected from H, OH, C ₁ -C ₆ alkyl, -(CO) C ₁ -C ₆ alkyl, -(CO)OC ₁ -C ₆ alkyl, -(CO)C ₅ -C ₁₀ aryl, -(CO)C ₅ -C ₁₀ heteroaryl, C ₅ -C ₁₀ Aryl or C ₅ -C ₁₀ heteroaryl; link is independently selected from the following groups: , wherein R ₇ or R ₈ is independently selected from H and C ₁ -C ₆ alkyl, and R ₇ and R ₈ can be fused to each other to form a ring; Preferably, wherein R ₃ or R ₄ is independently selected from H, D, F, Cl, Br, CH ₃ or CF ₃ ; Preferably, wherein R ₅ or R ₆ is independently selected from H, OH, C ₁ -C ₆ alkyl, -(CO)C ₁ -C ₆ alkyl base or -(CO)OC ₁ -C ₆ alkyl. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 5; and a pharmaceutically acceptable excipient. The use of a compound as described in any one of claims 1 to 5 or a pharmaceutical composition as described in claim 6 in the preparation of a medicament for treating and/or preventing viral infections. The use as described in claim 7, wherein the viral infection is a coronavirus infection. The use as described in claim 8, wherein the viral infection is COVID-19. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: .