SLC6A19 functional bicyclic heteroaryl-containing piperidine inhibitors

Abstract

Compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal levels of amino acids by regulating SLC6A19 transport are disclosed.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 532,264, filed on 11 August 2023; and to U.S. Provisional Patent Application No. 63 / 633,404, filed on 12 April 2024. [Background technology]

[0002] Phenyletonuria (PKU) is a congenital metabolic disorder caused by mutations in phenylalanine hydroxylase (PAH), an enzyme responsible for the metabolism of phenylalanine. PKU is an autosomal recessive metabolic disorder in which phenylalanine is not properly metabolized, resulting in abnormally high plasma concentrations of phenylalanine. Individuals with PKU have abnormally high blood levels of phenylalanine, and if left untreated, this can lead to irreversible nerve damage and various complications, including intellectual disability, seizures, neurodevelopmental disorders, and behavioral problems. PKU is difficult to manage because blood phenylalanine levels are directly related to diet. Patients must adhere to a strict diet for life, which affects every aspect of their lives. Current standard treatments are enzyme cofactor therapy and enzyme replacement therapy, but these therapies are not effective for all patients and carry a potential risk of adverse events.

[0003] The enzyme responsible for metabolizing phenylalanine and maintaining its homeostasis is phenylalanine hydroxylase (PAH). Loss-of-function (LOF) mutations in the PAH gene on chromosome 12q23.2 are known to result in most PKU types. These LOF mutations causing PKU can be diagnosed as classical PKU (the most severe type) and less severe forms of "mild PKU" or "hyperphenylalaninemia." In addition to PAH, mutations in other enzymes that affect phenylalanine metabolism, such as dihydropteridine reductase (DHPR), an enzyme involved in the synthesis of cofactors necessary for PAH activity, can also increase phenylalanine levels. In addition to diet, blood amino acid concentrations, including phenylalanine levels, are regulated by SCL6A19. SCL6A19 is located in the proximal tubule of the kidney and is responsible for reabsorbing amino acids and returning them to the bloodstream. [Overview of the project]

[0004] One aspect of the present invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal levels of amino acids by regulating SLC6A19 transport.

[0005] Therefore, in this specification, the structure of formula (I) is: [ka] (In the formula, L1 is alkyl; X1 and X2 are selected independently of -H and cycloalkyl; however, neither X1 nor X2 is necessarily -H; Y1 is an arbitrarily substituted 5,6-condensed bicyclic heteroaryl; Y2 is selected from -NH(Y2'), -OY2'', alkyl, and hydroxyalkyl; Y2' is selected from -H, alkyl, and -O-alkyl; Y2'' is alkyl; Y3 is selected from -H, hydroxyalkyl, and halogen. Compounds having the same property or pharmaceutically acceptable salts thereof are provided.

[0006] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder related to a gene defect in phenylalanine hydroxylase in a subject that requires such treatment or prevention, the method comprising administering an effective amount of a compound of formula (I) to the subject.

[0007] Another aspect of the present invention relates to a method for treating or preventing phenylketonuria, hyperphenylalaninemia, tyrosinemia, nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia in a subject requiring treatment or prevention of such conditions, comprising administering an effective amount of a compound of formula (I) to the subject.

[0008] Another aspect of the present invention relates to a method for modulating SLC6A19 transport in a subject that requires such modification, comprising administering an effective amount of a compound of formula (I) to the subject.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which the present invention pertains. Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present invention, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are invoked in their entirety by reference. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, substances, methods, and examples are illustrative and not intended to be limiting.

[0010] Other features, purposes, and advantages of the present invention will become apparent from the detailed description and the claims. [Brief explanation of the drawing]

[0011] [Figure 1] This table summarizes isoleucine transport data for exemplary compounds of the present invention. A = IC50 < 500 nM; B = IC50 500 nM ~ 1500 nM; C = IC50 > 1500 nM ~ 5000 nM; D = IC50 > 5000 nM ~ 10000 nM; and E = IC50 > 10000 nM. [Modes for carrying out the invention]

[0012] definition For convenience, prior to further description of the present invention, the specific terms used in the specification, examples, and appended claims are summarized here. These definitions should be interpreted in the context of the remainder of this disclosure and understood as understood by those skilled in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0013] To facilitate a quicker understanding of the present invention, certain terms and phrases are defined below and throughout this specification.

[0014] The articles "a" and "an" are used herein to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, "an element" means one or more elements.

[0015] When used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements thus combined, that is, elements that may be present either conjunctively or disjunctively. Multiple elements listed using "and / or" should be interpreted as being in the same manner, that is, "one or more" elements combined in this way. Other elements may optionally exist in addition to those specifically identified, whether related to or unrelated to the elements specifically identified by the "and / or" clause. Therefore, as a non-restrictive example, when referring to "A and / or B," when used in combination with an open-ended word such as "comprising," it may refer to A only in one embodiment (optionally including elements other than B), B only in another embodiment (optionally including elements other than A), and both A and B in yet another embodiment (optionally including other elements), and so on.

[0016] As used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as encompassing, i.e., including not only at least one of a substantial number or set of elements, but two or more, and optionally, additional items not listed. Only terms clearly indicated otherwise, such as “only one of” or “exactly one of” or, as used in the claims, “consisting of,” refer to including exactly one element of a substantial number or set of elements. In general, as used herein, the term “or” should be interpreted only as an exclusive alternative (i.e., “one or the other, but not both”) when preceded by terms indicating exclusivity, such as “either,” “one of,” “only one of” or “exactly one of.” As used in the claims, “essentially consisting of” should have the general meaning as used in the field of patent law.

[0017] As used herein and in the claims, the phrase “at least one” should be understood to mean, with respect to a list of one or more elements, at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the existence of any other elements besides those specifically identified in the list of elements, which the phrase “at least one” refers to, whether related to or unrelated to the elements specifically identified in the list of elements. Therefore, as a non-limiting example, "at least one of A and B" (or similarly, "at least one of A or B" or similarly, "at least one of A and / or B") may, in one embodiment, refer to the absence of B (and optionally including elements other than B) along with at least one A (including any two or more A's); in another embodiment, refer to the absence of A (and optionally including elements other than A) along with at least one B (including any two or more B's); and in yet another embodiment, refer to at least one A (including any two or more A's) and at least one B (including any two or more B's) (and optionally including other elements), and so on.

[0018] Unless otherwise clearly indicated, in any method claimed herein that includes two or more steps or operations, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are shown.

[0019] In the claims and the above specification, all transitional clauses, such as “comprising,” “including,” “carrying,” “having,” “containing,” “accompanying,” “holding,” and “composed of,” should be understood to be open-ended, meaning “including, but not limited to, ….” As set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03, only the transitional clause “composed of” is a closed transitional clause, and only the transitional clause “essentially consisting of” is a semi-closed transitional clause.

[0020] Certain compounds contained in the compositions of the present invention may exist in geometric forms or as stereoisomers. In addition, the polymers of the present invention may also be optically active. The present invention intends that all such compounds, including cis and trans isomers, (R)-enantiomers and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures, are within the scope of the present invention. Additional chiral carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0021] "Geometric isomers" refer to isomers in which the orientation of substituent atoms differs in relation to a carbon-carbon double bond, cycloalkyl ring, or bridging bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond may be in the E-isomer configuration (substituents are on the opposite side of the carbon-carbon double bond) or the Z-isomer configuration (substituents are on the same side). "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate configuration relative to the core molecule. Certain of the disclosed compounds may exist in "atropisomer" form, i.e., as "atropisomers". Atropisomers are stereoisomers resulting from rotational impairment of single bonds that is high enough to isolate their conformational isomers due to steric strain impairment. The compounds of the present invention may be prepared as individual isomers by synthesis specific to each isomer, or by separation from an isomer mixture. Conventional resolution techniques include using optically active acids to form salts of the free bases of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free bases), using optically active amines to form salts of the acidic forms of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free acid), using optically pure acids, amines, or alcohols to form esters or amides of the isomers in an isomer pair (followed by chromatographic separation and removal of chiral auxiliaries), or using various well-known chromatographic methods to resolve a mixture of isomers of either the starting material or the final product.

[0022] For example, if a specific enantiomer of the compound of the present invention is desired, the enantiomer can be prepared by asymmetric synthesis or by induction using a chiral auxiliary group. The resulting mixture of diastereomers is then separated, the auxiliary group is cleaved, and the desired pure enantiomer is obtained. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt can be formed using an optically active acid or base. Subsequently, the diastereomer thus formed can be separated by fractional crystallization or chromatography, which are well known in the art, and the pure enantiomer can be recovered.

[0023] As used herein, the term “tautomer” refers to structural isomers that exist in equilibrium as a result of the movement of hydrogen atoms. For example, two tautomers of 2-pyrimidinone are shown below. A single tautomer may be provided in the structural representation of a given compound. However, the present invention intends to encompass all such tautomers of a given compound. [ka]

[0024] The purity ratio by mole fraction is the molar ratio of the enantiomer (or diastereomer), or the ratio of moles of the enantiomer (or diastereomer) to moles of its optical isomer. When the stereochemistry of a disclosed compound is named or described by structure, the named or described stereoisomer has a purity of at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by mole fraction relative to the other stereoisomer. When a single enantiomer is named or described by structure, the described or named enantiomer has a purity of at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by mole fraction. When a single diastereomer is named or described by its structure, the described or named diastereomer has a purity of at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in mole fraction.

[0025] When a disclosed compound is named or described by structure without showing its stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to include any of the enantiomers of the compound that do not contain the corresponding optical isomer, a racemic mixture of the compound, or a mixture in which one enantiomer is concentrated relative to the corresponding optical isomer. When a disclosed compound is named or described by structure without showing its stereochemistry, and has two or more chiral centers, the name or structure should be understood to include a diastereomer that does not contain other diastereomers, a considerable number of diastereomers that do not contain other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is concentrated relative to the other diastereomer(s), or a mixture of diastereomers in which one or more diastereomers are concentrated relative to the other diastereomer. The present invention includes all of these forms.

[0026] The structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen may be replaced with deuterium or tritium, or carbon may be replaced with 13 C or 14 Compounds produced by replacing carbon with C-enriched carbon fall within the scope of the present invention.

[0027] The term "prodrug," as used herein, includes compounds that are converted into therapeutic agents under physiological conditions. A common method for preparing prodrugs involves including a selective moiety that is hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, prodrugs are converted by the enzymatic activity of a host animal.

[0028] The terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in transporting or delivering the chemical substance from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation, is not harmful to the patient, and is substantially nonpyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository waxes; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Examples include soybean oil; (10) glycols, e.g., propylene glycol; (11) polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic, suitable substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., they do not cause a significant rise in temperature when administered to a patient.

[0029] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by reacting the purified compound(s) in free base form separately with a suitable organic or inorganic acid and isolating the resulting salts. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitic acid, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.) In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, and thus pharmaceutically acceptable salts can be formed with pharmaceutically acceptable bases. In these cases, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic base addition salts and organic base addition salts of the compound(s). These salts can also be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free acid form with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, with ammonia, or with a pharmaceutically acceptable organic primary, organic secondary, or organic tertiary amine. Typical alkali salts or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine (see, for example, Berge et al. above).

[0030] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with small molecules.

[0031] The “therapeutic effective dose” (or “effective dose”) of a compound relating to its use in treatment refers to the amount of the compound in preparation form that, when administered (to a mammal, preferably a human) as part of a desired administration regimen, reduces symptoms, improves a condition, or delays the onset of a condition, according to a clinically acceptable standard or cosmetic purpose for the disorder or condition being treated, for example, in a reasonable benefit / risk ratio applicable to any medical treatment.

[0032] The terms “preventive or therapeutic” treatment are recognized in the art and include administration to one or more hosts of the composition. If the treatment is performed before the appearance of clinical symptoms of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is preventive (i.e., the treatment protects the host from the appearance of the undesirable condition), and if the treatment is performed after the appearance of the undesirable condition, the treatment is therapeutic (i.e., the treatment is intended to reduce, improve or stabilize an existing undesirable condition or its side effects).

[0033] The terms “patient” or “subject” refer to a mammal requiring a specific treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

[0034] Aliphatic chains include alkyl, alkenyl, and alkynyl groups as defined below. Straight aliphatic chains are limited to unbranched carbon chain portions. As used herein, the term “aliphatic group” refers to a straight, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0035] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain portion having a specified number of carbon atoms, or, if not specified, up to 30 carbon atoms. For example, alkyls with 1 to 8 carbon atoms refer to portions such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as positional isomers of these portions. Examples of alkyls with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, linear or branched alkyls have 30 or fewer carbon atoms in their main chain (for example, C1-C1 in a linear chain). 30 In branched chains, C3-C 30 ), more preferably 20 or fewer alkyl groups. The alkyl groups may be substituted or unsubstituted.

[0036] As used herein, the term "heteroalkyl" refers to the alkyl portion as defined above, which contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms instead of carbon atoms.

[0037] As used herein, the term "haloalkyl" refers to the alkyl moiety as defined above, in which at least one halogen is substituted.

[0038] As used herein, the term "hydroxyalkyl" refers to an alkyl group defined above, which is substituted with at least one hydroxyl group.

[0039] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, for example, 2 to 12 carbon atoms, with two bonding sites to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, and isopropylene-(CH2CH(CH3))-. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain portions, and may be optionally substituted with one or more substituents.

[0040] "Cycloalkyl" refers to a monocyclic, bicyclic, bridging, spirocyclic, or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Preferred cycloalkyls have 3 to 10 carbon atoms in the ring structure, and more preferably 3 to 6 carbon atoms in the ring structure. Cycloalkyls may be substituted or unsubstituted.

[0041] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above, which is substituted with at least one halogen.

[0042] A "cycloheteroalkyl" refers to a cycloalkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms instead of carbon atoms. Preferred cycloheteroalkyls have 4 to 8 carbon atoms and heteroatoms in their ring structure, and more preferably 4 to 6 carbon atoms and heteroatoms in their ring structure. Cycloheteroalkyls may be substituted or unsubstituted.

[0043] Unless otherwise specified, “lower alkyl” as used herein means an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In certain embodiments, substituents defined herein as alkyl are lower alkyl groups.

[0044] An "alkenyl" refers to a carbon chain portion that is cyclic or acyclic, branched or unbranched and unsaturated, having a predetermined number of carbon atoms, or up to 26 carbon atoms if no limit on the number of carbon atoms is specified, and containing one or more double bonds. Alkenyls with 6 to 26 carbon atoms are exemplified by the various isomers of hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicocenyl, heneicocenyl, dococenyl, tricocenyl, and tetracocenyl, whose unsaturated bonds(s) can be located anywhere in the portion, and whose double bonds(s) can be in either a (Z) configuration or an (E) configuration.

[0045] "Alkinyl" refers to the hydrocarbyl portion of the alkenyl group, but specifically to those that have one or more triple bonds in that portion.

[0046] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryls) or groups in which one or more atoms are heteroatoms (i.e., heteroaryls). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and in which at least one of the rings is aromatic, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol and aniline. Heteroaryl groups include substituted or unsubstituted 3- to 12-membered aromatic ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, the ring structure containing 1 to 4 heteroatoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. The aryl and heteroaryl groups may be monocyclic, bicyclic, or polycyclic.

[0047] The terms “halo,” “halide,” or “halogen” as used herein mean halogens, including, but not limited to, fluoro, chloro, bromo, and iodine in both radioactive and non-radioactive forms. In preferred embodiments, the halo is selected from the group consisting of fluoro, chloro, and bromo.

[0048] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, more preferably a 5- to 10-membered ring, the cyclic structure containing 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, sinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactam, such as azetidinone and pyrrolidinone, sultam, and sultone. The heterocyclic ring can be substituted at one or more positions with substituents such as halogens, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphates, phosphonates, phosphinates, carbonyls, carboxyls, silyls, sulfamoyls, sulfinyls, ethers, alkylthios, sulfonyls, ketones, aldehyde esters, heterocyclyl moieties, aromatic moieties or heteroaromatic moieties, -CF3 and -CN, etc.

[0049] The term “substituted” refers to a portion having substituents that replace one or more hydrogens on the carbons of its main chain. “Substituted” or “substituted with” should be understood to imply the condition that such substitution conforms to the acceptable bond valencies of the substituted atom and substituent, and that the substitution results in a stable compound (e.g., one that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc.). As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In broad embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. There may be one or more acceptable substituents, which may be the same or different for a given organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any acceptable substituents of the organic compound described herein that satisfy the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (thioesters, thioacetates, or thioformates), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, or aromatic or heteroaromatic moieties. In preferred embodiments, the substituent of the substituted alkyl is C 1-6 Alkyl, C 3-6 The substituents are selected from cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In preferred embodiments, the substituents on the substituted alkyl are selected from fluoro, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that, where appropriate, the substituents themselves may be substituted. Unless otherwise specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0050] As used herein, the definitions of each expression, such as alkyl, m, and n, are intended to be independent of their definitions elsewhere in any structure when they appear more than once in the same structure.

[0051] As used herein, "low molecular weight" means a low organic or inorganic molecule having a molecular weight of less than approximately 3,000 daltons. Generally, small molecules useful in this invention have a molecular weight of less than 3,000 daltons (Da). Small molecules can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2,500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1,500, about 500 to about 1,000, about 300 to about 1,000 Da, or about 100 to about 250 Da).

[0052] In some embodiments, “low molecular weight” typically refers to organic, inorganic, or organometallic compounds having a molecular weight of less than approximately 1000. In some embodiments, the low molecular weight is an organic compound having a size on the order of 1 nm. In some embodiments, the low molecular weight drugs of the present invention include oligopeptides and other biomolecules having a molecular weight of less than approximately 1000.

[0053] An "effective dose" is an amount sufficient to achieve a beneficial or desired outcome. For example, a therapeutic dose is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a prophylactic effective dose, which is the amount required to prevent the onset of a disease or symptoms of a disease. An effective dose can be administered in one or more doses, applications, or medications. The therapeutic effective dose of a composition varies depending on the composition selected. The compositions of the present invention can be administered at least once a day to at least once a week (including once every other day). It will be apparent to those skilled in the art that certain factors (including, but not limited to, the severity of the disease or disorder, past treatment history, the subject's overall health and / or age, and other pre-existing diseases) may influence the dose and timing required to effectively treat the subject. Furthermore, treatment of a subject with a therapeutically effective amount of the composition described herein may include a single treatment or a series of treatments.

[0054] The terms “decrease,” “reduce,” “reduced,” “reduce,” “decrease,” and “inhibit” are all used herein to generally mean a statistically significant reduction compared to a reference. However, to avoid any doubt, “decrease,” “reduce,” “decrease,” or “inhibit” usually mean a reduction of at least 10% compared to a reference level, and may include, for example, reductions of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, and at least about 99%, including any reduction between 10% and 99% compared to the complete absence of a given element or parameter or the absence of a given treatment compared to a reference level.

[0055] The terms “increased,” “increased,” “improved,” or “activated” are all used herein to generally mean an increase of a statistically significant amount. To avoid any doubt, the terms “increased,” “increased,” “improved,” or “activated” mean an increase of at least 10% compared to a reference level, e.g., at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to 100% (including this value), or any increase between 10% and 100% compared to a reference level, or at least about twice, or at least about three times, or at least about four times, or at least about five times, or at least about ten times, or any increase between two times and ten times or more compared to a reference level.

[0056] As used herein, the term “adjust” includes upward and downward control, for example, improving or inhibiting the response.

[0057] As defined herein, “radiopharmaceutical agent” means a pharmaceutical agent containing at least one radioactive isotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or treatment of various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain radioisotopes (RI) that function as a radiation source. As intended herein, the term “radioisotope” includes metallic and nonmetallic radioisotopes. Radioisotopes are selected based on the medical use of the radiolabeled pharmaceutical agent. When the radioisotope is a metallic radioisotope, a chelating agent is typically used to bind the metallic radioisotope to the remainder of the molecule. When the radioisotope is a nonmetallic radioisotope, it typically binds to the remainder of the molecule directly or via a linker.

[0058] For the purposes of this invention, chemical elements are identified according to the inside cover of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0059] The compound of the present invention In this specification, the structure of formula (I) is: [ka] (In the formula, L1 is alkyl; X1 and X2 are independently selected from -H and cycloalkyl groups; however, neither X1 nor X2 is -H. Y1 is an arbitrarily substituted 5,6-condensed bicyclic heteroaryl; Y2 is selected from -NH(Y2'), -OY2'', alkyl, and hydroxyalkyl; Y2' is selected from -H, alkyl, and -O-alkyl; Y2'' is alkyl; Y3 is selected from -H, hydroxyalkyl, and halogen. Compounds having the same; or pharmaceutically acceptable salts thereof are provided.

[0060] In a given embodiment, one of X1 and X2 is -H; the other of X1 and X2 is [ka] That is the case.

[0061] In a given embodiment, X1 is -H; X2 is [ka] That is the case.

[0062] In one embodiment, L1 is a -C1-C4 alkyl-. In another embodiment, L1 is a -CH2-.

[0063] In a given embodiment, Y1 is an unsubstituted 5,6-condensed bicyclic heteroaryl.

[0064] In a given embodiment, Y1 is [ka] Selected from.

[0065] In a given embodiment, Y1 is [ka] Selected from.

[0066] In a given embodiment, Y1 is a substituted 5,6-condensed bicyclic heteroaryl.

[0067] In a given embodiment, Y1 is [ka] and; The presence of R1, R2, R3, R4, and R5 is independently selected from -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF3, -OCHF2, and -OCF3; Z is either H or alkyl; however, at least one of R1, R2, R3, R4, R5, and Z is not -H.

[0068] In a given embodiment, the presence of R1, R2, R3, R4, and R5 is independently selected from -H, alkyl, cycloalkyl, halogen, -CN, -CF3, and -OCF3; Z is -H; however, at least one of R1, R2, R3, R4, and R5 is not -H.

[0069] In a given embodiment, the presence of R1, R2, R3, R4, and R5 corresponds to -H, -Cl, -Br, -F, -CH3, [ka] -Selected independently from -CF3 and -OCF3; provided that at least one of R1, R2, R3, R4, and R5 is not -H.

[0070] In a given embodiment, Y1 is [ka] Selected from.

[0071] In a given embodiment, each of R1, R2, R3, R4, and R5 is a halogen.

[0072] In a given embodiment, each of R1, R2, R3, R4, and R5 is -F.

[0073] In a given embodiment, Y1 is [ka] and; The presence of R6, R7, R8, and R9 is independently selected from -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF3, -OCHF2, and -OCF3; provided that at least one of R6, R7, R8, and R9 is not -H.

[0074] In a given embodiment, the presence of R6, R7, R8, and R9 corresponds to -H, -Cl, -Br, -F, -CH3, [ka] -Selected independently from -CF3 and -OCF3; however, at least one of R6, R7, R8, and R9 is not -H.

[0075] In a given embodiment, Y1 is [ka] Selected from.

[0076] In a given embodiment, Y1 is

Chemical formula

[0077] In a given embodiment, R 10 、R 11 、R 12 、and R 13 each presence is independently selected from -H, -Cl, -Br, -F, -CH3,

Chemical formula

[0078] In a given embodiment, Y1 is

Chemical formula

[0079] In a given embodiment, Y1 is

Chemical formula

[0080] In a given embodiment, the presence of R1, R2, R3, R4, and R5 corresponds to -H, -Cl, -Br, -F, -CH3, [ka] -Selected independently from -CF3 and -OCF3; provided that at least one of R1, R2, R3, R4, and R5 is not -H.

[0081] In a given embodiment, Y1 is [ka] Selected from.

[0082] In a given embodiment, Y1 is [ka] Selected from; The presence of R1, R2, R3, and R4 is independently selected from -H, alkyl, alkoxy, cyclopropyl, halogen, -OH, -CN, -CF3, -OCHF2, and -OCF3; provided that at least one of R1, R2, R3, and R4 is not -H.

[0083] In a given embodiment, the presence of R1, R2, R3, and R4 corresponds to -H, -Cl, -Br, -F, -CH3, [ka] -Selected independently of -CF3 and -OCF3; provided that at least one of R1, R1, R2, R3, and R4 is not -H.

[0084] In a given embodiment, Y1 is [ka] Selected from.

[0085] In a given embodiment, Y1 is [ka] and; The presence of R1, R2, R3, R4, and R5 is independently selected from -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF3, -OCHF2, and -OCF3; Z is either H or alkyl; however, at least one of R1, R2, R3, R4, R5, and Z is not -H.

[0086] In a given embodiment, the presence of R1, R2, R3, R4, and R5 is independently selected from -H, alkyl, cycloalkyl, halogen, -OH, -CN, -CF3, -OCHF2, and -OCF3; Z is -H; however, at least one of R1, R2, R3, R4, and R5 is not -H.

[0087] In a given embodiment, the presence of R1, R2, R3, R4, and R5 corresponds to -H, -Cl, -Br, -F, -CH3, [ka] -Selected independently from -CF3 and -OCF3; Z is -H; however, at least one of R1, R2, R3, R4, and R5 is not -H.

[0088] In a given embodiment, Y1 is [ka] Selected from.

[0089] In a given embodiment, Y1 is [ka] Selected from.

[0090] In a given embodiment, Y1 is [ka] Selected from.

[0091] In one embodiment, Y2 is -NH(Y2'). In another embodiment, Y2' is a C1-C4 alkyl group, for example, -CH3. In yet another embodiment, Y2' is -H.

[0092] In a given embodiment, Y2' is an -O-alkyl group. In a given embodiment, Y2' is an -O-(C1-C4 alkyl group), for example, -OCH3.

[0093] In a given embodiment, Y2 is -OY2''.

[0094] In a given embodiment, Y2'' is a C1-C4 alkyl group, for example, -CH3.

[0095] In a given embodiment, Y2 is an alkyl group.

[0096] In a given embodiment, Y2 is a C1-C4 alkyl group, for example, -CH3 or -CH2CH3. In a given embodiment, Y2 is a hydroxyalkyl group. In a given embodiment, Y2 is a (C1-C4 alkyl)-OH group, for example, -CH2OH, -CH2CH2OH, or -CH2CH2CH2OH.

[0097] In one embodiment, Y3 is -H. In another embodiment, Y3 is a hydroxyalkyl group.

[0098] In a given embodiment, Y3 is a (C1-C4 alkyl)-OH group, for example, -CH2OH.

[0099] In a given embodiment, Y3 is a halogen.

[0100] In a given embodiment, Y3 is -F.

[0101] In a predetermined embodiment, [ka] A compound having a structure selected from the above.

[0102] In a predetermined embodiment, [ka] A compound having a structure selected from the above.

[0103] In a given embodiment, L1 is alkyl; X1 and X2 are independently selected from H and cyclopropyl; however, neither X1 nor X2 is H; Y1 is optionally substituted indolyl; Y2 is NH(Y2'); Y2' is alkyl; Y3 is H or halogen or a pharmaceutically acceptable salt thereof.

[0104] In a given embodiment, L1 is alkyl; X1 and X2 are independently selected from H and cyclopropyl; however, X1 and X2 are H and not both; Y1 is optionally substituted indolyl; Y2 is alkyl; Y3 is H or halogen or a pharmaceutically acceptable salt thereof.

[0105] In a given embodiment, Y1 is a replaced indrill.

[0106] In a given embodiment, Y3 is a halogen.

[0107] In a given embodiment, Y3 is -F.

[0108] Exemplary compounds of formula (I): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0109] Exemplary compounds of additional formula (I): [ka] or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound is an atropisomer. Furthermore, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen is replaced with deuterium or tritium, or carbon is replaced with 13 C or 14 Compounds produced by replacing carbon with C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes for biological assays, or therapeutic agents according to the present invention. For example, the variable R 1 In this case, (C1-C4)alkyl or -O-(C1-C4)alkyl can be appropriately deuterated (e.g., -CD3, -OCD3).

[0111] Any of the compounds of the present invention can also be radiolabeled for the preparation of radiopharmaceuticals.

[0112] Treatment method One aspect of the present invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal levels of amino acids by regulating SLC6A19 transport.

[0113] Another aspect of the present invention relates to a method for modulating SLC6A19 transport in a subject that requires such modification, comprising administering an effective amount of a compound of formula (I) to the subject.

[0114] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder related to a gene defect in phenylalanine hydroxylase in a subject that requires such treatment or prevention, the method comprising administering an effective amount of a compound of formula (I) to the subject.

[0115] In some embodiments, the present invention relates to a method for treating or preventing phenylketonuria in a subject requiring treatment or prevention, comprising administering an effective amount of a compound of formula (I) to the subject.

[0116] In some embodiments, the present invention relates to a method for treating or preventing hyperphenylalaninemia in a subject requiring treatment or prevention, comprising administering an effective amount of a compound of formula (I) to the subject.

[0117] In some embodiments, the compound reduces systemic phenylalanine levels in the subject.

[0118] In some embodiments, the present invention relates to a method for treating or preventing tyrosinemia (type I, II, or III) in a subject requiring treatment or prevention, comprising administering an effective amount of a compound of formula (I) to the subject.

[0119] In some embodiments, the compound reduces systemic glycine levels in the subject.

[0120] In some embodiments, the present invention relates to a method for treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia in subjects requiring treatment or prevention, comprising administering an effective amount of a compound of formula (I) to the subject.

[0121] In some embodiments of any one of the disclosed methods, the compound modulates SLC6A19 in the subject.

[0122] In some embodiments of any one of the disclosed methods, the compound inhibits SLC6A19 in the subject.

[0123] In some embodiments of any one of the disclosed methods, the compound modulates SLC6A19 transport in the subject.

[0124] In some embodiments of any one of the disclosed methods, the compound inhibits SLC6A19 transport in the subject.

[0125] In some embodiments, the compound reduces the concentration of amino acids in the target body.

[0126] In some embodiments of any one of the disclosed methods, the subject is a mammal. In some embodiments of any one of the disclosed methods, the mammal is a human.

[0127] Pharmaceutical composition, route of administration, and drug administration In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0128] In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent other than the compound of the present invention.

[0129] The pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutically active agents.

[0130] As stated above, “effective dose” refers to any amount sufficient to achieve the desired biological effect. By combining the teachings provided herein and selecting from a variety of active compounds, and by weighting factors such as potential, relative bioavailability, patient weight, severity of adverse side effects, and method of administration, an effective preventive or therapeutic regimen can be planned that is effective in treating a particular target without causing substantially undesirable toxicity. The effective dose for any particular use may vary depending on factors such as the disease or condition being treated, the specific compound of the present invention administered, the size of the target, or the severity of the disease or condition. Those skilled in the art can experimentally determine the effective dose of a specific compound of the present invention, and / or other therapeutic agents, without requiring excessive experimentation. A maximum dose, i.e., the maximum safe dose according to some medical judgment, can be used. Multiple daily administrations may be planned to achieve an appropriate systemic dose of the compound. For example, an appropriate systemic dose can be determined by measuring the patient’s peak or sustained plasma concentration of the drug. “Dose” and “administered dose” are used interchangeably herein.

[0131] In certain embodiments, intravenous administration of the compound may typically be 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be 1 mg / kg / day to 10 mg / kg / day.

[0132] Generally, the daily oral dose of the compound in human subjects ranges from approximately 0.01 mg / kg to 1000 mg / kg per day. Oral doses in the range of 0.5 to 50 mg / kg, administered once or more times per day, are expected to produce a therapeutic effect. Dosages can be appropriately adjusted to achieve the desired local or systemic drug concentration, depending on the mode of administration. For example, with intravenous administration, the daily dose is expected to be one to several orders of magnitude smaller. If the response in the subject is insufficient at such doses, higher doses (or effective higher doses via a different, more localized delivery route) may be employed up to a level acceptable to the patient's tolerance. Multiple daily doses are intended to achieve an appropriate intracellular concentration of the compound.

[0133] For any of the compounds described herein, the therapeutically effective dose can initially be determined from animal models. Alternatively, the therapeutically effective dose can be determined from human data for compounds tested in humans and human data for compounds known to exhibit similar pharmacological activity, such as other relevant activators. Higher doses may be required for parenteral administration. The applicable dose can be adjusted according to the relative bioavailability and potency of the compound administered. Adjusting the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art is well within the capabilities of those skilled in the art.

[0134] The formulations of the present invention can be administered in a pharmaceutically acceptable solution, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, suitable carriers, adjuvants, and optionally other therapeutic components.

[0135] In therapeutic use, the compound can be administered to a target in an effective amount by any means of delivering the compound to the desired surface. Administration of the pharmaceutical composition can be carried out by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into tumors or abscesses), mucosal (e.g., topical to the eyes), inhalation, and topical administration.

[0136] For intravenous and other parenteral administration methods, the compounds of the present invention can be formulated as lyophilized preparations, as lyophilized preparations of active compounds intercalated or encapsulated in liposomes, as lipid complexes in aqueous suspensions, or as salt complexes. The lyophilized preparations are generally reconstituted immediately before administration with a suitable aqueous solution, such as sterile water or physiological saline.

[0137] For oral administration, the compounds can be readily formulated by combining the active compound(s) with a pharmaceutically acceptable carrier well known in the art. With such carriers, the compounds of the present invention can be formulated as tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by the subject being treated. Pharmaceutical preparations for oral use can be obtained as solid excipients, and optionally, the resulting mixture can be pulverized, and after the addition of suitable adjuvants as desired, the granular mixture can be processed to obtain tablets or sugar-coated cores. Suitable excipients include, in particular, fillers, such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added. Optionally, the oral formulation may also be formulated with physiological saline or a buffer, such as EDTA to neutralize acidic conditions in the body, or it may be administered without any carrier.

[0138] Furthermore, the specific target is an oral dosage form of the above-mentioned components(s). One or more components may be chemically modified to facilitate oral delivery of their derivatives. Generally, the intended chemical modification involves attaching at least one moiety to the component molecule itself, which (a) inhibits hydrolysis and (b) enables uptake from the stomach or intestines into the bloodstream. It is also desirable to increase the overall stability of one or more components and lengthen their circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp.367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-trioxocan. For pharmaceutical applications, the polyethylene glycol portion is suitable, as shown above.

[0139] The release site for the component (or derivative) may be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art can obtain formulations that do not dissolve in the stomach but release the substance in the duodenum or other part of the intestine. Preferably, the release avoids adverse effects in the gastric environment by either protecting the compound (or derivative) of the present invention or releasing the biologically active substance in the intestines or elsewhere after passing through the gastric environment.

[0140] To ensure complete gastric tolerance, a coating that is impermeable to at least pH 5.0 is essential. Examples of more common inert ingredients used as enteric coatings include cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used as mixed films.

[0141] Coatings or coating mixtures can also be used for tablets that are not intended to protect from the stomach. These may include sugar coatings or coatings that make tablets easier to swallow. Capsules may consist of a hard shell (such as gelatin) for the delivery of dry therapeutic agents (e.g., powders), while soft gelatin shells may be used for liquid forms. The shell material for cachets may be thick starch or other food paper. For pills, lozenges, molded tablets, or powder tablets, wet agglomeration techniques may be used.

[0142] The therapeutic agent can be incorporated into the formulation as fine multiparticles in the form of granules or pellets with a particle size of approximately 1 mm. Formulations of the material for capsule administration can also be in the form of powder, lightly compressed plugs, or tablets. The therapeutic agent can be prepared by compression.

[0143] The present invention may include both colorants and flavoring agents. For example, the compound (or derivative) of the present invention may be formulated (e.g., encapsulated in liposomes or microspheres) and then further incorporated into an edible product such as a refrigerated beverage containing colorants and flavoring agents.

[0144] The volume of therapeutic agents can be diluted or increased using inert materials. These diluents may include carbohydrates, particularly mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts can be used as fillers and include calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents include Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0145] The disintegrant may be included in the formulation of the therapeutic agent of the present invention to form a solid dosage form. Materials used as disintegrants include, but are not limited to, starch, and commercially available starch-based disintegrants such as Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, carboxymethylcellulose acid, sponge, and bentonite may be used. Another form of disintegrant is an insoluble cationic exchange resin. Powdered rubber can be used as a binder and may include powdered gums such as agar, karaya, or tragacanth. Alginic acid and its sodium salts are also useful as disintegrants.

[0146] The therapeutic agents may be bound together with a binder to form a hard tablet, and examples of such binders include natural products such as acacia, tragacanth, starch, and gelatin. Other examples include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Both polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) can be used in an alcoholic solution to granulate the therapeutic agents of the present invention.

[0147] To prevent sticking during the formulation process, antifriction agents may be included in the formulation of the therapeutic agent. Lubricants can be used as a layer between the therapeutic agent and the die wall and include, but are not limited to, stearic acid containing magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, and Carbowax 4000 and 6000 can also be used.

[0148] A flow enhancer may be added to improve the fluidity of the drug during formulation and to assist in rearrangement during compression. The flow enhancer may include starch, talc, pyrogenic silica, and hydrated aluminum silicate.

[0149] To aid in the dissolution of the therapeutic agent in an aqueous environment, surfactants may be added as wetting agents. Surfactants may include anionic surfactants such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic surfactants may also be used, including benzalkonium chloride and benzethonium chloride. Potential nonionic surfactants that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present in the formulation of the compounds or derivatives of the present invention, either alone or in mixtures of different proportions.

[0150] Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin, and soft, sealable capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All oral formulations must be in a dose suitable for such administration.

[0151] For oral administration, the composition may take the form of tablets or lozenges formulated using conventional methods.

[0152] For topical administration, the compound may be formulated as a solution, gel, ointment, cream, suspension, etc., as is well known in the art. Systemic formulations include formulations designed for administration by injection, such as subcutaneous injection, intravenous injection, intramuscular injection, intrathecal injection, or intraperitoneal injection, and formulations designed for transdermal administration, transmucosal administration, oral administration, or pulmonary administration.

[0153] The compounds for use according to the present invention may also be conveniently delivered for inhalation administration in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit may be determined by providing a valve that delivers a measured amount. For example, gelatin capsules and cartridges for use in inhalers or blowers may be formulated to contain a mixed powder of the compound and a suitable powder base such as lactose or starch.

[0154] Furthermore, the present invention aims at the pulmonary delivery of the compounds (or salts thereof) disclosed herein. The compounds are delivered to the lungs of mammals during inhalation, pass through the lining of the pulmonary epithelium, and reach the bloodstream. Other reports on inhalation molecules include: Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprorelin acetate); Braquet et al., J Cardiovasc Pharmacol 13 (suppl.5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-proteinase); Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery This includes II, Keystone, Colorado, March (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and U.S. Patent No. 5,284,656 by Platz et al. (granulocyte colony-stimulating factor; as incorporated by reference). Methods and compositions for pulmonary delivery of systemically acting drugs are described in U.S. Patent No. 5,451,569 issued to Wong et al. on September 19, 1995 (as incorporated by reference).

[0155] The invention is intended for use in its implementation, but is not limited to, a variety of mechanical devices designed for the lung delivery of therapeutic products, including nebulizers, metered-dose inhalers, and powder inhalers, all of which are well known to those skilled in the art.

[0156] Some specific examples of commercially available devices suitable for carrying out the present invention include the Ultravent nebulizer from Mallinckrodt, Inc., St. Louis, Mo., the Acorn II nebulizer from Marquest Medical Products, Englewood, Col., the Ventolin metered-dose inhaler from Glaxo Inc., Research Triangle Park, North Carolina, and the Spinhaler powder inhaler from Fisons Corp., Bedford, Mass.

[0157] Any such apparatus requires the use of a formulation suitable for dispensing the compounds of the present invention. Typically, each formulation is specific to the type of apparatus employed and may involve the use of appropriate propellant substances in addition to common diluents, adjuvants, and / or carriers useful for the therapeutic treatment. The use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is also considered. Chemically modified compounds of the present invention can be prepared into a variety of formulations depending on the type of chemical modification or the type of apparatus employed.

[0158] Formulations suitable for use in either jet or ultrasonic nebulizers typically contain the compound (or derivative) of the present invention dissolved in water at a concentration of approximately 0.1 to 25 mg per 1 mL of solution. The formulation may also contain a buffer and a simple sugar (e.g., for stabilizing the inhibitor and controlling osmotic pressure). Nebulizer formulations may also contain surfactants to reduce or prevent aggregation induced on the surface of the compound of the present invention, which occurs due to the atomization of the solution when forming an aerosol.

[0159] Formulations used in metered-dose inhalers generally consist of a finely powdered substance containing the compound (or derivative) of the present invention suspended in a propellant with the help of a surfactant. The propellant may be any conventional material employed for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid may also be useful as a surfactant.

[0160] A formulation for distribution administration from a powder inhalation device comprises a finely granulated dry powder containing the compound (or derivative) of the present invention, and may contain an extender such as lactose, sorbitol, sucrose, or mannitol in an amount that facilitates the dispersion of the powder from the device, for example, 50 to 90% by weight of the formulation. The compound (or derivative) of the present invention should be prepared in particle form having an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for the most effective delivery to the deep lungs.

[0161] Nasal delivery of the pharmaceutical composition of the present invention is also intended. Nasal delivery allows the pharmaceutical composition of the present invention to enter the bloodstream directly after the therapeutic product has been administered through the nose, without the product being deposited in the lungs. Nasal delivery formulations include those containing dextran or cyclodextran.

[0162] For nasal administration, a useful device is a small, rigid bottle fitted with a metered-dose sprayer. In one embodiment, the metered dose is delivered by drawing a solution of the pharmaceutical composition of the present invention into a chamber of a predetermined volume, which has a hole sized to aerosolize the aerosol formulation by forming a spray when the liquid inside the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In one specific embodiment, the chamber is in a piston configuration. Such devices are commercially available.

[0163] Alternatively, it is a plastic squeeze bottle with a hole or opening sized to aerosolize an aerosol formulation by forming a spray when squeezed. The opening is usually located at the top of the bottle, and the top is generally tapered to partially fit through the nasal passage for efficient administration of the aerosol formulation. Preferably, the nasal inhaler provides a measured amount of the aerosol formulation for administering a measured amount of drug.

[0164] The compound may be formulated for parenteral administration by injection, such as bolus injection or continuous infusion, when systemic delivery is desired. The injectable formulation may be provided in unit dosage forms with added preservatives, for example, in ampoules or multi-dose containers. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers and / or dispersants.

[0165] Pharmaceutical formulations for parenteral administration contain aqueous solutions of the active compound in a water-soluble form. Furthermore, suspensions of the active compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solutions or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. 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 increase the solubility of the compound to enable the preparation of high-concentration solutions.

[0166] Alternatively, the active compound may be in powder form for preparation with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0167] The compound may be formulated into a rectal or vaginal composition, such as a conventional suppository base, such as a suppository or retaining enema containing cocoa butter or other glycerides.

[0168] In addition to the above preparations, the compound may be formulated as a depot preparation. Such long-acting preparations can be formulated using suitable polymers or hydrophobic substances (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, e.g., as poorly soluble salts.

[0169] The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0170] Suitable liquid or solid pharmaceutical dosage forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, volute-shaped, coated on microscopic gold particles, contained in liposomes, atomized, aerosolized, pellets for implantation into the skin, or dried on a sharp object for rubbing on the skin. The pharmaceutical composition also includes granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or sustained-release preparations of the active compound, and for their preparation, excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are customarily used as described above. The pharmaceutical composition is suitable for use in various drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249:1527-33 (1990).

[0171] The compounds of the present invention, and optionally other therapeutic agents, may be administered straight or in the form of pharmaceutically acceptable salts or cocrystals. When used pharmacopoeia, the salts or cocrystals must be pharmaceutically acceptable, but pharmaceutically acceptable salts or cocrystals can be prepared by conveniently using pharmaceutically unacceptable salts or cocrystals. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts may also be prepared as alkali metal salts or alkaline earth metal salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0172] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0173] The pharmaceutical compositions of the present invention include compounds as described herein and optionally a therapeutic agent contained in an effective amount in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulants suitable for administration to humans or other vertebrates. The term "carrier" means natural or synthetic, organic or inorganic components that facilitate application in combination with the active ingredient. The components of the pharmaceutical compositions may also be mixed with the compounds of the present invention, or mixed with each other, in a manner that does not substantially impair the desired pharmaceutical effect.

[0174] Therapeutic agents (plural) (specifically, the compounds of the present invention, but not limited to them) may be provided in the form of particles. As used herein, particles mean nanoparticles or microparticles (or, in some cases, larger particles) that may constitute all or part of the compounds of the present invention or other therapeutic agents (plural) described herein. The particles may contain the therapeutic agent (plural) in a core surrounded by a coating, including but not limited to an enteric coating. The therapeutic agent (plural) may also be dispersed throughout the particles. The therapeutic agent (plural) may also be adsorbed onto the particles. The particles may have release rates in any order, including zero-order release, primary release, secondary release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent (plural), the particles may contain, but not limited to, any substances commonly used in the pharmaceutical and medical arts, including disintegrating, non-disintegrating, biodegradable, or non-biodegradable substances or combinations thereof. The particles may be microcapsules containing the compounds of the present invention in solution or semi-solid form. The particles can be virtually any shape.

[0175] Both non-biodegradable and biodegradable polymer materials can be used to manufacture particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic. The polymer is selected based on the desired release period. Of particular interest among bioadhesive polymers are the biodegradable hydrogels described by Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydride, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0176] The therapeutic agent(s) may be included in a controlled-release system. The term “controlled-release” is intended to refer to any drug-containing formulation in which the mode and profile of drug release from the formulation are controlled. This includes immediate-release and non-immediate-release formulations, and non-immediate-release formulations include, but are not limited to, sustained-release and delayed-release formulations. The term “sustained-release” (also called “long-release”) is used in its conventional sense to refer to a drug formulation that results in sustained release of the drug over a long period, preferably, but not necessarily, resulting in substantially constant drug blood concentrations over a long period. The term “delayed-release” is used in its conventional sense to refer to a drug formulation in which there is a time lag between the administration of the formulation and the release of the drug from the formulation. “Delayed-release” may or may not involve sustained release of the drug over a long period, and therefore may or may not be “sustained-release.”

[0177] For the treatment of chronic conditions, the use of long-term sustained-release implants may be particularly appropriate. “Long-term” release, as used herein, means that the implant is configured and positioned to deliver therapeutic concentrations of the active ingredient for at least 7 days, preferably 30 to 60 days. Long-term sustained-release implants are well known to those skilled in the art and include some of the release systems described above.

[0178] Other suitable changes and modifications to the compositions and methods described herein are readily apparent from the description of the invention contained herein, in light of information known to those skilled in the art, and may be made without departing from the scope of the invention or any of its embodiments, as will be understood by those skilled in the art in the relevant field. Although the invention has been described in detail herein, it will be understood more clearly by referring to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the invention. [Examples]

[0179] The present invention is further described in the following embodiments, but this does not limit the scope of the invention as described in the claims.

[0180] Example 1: SLC6A19 Isoleucine Transport Assay Cell line generation and maintenance The Flp-In®T-REx®293 cell line was purchased from Thermo Fisher Scientific. Using this cell line, a stable cell line was constructed that inductively expresses human SLC6A19 with a V5 tag at the C-terminus and stably expresses human TMEM27 (also known as Collectrin) with a myc-DDK tag at the C-terminus. The stable cell line was constructed by transfecting plasmids encoding SLC6A19 and TMEM27 using a standard protocol, followed by antibiotic selection. Stable cells were maintained in DMEM / F12 supplemented with Glutamax, 10% fetal bovine serum, 100 U / mL penicillin, 100 ug / mL streptomycin, 200 ug / mL hygromycin, 10 ug / mL blastosidine, and 300 ug / mL neomycin (Thermo Fisher).

[0181] Assay: Isoleucine transport assay in 96-well format On day 0, stable cell lines were seeded at a density of 35,000 cells / well into 96-well cell culture-treated plates coated with poly-D-lysine. On day 1, SLC6A19 expression was induced by dispensing tetracycline at a final concentration of 1 ug / mL using a Tecan D300e digital dispenser. On day 2, a transport assay was performed. The medium was removed from the plates using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio), and the cells were washed with 175 uL of live cell imaging solution (Thermo Fisher) using the Blue Washer. After washing, the cells were treated at room temperature with either 70 uL of DMSO diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, 11 mM HEPES, 10 mM glucose, pH 7.4), a positive control, or a compound. 20-60 minutes later, 13 C6, 1530 μL of a 3.3 mM solution of NL-isoleucine (Cambridge Isotope Laboratories) was added. After incubation with the isoleucine substrate at room temperature for 20 minutes, the cells were washed with 175 μL of live cell imaging solution using a Blue Washer. The cells were then lysed with 150 μL of 15 μM D-Leucine-d10 (CDN Isotopes) in ultrapure water. To promote lysis, the plate was shaken at 700 rpm for at least 40 minutes. After lysis, the standard dilution curve of 13C6,15N-L-isoleucine was added to the wells containing the lysates of untreated cells. To ensure proper mixing of the standard curve, the plate was returned to the shaker for at least 2 minutes. The plate was then centrifuged at 4,000 rpm for 5 minutes to pellet the cell debris and precipitate. The supernatant was diluted 1:10 with acetonitrile + 0.1% formic acid in a polypropylene plate.

[0182] Assay: Isoleucine transport assay in 384-well format On day 0, stable cell lines were seeded at a density of 20,000 cells / well using a Viaflo 384-well pipette into poly-D-lysine coated 384-well cell culture-treated plates containing medium with 1 ug / mL of tetracycline. The transport assay was performed the following day (day 1). The medium was removed from the plates using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio), and the cells were washed with 80 μL of live cell imaging solution (Thermo Fisher) using the Blue Washer. After washing, the cells were treated with either 20 μL of DMSO diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, 11 mM HEPES, 10 mM glucose, pH 7.4), a positive control, or a compound, using a TECAN liquid handler. After incubation at room temperature for 20–60 minutes, 8.6 μL of 3.3 mM solution of 13C6,15N-L-isoleucine (Cambridge Isotope Laboratories) was added. After incubation with the isoleucine substrate at room temperature for 20 minutes, the cells were washed with 80 μL of live cell imaging solution using a Blue Washer. The cells were then lysed with 80 μL of 15 μM D-Leucine-d10 (CDN Isotopes) in ultrapure water. To promote lysis, the plate was shaken at 700 rpm for at least 2 hours. After lysis, the standard dilution curve of 13C6,15N-L-isoleucine was added to the wells containing the lysate of untreated cells. To ensure proper mixing of the standard curve, the plate was returned to the shaker for at least 5 minutes. The plate was then centrifuged at 4,000 rpm for 10 minutes to pelletize the cell debris and precipitate. The supernatant was diluted 1:10 with acetonitrile + 0.1% formic acid on a polypropylene plate.

[0183] Using RapidFire365-QTOF 6545 (Agilent), 13 C6, 15N-L-isoleucine analysis was performed. For quantitative sample analysis, after using automated solid-phase extraction (HILIC H6 cartridge), mass spectrometry injection was carried out. The sample was loaded using 95% acetonitrile and 0.1% formic acid, directly eluted from the cartridge using 5% acetonitrile and 0.1% formic acid, and ESI-MS (electrospray ionization) analysis was performed. The quantification of the analyte was carried out using Agilent Masshunter Quant software from high-resolution full scan data.

[0184] Example 2: Synthesis of exemplary compounds Synthesis of common intermediate Synthesis of A12

Chemical formula

[0185] Step 2: Synthesis of A3 NaHCO3 (76 g, 904.7 mmol) and Boc2O (66.4 g, 304.2 mmol) were added to a solution of A2 (50 g, 248.5 mmol) in DCM (500 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (500 mL) and extracted with DCM (500 mL×2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified via flash column chromatography (eluted with 0 - 15% EtOAc in PE) to obtain cis isomer A3 (24.0 g, 32% yield) as a white solid (LC / MS (ESI) m / z: 246 (M+H - 56) + . 1¹H NMR (400 MHz, CDCl3) δ 4.35 (br s, 2H), 3.69 (s, 6H), 2.88 - 2.36 (m, 6H), 1.45 (s, 9H)); and the trans isomer (9.1 g, 12% yield) was obtained as a colorless oil (LC / MS(ESI) m / z: 246(M+H-56) + . 1 H NMR (400 MHz, CDCl3) δ 3.82 - 3.70 (m, 2H), 3.68 (s, 6H), 3.60 - 3.42 (m, 2H), 2.85 - 2.77 (m, 2H), 2.15 - 1.96 (m, 2H), 1.44 (s, 9H)) got it.

[0186] Step 3: Synthesis of A4 A solution of A3 (24 g, 79.6 mmol) in MeOH (240 mL) was mixed with 2 M NaOH (42 mL, 84.0 mmol, aqueous) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (250 mL) and extracted with ethyl acetate (250 mL). The aqueous layer was adjusted to pH=4 with HCl (1 M) and then extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 0-70% ethyl acetate in PE) to obtain A4 (16 g, 70% yield) as a white solid. LC / MS (ESI) m / z: 232 (M+H-56) + .

[0187] Step 4: Synthesis of A5 To a solution of A4 (16 g, 55.7 mmol) in toluene (160 mL), DPPA (18.4 g, 66.8 mmol) and TEA (6.8 g, 66.8 mmol) were added at 0°C. The resulting mixture was stirred at 110°C for 2 hours under an N2 atmosphere. Then, BnOH (30.1 g, 278.5 mmol) and TEA (6.8 g, 66.8 mmol) were added to the above mixture at 0°C. The resulting mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was diluted with water (250 mL) and extracted with SiO2 (250 mL x 2). The combined organic layer was washed with brine (250 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-40% SiO2 in PE) to obtain A5 (12.8 g, 59% yield) as a white solid. LC / MS(ESI)m / z:293(M+H-100) + .

[0188] Step 5: Synthesis of A6 To a solution of A5 (12.8 g, 32.6 mmol) in EtOH (150 mL), NaBH4 (3.0 g, 81.5 mmol) was added in portions at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then quenched with water (200 mL) and extracted with siRNA (200 mL x 2). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-60% siRNA in PE) to obtain A6 (10.2 g, 28.0 mmol) as a white solid. LC / MS (ESI) m / z: 265 (M + H - 100) + .

[0189] Step 6: Synthesis of A7 Pd / C (1.0 g, 10 wt%) was added to a solution of A6 (10.0 g, 27.5 mmol) in i-PrOH (150 mL) under a nitrogen atmosphere at room temperature. The suspension was degassed under vacuum and purged several times with H2. The resulting mixture was stirred under an H2 atmosphere at room temperature for 18 hours. The mixture was then filtered through a Celite® pad, and the filter cake was washed with MeOH (100 mL). The combined filtrate was concentrated to dry to obtain crude A7 (6.1 g, 97% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 231 (M+H) + .

[0190] Step 7: Synthesis of A8 To a solution of A7 (2.4 g, 10.4 mmol) in DCM (50 mL), AcOH (1.2 g, 20.8 mmol) and 2,4-dimethoxybenzaldehyde (8.9 g, 71.5 mmol) were added at room temperature. The resulting mixture was stirred under an N2 atmosphere for 1 hour. Then, NaBH(OAc)3 (2.65 g, 12.48 mmol) was added to the mixture in portions at 0°C, and the resulting mixture was stirred under an N2 atmosphere at room temperature for 3 hours. The mixture was then filtered and rinsed with DCM (50 mL x 2). The filtrate was diluted with water (70 mL) and extracted with DCM (40 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 5-10% MeOH in DCM) to obtain A8 (2.7 g, 68% yield) as a pale yellow oil. LC / MS(ESI)m / z:381(M+H) + .

[0191] Step 8: Synthesis of A9 To a solution of A8 (2.7 g, 7.1 mmol) in THF / EtOH (60 mL, v / v=2:1), AcOH (4.3 g, 71 mmol), (1-ethoxycyclopropoxy)trimethylsilane (2.5 g, 14.2 mmol), and NaBH3CN (1.3 g, 21.3 mmol) were added. The resulting mixture was stirred at 80°C for 4 hours under an N2 atmosphere. The mixture was then neutralized with NaHCO3 (aqueous solution) until the pH was adjusted to H=8. The mixture was diluted with water (80 mL) and extracted with SiO2 (70 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 5-10% MeOH in DCM) to obtain A9 (2.0 g, 67% yield) as a colorless oil. LC / MS(ESI)m / z:421(M+H) + .

[0192] Step 9: Synthesis of A10 To a solution of A9 (2.0 g, 4.8 mmol) in DCM (20 mL), TFA (4 mL) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and neutralized with NaHCO3 (aqueous solution) until the pH was adjusted to pH=8. The mixture was then extracted with DCM (40 mL x 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 10-15% MeOH in DCM) to obtain A10 (1.3 g, 86% yield) as a pale yellow oil. LC / MS (ESI) m / z: 321 (M+H) + .

[0193] Step 10: Synthesis of A11 To a solution of A10 (1.3 g, 4.1 mmol) in DCM (20 mL), TEA (1.2 g, 8.2 mmol) and 2,5-dioxopyrrolidine-1-ylmethylcarbamate (0.8 g, 4.9 mmol) were added at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 12 hours. The mixture was then diluted with water (30 mL) and extracted with DCM (15 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 10-15% MeOH in DCM) to obtain A11 (1.2 g, 80% yield) as a colorless oil. LC / MS (ESI) m / z: 378 (M+H) + .

[0194] Step 11: Synthesis of A12 To a solution of A11 (1.2 g, 3.2 mmol) in DCM (20 mL), TFA (5 mL) was added dropwise at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (30 mL) and neutralized with NaHCO3 (aqueous solution) until the pH was adjusted to pH=8. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 25-30% MeOH in DCM) to obtain A12 (0.6 g, 83% yield) as a pale yellow oil. LC / MS (ESI) m / z: 228 (M+H) + .

[0195] B7 synthesis [ka] Step 1: Synthesis of B1 To a solution of A7 (6.1 g, 26.5 mmol) in DCM (100 mL), TEA (4.0 g, 40.0 mmol) and NsCl (6.4 g, 29.1 mmol) were added at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 5-10% MeOH in DCM) to obtain B1 (6.5 g, 59% yield) as a white solid. LC / MS (ESI) m / z: 360 (M+H-56) + .

[0196] Step 2: Synthesis of B2 A mixture of B1 (6.5 g, 15.7 mmol) and K2CO3 (4.3 g, 31.4 mmol) in DMF (100 mL) was partially added with allyl bromide (3.8 g, 31.4 mmol) at 0°C. The resulting mixture was stirred at room temperature under an N2 atmosphere for 18 hours. The mixture was then filtered and rinsed with DCM (50 mL x 2). The filtrate was diluted with water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain B2 (6.5 g, 91% yield) as a yellow oil. LC / MS (ESI) m / z: 400 (M+H-56) + .

[0197] Step 3: Synthesis of B3 To a solution of B2 (6.5 g, 14.3 mmol) in MeCN (120 mL), K2CO3 (9.9 g, 71.5 mmol) and thiophenol (8.9 g, 71.5 mmol) were added. The resulting mixture was stirred at 80°C for 18 hours under an N2 atmosphere. The mixture was then diluted with water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 5-10% MeOH in DCM) to obtain B3 (3.1 g, 83% yield) as a pale yellow oil. LC / MS (ESI) m / z: 271 (M+H) + .

[0198] Step 4: Synthesis of B4 A mixture of B3 (3.1 g, 11.5 mmol), (1-ethoxycyclopropoxy)trimethylsilane (4.0 g, 23.0 mmol), AcOH (6.9 g, 115 mmol), and NaBH3CN (2.2 g, 34.5 mmol) in a THF / EtOH solution (90 mL, V / V=2:1) ​​was stirred at 80°C for 4 hours under an N2 atmosphere. The mixture was then neutralized with NaHCO3 (saturated aqueous solution) until the pH was adjusted to H=8. The mixture was diluted with water (60 mL) and extracted with SiO2 (40 mL x 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 5-10% MeOH in DCM) to obtain B4 (3.2 g, 90% yield) as a colorless oil. LC / MS(ESI)m / z:311(M+H) + .

[0199] Step 5: Synthesis of B5 To a solution of B4 (1.0 g, 3.2 mmol) in DCM (12 mL), TFA (3 mL) was added in portions at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure until dry. The residue was diluted with water (20 mL), neutralized with NaHCO3 (saturated aqueous solution) until pH=8, and then extracted with DCM (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 20-30% MeOH in DCM) to obtain B5 (0.62 g, 92% yield) as a pale yellow oil. LC / MS (ESI) m / z: 211 (M+H) + .

[0200] Step 6: Synthesis of B6 A mixture of B5 (200 mg, 0.95 mmol) and TEA (144 mg, 1.4 mmol) in dry DCM (12 mL) was added dropwise with methyl chloroformate (89 mg, 0.95 mmol) at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (20 mL) and extracted with DCM (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 10-15% MeOH in DCM) to obtain B6 (140 mg, 55% yield) as a colorless oil. LC / MS (ESI) m / z: 269 (M+H) + .

[0201] Step 7: Synthesis of B7 To a solution of B6 (140 mg, 0.52 mmol) in DCM (8 mL), Pd(PPh3)4 (57 mg, 0.05 mmol) and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (162 mg, 1.04 mmol) were added at 0°C under an N2 atmosphere. The resulting mixture was warmed to room temperature and stirred for 50 minutes. The mixture was then diluted with water (30 mL) and extracted with DCM (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 20-25% MeOH in DCM) to obtain B7 (107 mg, 90% yield) as a brown oil. LC / MS (ESI) m / z: 229 (M+H) + .

[0202] C4 synthesis [ka] Step 1: Synthesis of C2 To a solution of C1 (7.0 g, 34.9 mmol) in DCM (140 mL), 2,4-dimethoxybenzene-1-carbaldehyde (5.8 g, 34.9 mmol) and HOAc (5.9 mL, 104.8 mmol) were added at room temperature under an N2 atmosphere. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (22.1 g, 104.8 mmol) was added to the mixture in portions, and the resulting mixture was stirred at room temperature for a further 6 hours. The mixture was then quenched with H2O (150 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain C2 (7.3 g, 60% yield) as a yellow oil. LC / MS(ESI)m / z:351(M+H) + .

[0203] Step 2: Synthesis of C3 To a mixture of C2 (7.3 g, 20.8 mmol) in THF (200 mL) and EtOH (50 mL), acetic acid (17.9 mL, 312 mmol), (1-ethoxycyclopropoxy)trimethylsilane (12.5 mL, 62.4 mmol), and sodium cyanoborohydride (3.2 g, 52.0 mmol) were added at room temperature under an N2 atmosphere. The resulting mixture was stirred at 80°C for 8 hours. The mixture was then concentrated under reduced pressure, the residue was diluted with H2O (160 mL), and extracted with ELISA (100 mL × 2). The combined organic layer was washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-5% MeOH in DCM) to obtain C3 (6.7 g, 82% yield) as a yellow oil. LC / MS(ESI)m / z:391(M+H) + .

[0204] Step 3: Synthesis of C4 To a solution of C3 (6.7 g, 17.1 mmol) in DCM (50 mL), TFA (8 mL) was added dropwise at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure until dry. The residue was redissolved in DCM (50 mL), neutralized with NaHCO3 (saturated aqueous solution) until the pH was adjusted to pH=8, then diluted with H2O (150 mL) and extracted with DCM (120 mL x 2). The combined organic layer was washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain C4 (4.5 g, 91% yield) as a yellow oil. LC / MS (ESI) m / z: 291 (M+H) + .

[0205] D2 Synthesis [ka] Step 1: Synthesis of D1 A mixture of C4 (4.5 g, 15.5 mmol) and TEA (2.1 mL, 15.5 mmol) in DCM (100 mL) was added dropwise with 2,5-dioxopyrrolidine-1-ylmethylcarbamate (3.2 g, 18.6 mmol) at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with H2O (80 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain D1 (3.4 g, 63%) as a white solid. LC / MS (ESI) m / z: 348 (M+H) + .

[0206] Step 2: Synthesis of D2 A solution of D1 (3.4 g, 9.7 mmol) in TFA (50 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. After completion, the resulting mixture was concentrated under reduced pressure until dry. The residue was dissolved in DCM (30 mL) and neutralized with NaHCO3 (saturated aqueous solution) until the pH was adjusted to pH=8. The resulting mixture was diluted with H2O (70 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain D2 (1.7 g, 89% yield) as a colorless oil. LC / MS (ESI) m / z: 198 (M+H) + .

[0207] E2 synthesis [ka] Step 1: Synthesis of E1 A mixture of C4 (2 g, 6.8 mmol) and TEA (2.8 mL, 20.6 mmol) in dry THF (40 mL) was mixed with TMSNCO (0.75 g, 7.5 mmol) at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with H2O (50 mL) and extracted with ₹ (30 mL × 2). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain E1 (1.76 g, 77%) as a white solid. LC / MS (ESI) m / z: 334 (M+H) + .

[0208] Step 2: Synthesis of E2 A solution of E1 (1.76 g, 5.2 mmol) in TFA (40 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. After completion, the resulting mixture was concentrated under reduced pressure until dry. The residue was dissolved in DCM (30 mL) and neutralized with NaHCO3 (aqueous, saturated) until the pH was adjusted to pH=8. The resulting mixture was diluted with H2O (70 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain E2 (823 mg, 85% yield) as a colorless oil. LC / MS (ESI) m / z: 184 (M+H) + .

[0209] F2 synthesis [ka] Step 1: Synthesis of F1 To a solution of C4 (600 mg, 2.06 mmol) in DMSO (12 mL), DIEA (667 mg, 5.17 mmol) and 2,4-dichloropyrimidine (367 mg, 2.48 mmol) were added at room temperature under an N2 atmosphere. The resulting mixture was stirred at 100°C for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine (60 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 0-10% ethyl acetate in PE) to obtain F1 (578 mg, 69% yield) as a yellow solid. LC / MS (ESI) m / z: 403 (M+H) + .

[0210] Step 2: Synthesis of F2 A solution of F1 (578 mg, 1.4 mmol) in TFA (10 mL) was stirred at 80°C for 3 hours. The mixture was then concentrated under reduced pressure to obtain crude F2 (351 mg, 96% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 253 (M+H) + .

[0211] G2 synthesis [ka] Step 1: Synthesis of G1 A solution of C4 (400 mg, 1.38 mmol) in dry DCM (12 mL) was mixed with TEA (418 mg, 4.13 mmol) and acetic anhydride (211 mg, 2.07 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 30 minutes. The mixture was then diluted with H2O (30 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product 2 (440 mg, quantitative) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 333 (M+H) + .

[0212] Step 2: Synthesis of G2 G1 (440 mg, 1.32 mmol) and TFA (10 mL) were placed in a round-bottom flask, and the reaction mixture was stirred at 80°C for 4 hours. The mixture was then concentrated under reduced pressure to obtain crude G2 (241 mg, quantitatively determined) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 183 (M+H) + .

[0213] Synthesis of H2 [ka] Step 1: Synthesis of H2 A mixture of C4 (400 mg, 1.4 mmol) and TEA (212 mg, 2.1 mmol) in dry DCM (12 mL) was added dropwise with 2-chloro-2-oxoethyl acetate (231 mg, 1.7 mmol) at 0°C. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The mixture was then quenched with water (20 mL) and extracted with RINKAN (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 0-4% MeOH in DCM) to obtain H1 (414 mg, 77% yield) as a colorless oil. LC / MS (ESI) m / z: 391 (M+H) + .

[0214] Step 2: Synthesis of H2 A solution of H1 (414 mg, 1 mmol) in TFA (10 mL) was stirred at 80°C for 2 hours. The mixture was then concentrated under reduced pressure to obtain crude H2 (234 mg, 92% yield) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 241 (M+H) + .

[0215] Synthesis of Selected Examples Synthesis of Example 1 [ka] Step 1: Synthesis of I2 To a solution of I1 (370 mg, 1.4 mmol) in anhydrous DMF (8 mL), NaH (51 mg, 2.1 mmol) was added in portions at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEMCl (360 mg, 2.1 mmol) was added dropwise at 0°C. The resulting mixture was warmed at room temperature for 4 hours. The mixture was then quenched with saturated NH4Cl (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-6% siRNA in PE) to obtain I2 (410 mg, 73% yield) as a colorless oil.

[0216] Step 2: Synthesis of I3 LiAlH4 (48 mg, 1.2 mmol) was added in portions to a solution of I2 (410 mg, 1.0 mmol) in anhydrous THF (8 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The mixture was then quenched with H2O (0.1 mL), followed by the addition of 15% NaOH (0.1 mL) and H2O (0.3 mL), after which it was filtered and rinsed with RINKAN (20 mL). The filtrate was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-18% RINKAN in PE) to obtain I3 (260 mg, 71% yield) as a colorless oil. LC / MS (ESI) m / z: 346 (M+H) + .

[0217] Step 3: Synthesis of I4 To a solution of I3 (260 mg, 0.7 mmol) in toluene (8 mL), DBU (137 mg, 0.8 mmol) and DPPA (248 mg, 0.8 mmol) were added at 0°C. The resulting mixture was stirred at 110°C for 2 hours under an N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was concentrated under reduced pressure to obtain crude I4 (210 mg, 75% yield) as a yellow oil, which was used directly in the next step without further purification.

[0218] Step 4: Synthesis of I5 To a solution of I4 (210 mg, 0.6 mmol) in THF (5 mL) and H2O (1 mL), PPh3 (223 mg, 0.9 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with H2O (30 mL) and extracted with RINKAN (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-8% MeOH in DCM) to obtain I5 (170 mg, 87% yield) as a pale yellow oil. LC / MS (ESI) m / z: 345 (M+H) + .

[0219] Step 5: Synthesis of I6 Ethylenediamine (177 mg, 2.94 mmol) and TBAF (1 N in THF, 0.73 ml, 1.47 mmol) were added to a solution of I5 (170 mg, 0.49 mmol) in DMF (6 mL). The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The mixture was then diluted with saturated NH4Cl solution (30 mL) and extracted with ₹ (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-6% MeOH in DCM) to obtain I6 (83 mg, 79% yield) as a colorless oil. LC / MS (ESI) m / z: 215 (M+H) + .

[0220] Step 6: Synthesis of I7 / Example 1 To a solution of I6 (83 mg, 0.38 mmol) in anhydrous THF (4 mL), CDI (62 mg, 0.38 mmol) was added under an N2 atmosphere at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The mixture was then concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-6% MeOH in DCM) to obtain acylimidazole (105 mg, 88% yield) as a white solid. LC / MS (ESI) m / z: 309 (M+H) + A solution of acylimidazole (105 mg, 0.34 mmol) in THF (8 mL) was mixed with TEA (0.22 mL, 1.02 mmol) and A12 (77 mg, 0.34 mmol). The resulting mixture was stirred at 60°C for 2 hours. The mixture was then diluted with water (30 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain a white solid (63 mg, 52% yield). LC / MS (ESI) m / z: 468 (M+H) + The product was further separated by SFC (Waters Thar 80 fraction SFC; ChiralPak AD, 250 × 4.6 mm ID 5 μm; AD_MeOH_DEA_40) to provide ent-Example 1 and I7 / Example 1 (19 mg, 30% yield, ee 99%) as white solids. 1H NMR (400 MHz, CD3OD) 1H NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.51-7.48(m, 1H),7.47 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.45 (s, 1H), 4.56 (s, 2H), 4.11 (d, J = 12.7 Hz, 1H), 3.94 (d, J = 11.9 Hz, 1H), 3.75 (dd, J = 9.9, 5.7 Hz, 1H), 3.51 - 3.44 (m, 2H), 3.15 (t, J = 12.0 Hz, 1H), 2.73 (s, 3H), 2.58 - 2.52 (m, 1H), 2.48 - 2.40 (m, 1H), 1.89 (dd, J = 23.7, 11.7 Hz, 2H), 1.81 - 1.69 (m, 1H), 0.96 (dd, J = 6.4, 3.1 Hz, 2H), 0.80 (d, J = 4.0 Hz, 2H). 19 F NMR (377 MHz, CD3OD) δ -61.60 (s).

[0221] Synthesis of Example 2 [ka] Step 1: Synthesis of J2 To a solution of J1 (2 g, 10.5 mmol) in anhydrous THF (60 mL), NaH (634 mg, 15.7 mmol) was added in portions at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEMCl (2.5 g, 15.7 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The mixture was then quenched with saturated NH4Cl (80 mL) and extracted with siRNA (50 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-6% siRNA in PE) to obtain J2 (3.0 g, 90% yield) as a yellow oil.

[0222] Step 2: Synthesis of J3 LiAlH4 (428 mg, 23.2 mmol) was added in portions to a solution of J2 (3.0 g, 19.4 mmol) in anhydrous THF (80 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The mixture was then quenched with H2O (0.5 mL), followed by the addition of 15% NaOH (0.5 mL) and H2O (1.5 mL), after which it was diluted with RINKAN (100 mL) and filtered. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 0-18% RINKAN in PE) to obtain J3 (2.1 g, 80% yield) as a yellow oil. LC / MS(ESI) m / z: 278(M+H) + .

[0223] Step 3: Synthesis of J4 To a solution of J3 (2.1 g, 7.5 mmol) in toluene (50 mL), DBU (1.3 g, 9 mmol) and DPPA (2.5 g, 9 mmol) were added. The resulting mixture was stirred at 110 °C for 2 hours under an N2 atmosphere. The mixture was then diluted with water (80 mL) and extracted with SiO2 (60 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude J4 (1.8 g, 78% yield) as a yellow oil, which was used directly in the next step without further purification.

[0224] Step 4: Synthesis of J5 To a solution of J4 (1.8 g, 5.9 mmol) in THF (30 mL) and H2O (6 mL), PPh3 (1.8 g, 7.0 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with H2O (60 mL) and extracted with SiO2 (40 mL x 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-8% MeOH in DCM) to obtain J5 (1.2 g, 75% yield) as a pale yellow oil. LC / MS (ESI) m / z: 277 (M+H) + .

[0225] Step 5: Synthesis of J6 Ethylenediamine (1.5 g, 25.8 mmol) and TBAF (1 N in THF, 1.3 ml, 12.9 mmol) were added to a solution of J5 (1.2 g, 4.3 mmol) in DMF (30 mL) at 0°C. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The mixture was then diluted with saturated NH4Cl solution (80 mL) and extracted with ₹ (30 mL × 2). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-6% MeOH in DCM) to obtain J6 (608 mg, 95% yield) as a yellow solid. LC / MS (ESI) m / z: 147 (M+H) + .

[0226] Step 6: Synthesis of J7 / Example 2 To a solution of J6 (608 mg, 4.1 mmol) in anhydrous THF (15 mL), CDI (674 mg, 4.1 mmol) was added under an N2 atmosphere at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The mixture was then concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-6% MeOH in DCM) to obtain acylimidazole (762 mg, 76% yield) as a white solid. LC / MS (ESI) m / z: 241 (M+H) +A mixture of B7 (50 mg, 0.22 mmol) and TEA (44 mg, 0.44 mmol) in THF (6 mL) was mixed with purified acylimidazole (53 mg, 0.22 mmol). The resulting mixture was stirred at 60°C for 3 hours under an N2 atmosphere. The mixture was then diluted with water (20 mL) and extracted with  (15 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC to provide the product (34 mg, 39% yield) as a white solid, which was further separated by SFC (Waters Thar 80-part SFC; ChiralPak C-IG, 250 × 30 mm ID 5 μm; AD_MeOH_DEA_40) to obtain the ent-Example 2 (9.0 mg, 26% yield, e99%) ( 1 H NMR (400 MHz, CD3OD) δ 7.49 - 7.39 (m, 1H), 7.35 - 7.22 (m, 1H), 7.11 - 6.99 (m, 1H), 6.98 - 6.90 (m, 1H), 6.28 (s, 1H), 4.50 (s, 2H), 4.22 (d, J = 12.0 Hz, 1H), 4.08 (d, J = 10.8 Hz, 1H), 3.78 - 3.62 (m, 4H), 3.53 - 3.45 (m, 1H), 3.42 (d, J = 6.6 Hz, 1H), 3.25 - 3.13 (m, 1H), 2.56 - 2.32 (m, 2H), 1.95 - 1.80 (m, 2H), 1.78 - 1.66 (m, 1H), 0.99 - 0.89 (m, 2H), 0.79 - 0.71 (m, 2H)); and Example 2 / J7 (10.0 mg, 29% yield, ee 99%) ( 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 7.8 Hz, 1H), 7.38 - 7.24 (m, 1H), 7.12 - 7.01 (m, 1H), 6.99 - 6.93 (m, 1H), 6.29 (s, 1H), 4.51 (s, 2H), 4.23 (d, J = 11.2 Hz, 1H), 4.09 (d, J = 10.0 Hz, 1H), 3.78 - 3.62 (m, 4H), 3.53 - 3.46 (m, 1H), 3.43 (d, J = 6.8 Hz, 1H), 3.25 - 3.13 (m, 1H), 2.56 - 2.31 (m, 2H), 1.95 - 1.83 (m, 2H), 1.78 - 1.66 (m, 1H), 1.00 - 0.90 (m, 2H), 0.80 - 0.70 (m, 2H)) were provided.

[0227] Synthesis of Example 3 [ka] Step 1: Synthesis of K2 SelectFluor (1.85 g, 5.23 mmol) was added at 0°C to a solution of K1 (1.06 g, 4.36 mmol) in MeCN (25 mL), and the resulting mixture was stirred under N2 atmosphere at room temperature for 16 hours. The mixture was then diluted with H2O (50 mL) and extracted with siRNA (30 mL × 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (PE:siRNA = 100:0 to 100:8) to obtain K2 (301 mg, 26% yield) as a white solid. LC / MS (ESI) m / z: 262 (M + H) + .

[0228] Step 2: Synthesis of K3 A solution of K2 (300 mg, 1.15 mmol) in dry THF (10 mL) was mixed with NaH (60 wt%) (69 mg, 1.72 mmol) at 0°C under an N2 atmosphere, and the mixture was stirred at 0°C for 30 minutes. Then, SEMCl (287 mg, 1.72 mmol) was added dropwise to the mixture at 0°C, and the resulting mixture was warmed to room temperature for a further 1 hour. The mixture was then quenched with saturated NH4Cl solution (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude K3 (449 mg, quantitative) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 274 (M-117) + .

[0229] Step 3: Synthesis of K4 LiAlH4 (65 mg, 1.72 mmol) was partially added at 0°C to a solution of K3 (449 mg, 1.15 mmol) in dry THF (10 mL). The resulting mixture was stirred at 0°C under an N2 atmosphere for 1 hour. The mixture was then quenched at 0°C by adding H2O (0.1 mL), 15% NaOH (aqueous solution) (0.1 mL), and H2O (0.3 mL), and the mixture was stirred at room temperature for 30 minutes. The suspension was then filtered and rinsed with siRNA (20 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (PE:siRNA = 100:0 to 100:10) to obtain K4 (260 mg, 62% yield) as a colorless oil. LC / MS (ESI) m / z: 246 (M-117) + .

[0230] Step 4: Synthesis of K5 To a solution of K4 (260 mg, 0.72 mmol) in toluene (8 mL), DBU (131 mg, 0.86 mmol) and DPPA (236 mg, 0.86 mmol) were added, and the resulting mixture was stirred at 100°C for 3 hours under an N2 atmosphere. The mixture was then diluted with H2O (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude K5 (275 mg, quantitative), which was used directly in the next step without further purification.

[0231] Step 5: Synthesis of K6 Pd / C (200 mg, 10 wt%) was added to a solution of K5 (275 mg, 0.71 mmol) in MeOH (10 mL) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged several times with H2. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then filtered through a Celite® pad, and the filter cake was washed with MeOH (10 mL). The combined filtrate was concentrated until dry. The residue was purified by silica gel column chromatography (DCM:MeOH=100:0~100:5) to obtain K6 (184 mg, 72% yield) as a colorless oil. LC / MS(ESI) m / z:346(M-16) + .

[0232] Step 6: Synthesis of K7 To a solution of K6 (184 mg, 0.51 mmol) in THF (8 mL), CDI (99 mg, 0.61 mmol) was added at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. The mixture was then concentrated under reduced pressure to obtain crude acylimidazole (230 mg, quantitative), which was used directly in the next step without further purification. To a solution of D2 (99 mg, 0.50 mmol) in THF (6 mL), TEA (152 mg, 1.50 mmol) and acylimidazole (230 mg, 0.50 mmol) were added. The resulting mixture was stirred at 55°C for 16 hours. The mixture was then diluted with H2O (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:3) to obtain K7 (189 mg, 64% yield) as a colorless oil. LC / MS (ESI) m / z: 586 (M+H) + .

[0233] Step 8: Synthesis of K8 / Example 3 Ethylenediamine (119 mg, 1.987 mmol) and TBAF (1.0 mL, 1 mol / L in THF) were added to a solution of K7 (189 mg, 0.33 mmol) in DMF (5 mL). The resulting mixture was stirred at 80°C for 1 hour. The mixture was then diluted with H2O (20 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC to obtain K8 / Example 3 (37.6 mg, 26% yield) as a white solid. LC / MS (ESI) m / z: 456 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 7.80 (s, 1H), 7.50-7.44 (m, 1H), 7.41-7.35 (m, 1H), 4.58 (s, 2H), 4.02-3.89 (m, 2H), 3.76-3.65 (m, 1H), 3.20-3.10 (m, 1H), 2.73 (s, 3H), 2.71-2.63 (m, 1H), 2.55-2.45 (m, 1H), 2.18-2.06 (m, 1H), 1.97-1.87 (m, 1H), 1.82-1.72 (m, 1H), 1.60-1.44 (m, 1H), 0.98-0.89 (m, 2H), 0.82-0.71 (m, 2H). 19 F NMR (376 MHz, CD3OD) δ -61.96 (s), -179.31 (s).

[0234] Synthesis of Example 4 [ka] Step 1: Synthesis of L2 Select Fluor (1.9 g, 5.4 mmol) was added to a solution of L1 (1 g, 4.5 mmol) in MeCN (30 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred overnight at room temperature. The mixture was then quenched with water (40 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-10% ethyl acetate in PE) to obtain L2 (290 mg, 27% yield) as a white solid. LC / MS (ESI) m / z: 242 (M+H) + .

[0235] Step 2: Synthesis of L3 To a solution of L2 (290 mg, 1.2 mmol) in anhydrous THF (12 mL), NaH (72 mg, 1.8 mmol) was added in portions at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEMCl (300 mg, 1.8 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NH4Cl solution (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude L3 (320 mg, 72% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 372 (M+H) + .

[0236] Step 3: Synthesis of L4 LiAlH4 (48 mg, 1.27 mmol) was added in portions to a solution of L3 (320 mg, 0.86 mmol) in anhydrous THF (10 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then quenched with H2O (10 mL), followed by the addition of 15% NaOH (20 mL) and H2O (10 mL), after which it was filtered and rinsed with THF (20 mL). The filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-15% Â in PE) to obtain L4 (270 mg, 95% yield) as a colorless oil. LC / MS(ESI) m / z: 330(M+H) + .

[0237] Step 4: Synthesis of L5 To a solution of L4 (270 mg, 0.82 mmol) in toluene (10 mL), DBU (129 mg, 0.98 mmol) and DPPA (270 mg, 0.98 mmol) were added. The resulting mixture was stirred at 110°C for 3 hours under an N2 atmosphere. The mixture was then diluted with H2O (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 5 (220 mg, 76% yield) as a yellow oil, which was used directly in the next step without further purification.

[0238] Step 5: Synthesis of L6 To a solution of L5 (220 mg, 0.62 mmol) in THF (8 mL) and H2O (2 mL), PPh3 (325 mg, 1.44 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with H2O (30 mL) and extracted with RINKAN (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-5% MeOH in DCM) to obtain L6 (190 mg, 93% yield) as a brown oil. LC / MS (ESI) m / z: 312 (M-16) + .

[0239] Step 6: Synthesis of L7 To a solution of L6 (190 mg, 0.58 mmol) in anhydrous THF (8 mL), CDI (103 mg, 0.64 mmol) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at 0°C for 30 minutes. The mixture was then concentrated under reduced pressure to obtain crude acylimidazole (212 mg, 86% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 423 (M+H) +A solution of acylimidazole (80 mg, 0.19 mmol) in anhydrous THF (10 mL) was mixed with TEA (95 mg, 0.94 mmol) and D2 (37 mg, 0.19 mmol) at 0°C. The resulting mixture was stirred overnight at 50°C under an N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-5% MeOH in DCM) to obtain L7 (92 mg, 87% yield) as a colorless oil. LC / MS (ESI) m / z: 552 (M+H) + .

[0240] Step 8: Synthesis of L8 / Example 4 Ethylenediamine (64 mg, 1.07 mmol) and TBAF (1 M in THF, 0.51 ml, 0.51 mmol) were added to a solution of L7 (92 mg, 0.17 mmol) in DMF (5 mL). The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The mixture was then diluted with saturated NH4Cl solution (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC to obtain Example 4 / L8 (21 mg, 29% yield) as a white solid. LC / MS (ESI) m / z: 422 (M + H) + . 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 8.7, 2.4 Hz, 1H), 7.06 (dd, J = 8.7, 2.0 Hz, 1H), 4.54-4.47 (m, 2H), 3.99-3.86 (m, 2H), 3.72-3.61 (m, 1H), 3.13 (t, J = 12.0 Hz, 1H), 2.70 (s, 3H), 2.68-2.60 (m, 1H), 2.51-2.43 (m, 1H), 2.17-2.03 (m, 1H), 1.94-1.83 (m, 1H), 1.81-1.68 (m, 1H), 1.57-1.41 (m, 1H), 0.95-0.85 (m, 2H), 0.78-0.66 (m, 2H). 19 F NMR (376 MHz, MeOD) δ -179.81 - -180.01 (m).

[0241] Synthesis of Example 5 [ka] Step 1: Synthesis of M2 To a solution of M1 (600 mg, 4.79 mmol) in DCM (20 mL) and MeOH (4 mL), CaCO3 (960 mg, 9.58 mmol) and benzyltrimethylammonium dichloroiodate (1827 mg, 5.27 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. The suspension was then filtered, and the filtrate was concentrated under reduced pressure until dry. The residue was redissolved in DCM (20 mL), washed sequentially with 5% NaHSO4 (20 mL), saturated NaHCO3 (30 mL), and brine (30 mL), and dried over anhydrous MgSO4. The organic layer was filtered and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 10% siRNA in PE) to obtain M2 (830 mg, 69% yield) as a brown oil. LC / MS (ESI) m / z: 252 (M+H) + .

[0242] Step 2: Synthesis of M3 A mixture of M2 (630 mg, 2.51 mmol) and TEA (762 mg, 7.53 mmol) in DCM (12 mL) was added dropwise with TFAA (1739 mg, 8.28 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was then diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 10% siRNA in PE) to obtain M3 (690 mg, 79% yield) as a brown solid. LC / MS (ESI) m / z: 346 (MH) - .

[0243] Step 3: Synthesis of M4 To a suspension of M3 (700 mg, 2.02 mmol) and K3PO4 (856 mg, 4.03 mmol) in toluene (12 mL), tert-butylprop-2-in-1-ylcarbamate (470 mg, 3.03 mmol) and Cu(phen)(PPh3)2NO3 (169 mg, 0.2 mmol) were added. The resulting mixture was stirred at 110°C for 24 hours under an N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 10% ethyl acetate in PE) to obtain M4 (150 mg, 27% yield) as a yellow solid. LC / MS (ESI) m / z: 279 (M+H) + .

[0244] Step 4: Synthesis of M5 To a solution of M4 (140 mg, 0.5 mmol) in DCM (10 mL), TFA (2 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure to obtain crude M5 (76 mg, quantitative) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 162 (M-16) + .

[0245] Step 5: Synthesis of M6 / Example 5 CDI (83 mg, 0.51 mmol) was added to a mixture of M5 (76 mg, 0.43 mmol) and TEA (86 mg, 0.85 mmol) in THF (10 mL), and the resulting mixture was stirred at 0 °C for 30 min. The mixture was then concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 70% EtOAc in PE) to give acyl imidazole (82 mg, 71% yield) as a white solid. LC / MS (ESI) m / z: 273 (M+H) + . TEA (80 mg, 0.9 mmol) and D2 (65 mg, 0.33 mmol) were added to a solution of acyl imidazole (82 mg, 0.3 mmol) in THF (10 mL). The resulting mixture was heated to 60 °C and stirred for 3 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via prep-HPLC to give Example 5 / M6 (29 mg, 24% yield) as a white solid. LC / MS (ESI) m / z: 402 (M+H) + . 1 1H NMR (400 MHz, CD3OD) δ 7.23 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 10.7 Hz, 1H), 6.76 (t, J = 5.7 Hz, 1H), 6.19 (s, 1H), 4.45 (d, J = 4.5 Hz, 2H), 4.02 - 3.82 (m, 2H), 3.70 - 3.54 (m, 1H), 3.14 (t, J = 12.0 Hz, 1H), 2.79 - 2.54 (m, 4H), 2.52 - 2.41 (m, 1H), 2.28 (d, J = 1.8 Hz, 3H), 2.17 - 2.00 (m, 1H), 1.93 - 1.85 (m, 1H), 1.80 - 1.70 (m, 1H), 1.61 - 1.42 (m, 1H), 0.96 - 0.88 (m, 2H), 0.80 - 0.56 (m, 2H). 19F NMR (376 MHz, CD3OD) δ -127.80 (s).

[0246] Synthesis of Example 6 [ka] Step 1: Synthesis of N1 Select Fluor (6.73 g, 18.9 mmol) was added to a solution of J1 (3 g, 15.8 mmol) in MeCN (60 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred overnight at room temperature. The mixture was then quenched with water (100 mL) and extracted with RINKAN (80 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 0-10% RINKAN in PE) to obtain N1 (760 mg, 23% yield) as a white solid. LC / MS (ESI) m / z: 208 (M+H) + .

[0247] Step 2: Synthesis of N2 To a solution of N1 (660 mg, 3.2 mmol) in anhydrous THF (20 mL), NaH (153 mg, 3.8 mmol) was added in portions at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEMCl (673 mg, 3.8 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NH4Cl (30 mL, saturated aqueous solution) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude N2 (860 mg, 80% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 338 (M+H) + .

[0248] Step 3: Synthesis of N3 A solution of N2 (860 mg, 2.5 mmol) in anhydrous THF (12 mL) was added portionwise with LiAlH4 (145 mg, 3.8 mmol) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (eluted with 0–15% EtOAc in PE) to afford N3 (740 mg, 98% yield) as a colorless oil. LC / MS (ESI) m / z: 296 (M+H) + .

[0249] Step 4: Synthesis of N4 DBU (827 mg, 3.0 mmol) and DPPA (457 mg, 3.0 mmol) were added to a solution of N3 (740 mg, 2.5 mmol) in toluene (12 mL). The resulting mixture was stirred at 110 °C for 3 h under a N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude N4 (710 mg, 88% yield) as a yellow oil, which was used directly in the next step without further purification.

[0250] Step 5: Synthesis of N5 10% Pd / C (132 mg) was added to a solution of N4 (660 mg, 2.1 mmol) in MeOH (10 mL) under nitrogen. The suspension was degassed under vacuum and purged with H2 several times. The resulting mixture was stirred at room temperature for 2 h under a H2 atmosphere. The mixture was then filtered through a pad of Celite® and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated under reduced pressure until dry. The residue was purified via flash column chromatography (eluted with 0–5% MeOH in DCM) to afford N5 (520 mg, 86% yield) as a brown oil. LC / MS (ESI) m / z: 278 (M−16) + .

[0251] Step 6: Synthesis of N6 To a solution of N5 (300 mg, 1.0 mmol) in anhydrous THF (8 mL), CDI (181 mg, 1.1 mmol) was added at 0°C under a N2 atmosphere. The resulting mixture was stirred at 0°C for 30 minutes. The mixture was then concentrated under reduced pressure to obtain crude acylimidazole (380 mg, quantitative) as a pale yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 389 (M+H) + A solution of acylimidazole (380 mg, 0.97 mmol) in anhydrous MeCN (12 mL) was mixed with TEA (492 mg, 4.87 mmol) and D2 (192 mg, 0.97 mmol). The resulting mixture was stirred overnight at 50°C under an N2 atmosphere. The mixture was then quenched with water (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-5% MeOH in DCM) to obtain N6 (280 mg, 55% yield) as a colorless oil. LC / MS (ESI) m / z: 518 (M+H) + .

[0252] Step 8: Synthesis of N7 / Example 6 Ethylenediamine (103 mg, 1.73 mmol) and TBAF (1 M in THF, 0.81 mL, 0.81 mmol) were added at 0°C to a solution of 9 (140 mg, 0.27 mmol) in DMF (5 mL). The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The mixture was then diluted with saturated NH4Cl solution (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via prep-HPLC to obtain N7 / Example 6 (18 mg, 12% yield) as a white solid. LC / MS (ESI) m / z: 388 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 7.9 Hz, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 4.54 - 4.47 (m, 2H), 4.01 - 3.93 (m, 1H), 3.92 - 3.85 (m, 1H), 3.73 - 3.62 (m, 1H), 3.13 (t, J = 11.9 Hz, 1H), 2.70 (s, 3H), 2.68 - 2.61 (m, 1H), 2.51 - 2.40 (m, 1H), 2.16 - 2.04 (m, 1H), 1.94 - 1.84 (m, 1H), 1.80 - 1.69 (m, 1H), 1.56 - 1.41 (m, 1H), 0.95 - 0.86 (m, 2H), 0.76 - 0.67 (m, 2H). 19 F NMR (377 MHz, MeOD) δ -180.37 - -180.56 (m).

[0253] Synthesis of Example 7 [ka] Step 1: Synthesis of O2 Br2 (120 mg, 0.75 mmol) was added to a solution of O1 (150 mg, 0.75 mmol) in AcOH (10 mL). The resulting mixture was stirred at 100°C for 4 hours. The mixture was then diluted with water (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash column chromatography (eluted by 0-20% siRNA in PE) to obtain O2 (103 mg, 49% yield) as a yellow solid. LC / MS (ESI) m / z: 278 (M+H) + .

[0254] Step 2: Synthesis of O3 To a solution of O2 (103 mg, 0.37 mmol) in MeOH (5 mL) and siRNA (5 mL), stannous chloride dihydrate (250 mg, 1.11 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was then diluted with water (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-30% siRNA in PE) to obtain O3 (67 mg, 73% yield) as a yellow oil. LC / MS (ESI) m / z: 246 (M+H) + .

[0255] Step 3: Synthesis of O4 A solution of di-tert-butyliminodicarbonate (60 mg, 0.33 mmol) in dry THF (10 mL) was partially added with NaH (13 mg, 0.33 mmol) at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 30 minutes. Then, a solution of O3 (67 mg, 0.27 mmol) in 1 mL of THF was added dropwise to the mixture at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NH4Cl solution (20 mL) and extracted with  (15 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 0-50%  in PE) to obtain O4 (83 mg, 81% yield) as a yellow oil. LC / MS (ESI) m / z: 283 (M + H - 100) + .

[0256] Step 4: Synthesis of O5 To a solution of O4 (83 mg, 0.22 mmol) in DCM (10 mL), TFA (2 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure to obtain crude O5 (32 mg, 80% yield) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 183 (M+H) + .

[0257] Step 5: Synthesis of O6 / Example 7 A mixture of O5 (32 mg, 0.18 mmol) and TEA (55 mg, 0.54 mmol) in THF (5 mL) was mixed with CDI (29 mg, 0.18 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (20 mL) and extracted with ₹ (10 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 0-15% MeOH in DCM) to obtain acylimidazole (35 mg, 70% yield) as a white solid. LC / MS (ESI) m / z: 277 (M + H) + A solution of acylimidazole (26 mg, 0.13 mmol) in THF (5 mL) was mixed with TEA (30 mg, 0.30 mmol) and D2 (35 mg, 0.13 mmol). The resulting mixture was stirred at 60°C for 4 hours. The mixture was then diluted with water (20 mL) and extracted with  (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC to obtain O6 / Example 7 (26 mg, 49% yield) as a white solid. LC / MS (ESI) m / z: 406 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J = 0.8 Hz, 1H), 7.55 (s, 1H), 7.35 - 7.26 (m, 1H), 6.98 (d, J = 1.6 Hz, 1H), 4.92 - 4.86 (m, 2H), 3.98 - 3.82 (m, 2H), 3.67 - 3.54 (m, 1H), 3.20 - 3.10 (m, 1H), 2.69 (s, 3H), 2.66 - 2.60 (m, 1H), 2.58 - 2.49 (m, 1H), 2.16 - 2.02 (m, 1H), 1.92 - 1.81 (m, 1H), 1.78 - 1.69 (m, 1H), 1.56 - 1.41 (m, 1H), 1.01 - 0.91 (m, 2H), 0.81 - 0.70 (m, 2H).

[0258] Synthesis of Example 8 [ka] Step 1: Synthesis of P2 To a solution of P1 (1.0 g, 6.8 mmol) in acetyl chloride (1.1 mL, 30.71 mmol), AlCl3 (1.36 g, 10.2 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction was then stirred at 140°C for 5 hours. The mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with siRNA (30 mL x 2). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% siRNA in PE) to obtain P2 (1.0 g, 77% yield) as an orange solid. LC / MS (ESI) m / z: 187 (MH) - .

[0259] Step 2: Synthesis of P3 To a solution of P2 (1 g, 5.3 mmol) in toluene (25 mL), NaH (60 wt%) (1.06 g, 26.5 mmol) and ethyl ethoxymethanoate (1.57 g, 13.2 mmol) were added at 0°C, and the resulting mixture was stirred at 100°C for 20 hours under an N2 atmosphere. The mixture was then quenched dropwise with 1N HCl (aqueous solution) (30 mL) at 0°C and extracted with SiO2 (30 mL x 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude P3 (370 mg, 32% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 213 (MH) - .

[0260] Step 3: Synthesis of P4 To a solution of P3 (370 mg, 1.72 mmol) in EtOH (12 mL), NaOAc (424 mg, 5.17 mmol) and hydroxylamine hydrochloride (359 mg, 5.17 mmol) were added, and the reaction mixture was stirred at 80°C for 16 hours. The mixture was then concentrated under reduced pressure until dry. The residue was dissolved in 1N HCl (aqueous solution) (10 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 0-5% MeOH in DCM) to obtain P4 (270 mg, 68% yield) as a brown solid. LC / MS (ESI) m / z: 228 (MH) - .

[0261] Step 4: Synthesis P5 / Example 8 To a solution of P4 (220 mg, 0.96 mmol) in dry toluene (8 mL), TEA (291 mg, 2.88 mmol) and DPPA (316 mg, 1.15 mmol) were added, and the reaction mixture was stirred at 120 °C for 1 hour under an N2 atmosphere. The mixture was then concentrated under reduced pressure to obtain crude isocyanate (210 mg, 97% yield) as a yellow oil, which was used directly in the next step without further purification. To a mixture of D2 (510 mg, 2.25 mmol) and TEA (683 mg, 6.76 mmol) in dry DCM (10 mL), a solution of isocyanate (510 mg, 2.25 mmol) in DCM (4 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with H2O (20 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC to obtain P5 Example 8 (13 mg, 1% yield) as a white solid. LC / MS(ESI) m / z: 424(M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.14 (t, J = 5.7 Hz, 1H), 4.75 (d, J = 5.5 Hz, 2H), 4.01 - 3.80 (m, 2H), 3.66 - 3.54 (m, 1H), 3.19 (t, J = 12.0 Hz, 1H), 2.70 (s, 3H), 2.67 - 2.60 (m, 1H), 2.56 - 2.49 (m, 1H), 2.20 - 2.06 (m, 1H), 1.89 (d, J = 12.1 Hz, 1H), 1.75 (d, J = 13.2 Hz, 1H), 1.57 - 1.43 (m, 1H), 0.99 - 0.85 (m, 2H), 0.80 - 0.65 (m, 2H). 19 F NMR (376 MHz, CD3OD) δ -111.81 (d, J = 5.4 Hz).

[0262] Synthesis of Example 9 [ka] Step 1: Synthesis of Q2 SelectFluor (797 mg, 2.25 mmol) was added to a solution of Q1 (500 mg, 1.87 mmol) in dry MeCN (16 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-8% siRNA in PE) to obtain Q2 (163 mg, 30% yield) as a white solid.

[0263] Step 2: Synthesis of Q3 To a solution of Q2 (163 mg, 0.57 mmol) in anhydrous DMF (4 mL), NaH (16 mg, 2.2 mmol) was added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 30 minutes, and then SEMCl (142 mg, 2.4 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The mixture was then quenched with saturated NH4Cl (30 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-7% siRNA in PE) to obtain Q3 (223 mg, 94% yield) as a colorless oil.

[0264] Step 3: Synthesis of Q4 LiAlH4 (25 mg, 0.65 mmol) was partially added to a solution of Q3 (223 mg, 0.54 mmol) in anhydrous THF (10 mL) at 0°C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The mixture was then quenched with H2O (0.1 mL), 15% NaOH (0.1 mL), and H2O (0.3 mL). The suspension was then filtered and rinsed with siRNA (20 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-16% siRNA in PE) to obtain Q4 (170 mg, 85% yield) as a colorless oil. LC / MS (ESI) m / z: 374 (M+H) + .

[0265] Step 4: Synthesis of Q5 To a solution of Q4 (170 mg, 0.45 mmol) in toluene (10 mL), DBU (104 mg, 0.68 mmol) and DPPA (148 mg, 0.54 mmol) were added at 0°C. The resulting mixture was stirred at 110°C for 2 hours under an N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with ELISA (20 mL x 2). The combined organic layer was concentrated under reduced pressure to obtain crude Q5 (158 mg, 87% yield), which was used directly in the next step without further purification.

[0266] Step 5: Synthesis of Q6 To a solution of Q5 (158 mg, 0.39 mmol) in THF (8 mL) and H2O (2 mL), PPh3 (157 mg, 0.59 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with H2O (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-8% MeOH in DCM) to obtain Q6 (122 mg, 83% yield) as a pale yellow oil. LC / MS (ESI) m / z: 356 (M-16) + .

[0267] Step 6: Synthesis of Q7 To a solution of Q6 (60 mg, 0.16 mmol) in anhydrous THF (6 mL), CDI (30 mg, 0.19 mmol) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at 0°C for 30 minutes. The mixture was concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-6% MeOH in DCM) to obtain acylimidazole (58 mg, 77% yield) as a white solid. To a solution of acylimidazole (58 mg, 0.12 mmol) in anhydrous MeCN (6 mL), TEA (24 mg, 0.24 mmol) and D2 (22 mg, 0.12 mmol) were added at 0°C. The resulting mixture was stirred at 50°C for 18 hours under an N2 atmosphere. The mixture was then quenched with water (30 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 0-6% MeOH in DCM) to obtain Q7 (42 mg, 58% yield) as a colorless oil. LC / MS(ESI) m / z: 464 (M-117) + .

[0268] Step 8: Synthesis of Q8 / Example 9 Ethylenediamine (25 mg, 0.42 mmol) and TBAF (1 N in THF, 0.21 ml, 0.21 mmol) were added at 0°C to a solution of Q7 (42 mg, 0.07 mmol) in DMF (4 mL). The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with  (15 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC to obtain Q8 / Example 9 (10 mg, 30% yield) as a white solid. LC / MS (ESI) m / z: 452 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 1.3 Hz, 1H), 7.26-7.16 (m, 2H), 4.52 (s, 2H), 4.03-3.86 (m, 2H), 3.77-3.64 (m, 1H), 3.22-3.08 (m, 1H), 2.76-2.63 (m, 1H), 2.55-2.44 (m, 1H), 2.21-2.05 (m, 1H), 1.91 (d, J = 12.6 Hz, 1H), 1.77 (d, J = 13.3 Hz, 1H), 1.53 (d, J = 13.1Hz, 1H), 0.94-0.87 (m, 2H), 0.82-0.69 (m, 2H). 19 F NMR (377 MHz, CD3OD) δ -179.89 (s).

[0269] Synthesis of Example 11 [ka] Step 1: Synthesis of S1 To a solution of S1 (200 mg, 0.96 mmol) in dry DMF (8 mL), NaH (77 mg, 1.90 mmol) was added in portions at 0°C. The resulting mixture was stirred under an N2 atmosphere at 0°C for 1 hour, and SEMCl (206 mg, 1.24 mmol) was added dropwise to the mixture. The resulting mixture was stirred under an N2 atmosphere at room temperature for 3 hours. The mixture was then quenched with saturated NH4Cl solution (20 mL) and extracted with DCM (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted by 15-20% siRNA in PE) to obtain S2 (270 mg, 83% yield) as a pale yellow oil.

[0270] Step 2: Synthesis of S3 LiAlH4 (60 mg, 1.60 mmol) was added in part to a solution of S2 (270 mg, 0.80 mmol) in dry THF (12 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then quenched with H2O (0.1 mL), followed by the addition of 15% NaOH (0.1 mL) and H2O (0.3 mL), after which it was diluted with  (20 mL), filtered, and rinsed with  (20 mL). The filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 20-25%  in PE) to obtain S3 (202 mg, 82% yield) as a colorless oil. LC / MS (ESI) m / z: 296 (M+H) + .

[0271] Step 3: Synthesis of S4 A solution of S3 (202 mg, 0.68 mmol) in toluene (10 mL) was mixed with DBU (206 mg, 1.36 mmol) and DPPA (226 mg, 0.82 mmol). The resulting mixture was stirred at 110°C for 4 hours under an N2 atmosphere. The mixture was then diluted with water (20 mL) and extracted with siRNA (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude S4 (219 mg, quantitative), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 292 (M-28) + .

[0272] Step 4: Synthesis of S5 To a solution of crude S4 (219 mg, 0.68 mmol) in THF / H2O (6 mL, v / v=5:1), PPh3 (356 mg, 1.36 mmol) was added. The resulting mixture was stirred at 50°C for 3 hours under an N2 atmosphere. The mixture was then diluted with water (20 mL) and extracted with siRNA (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude S5 (201 mg, quantitative), which was used directly in the next step without further purification. LC / MS(ESI) m / z:278(M-16) + .

[0273] Step 5: Synthesis of S6 To a solution of S5 (201 mg, 0.68 mmol) in THF (10 mL), CDI (111 mg, 0.68 mmol) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (20 mL) and extracted with  (15 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with 5-10% MeOH in DCM) to obtain S6 (102 mg, 39% yield) as a pale yellow oil. LC / MS (ESI) m / z: 389 (M+H) + .

[0274] Step 6: Synthesis of S7 To a solution of G2 (50 mg, 0.27 mmol) in dry THF (10 mL), TEA (100 mg, 0.99 mmol) and S6 (107 mg, 0.27 mmol) were added at 0°C, and the reaction mixture was stirred at 55°C for 16 hours. The mixture was then diluted with H2O (20 mL) and extracted with  (15 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:0~100:3) to obtain S7 (118 mg, 85% yield) as a colorless oil. LC / MS(ESI) m / z:503(M+H) + .

[0275] Step 2: Synthesis of S8 / Example 11 To a solution of S7 (100 mg, 0.20 mmol) in THF (6 mL), ethylenediamine (72 mg, 1.2 mmol) and TBAF (1 mol / L in THF) (0.6 mL) were added, and the reaction mixture was stirred at 80°C for 1 hour. The mixture was then diluted with H2O (30 mL) and extracted with  (15 mL × 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via prep-HPLC to obtain S8 / Example 11 (20.5 mg, 29% yield) as a white solid. LC / MS (ESI) m / z: 373 (M + H) + . 1 H NMR (400 MHz, CD3OD) δ 7.25 (dd, J = 8.8, 4.5 Hz, 1H), 7.10 (dd, J = 9.8, 2.4 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.80 - 6.72 (m, 1H), 6.27 (d, J = 3.3 Hz, 1H), 4.53 - 4.45 (m, 3H), 3.92 - 3.75 (m, 1.5H), 3.61 - 3.48 (m, 0.5H), 3.35 (s, 0.5H), 3.14 - 2.95 (m, 1H), 2.58 - 2.44 (m, 1.5H), 2.27 - 2.13 (m, 1H), 2.10 (d, J = 6.5 Hz, 3H), 1.99 - 1.78 (m, 2H), 1.60 - 1.40 (m, 1H), 0.98 - 0.87 (m, 2H), 0.84 - 0.68 (m, 2H). 19 F NMR (377 MHz, CD3OD) δ -127.94--128.09 (m).

[0276] Synthesis of Example 12 [ka] Step 1: Synthesis of T1 To a solution of H2 (60 mg, 0.25 mmol) in anhydrous THF (6 mL), TEA (50 mg, 0.5 mmol) and R6 (97 mg, 0.25 mmol) were added at 0°C. The resulting mixture was stirred at 50°C for 18 hours under an N2 atmosphere. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted by 0-5% MeOH in DCM) to obtain T1 (95 mg, 68% yield) as a yellow oil. LC / MS (ESI) m / z: 443 (M-117) + .

[0277] Step 2: Synthesis of T2 / Example 12 Ethylenediamine (60 mg, 1 mmol) and TBAF (1N in THF, 0.51 ml, 0.51 mmol) were added at 0°C to a solution of T1 (95 mg, 0.17 mmol) in DMF (5 mL). The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The mixture was then diluted with saturated NH4Cl solution (30 mL) and extracted with  (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via prep-HPLC to obtain T2 / Example 12 (25 mg, 38% yield) as a white solid. LC / MS (ESI) m / z: 389 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 7.26 (dd, J = 8.8, 4.5 Hz, 1H), 7.11 (dd, J = 9.9, 2.5 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.27 (s, 1H), 4.48 (t, J = 7.8 Hz, 3H), 4.31 (d, J = 15.2 Hz, 0.5H), 4.20 (t, J = 10.1 Hz, 1.5H), 3.80 - 3.55 (m, 2H), 3.25 (d, J = 12.1 Hz, 0.5H), 3.16 (t, J = 11.9 Hz, 0.5H), 2.92 (t, J = 12.0 Hz, 0.5H), 2.60 - 2.45 (m, 1.5H), 2.27 - 2.13 (m, 1H), 2.00 - 1.77 (m, 2H), 1.62 - 1.42 (m, 1H), 0.99 - 0.86 (m, 2H), 0.84 - 0.67 (m, 2H). 19 F NMR (376 MHz, CD3OD) δ -128.01 (d, J = 14.6 Hz).

[0278] The compounds listed in the table below were prepared according to the method described above.

[0279] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0280] The examples in the following table were prepared according to the adaptation of the methods used to prepare Examples 1-9 and 11-12.

[0281] [Table 2-1] Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29] [Table 2-30]

[0282] Synthesis of additional common intermediates U6 synthesis [ka] Step 1: Synthesis of U2 To a solution of U1 (2.5 g, 9.84 mmol) in DCM (50 mL), TEA (3 g, 29.52 mmol) and 2,5-dioxopyrrolidine-1-ylmethylcarbamate (1.9 g, 11.04 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-8% MeOH in DCM) to obtain U2 (2.62 g, 96% yield) as a colorless oil. LC / MS (ESI) m / z: 276 (M+H) + .

[0283] Step 2: Synthesis of U3 To a solution of U2 (2.62 g, 9.54 mmol) in DCM (50 mL), TFA (10 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure until dry to obtain crude U3 (1.66 g, 99% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 176 (M+H) + .

[0284] Step 3: Synthesis of U4 A mixture of U3 (1.66 g, 9.47 mmol) and 2,4-dimethoxybenzaldehyde (1.65 g, 9.95 mmol) in MeOH (60 mL) was mixed with NaOAc (2.33 g, 28.42 mmol) and AcOH (0.5 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0°C, and NaBH3CN (1.79 g, 28.42 mmol) was added to the mixture in portions. The resulting mixture was stirred at room temperature for a further 4 hours. After completion, the reaction mixture was concentrated under reduced pressure until dry. The residue was dissolved in DCM (60 mL) and basicized with saturated NaHCO3 solution to adjust the pH to 8. The mixture was then extracted with DCM (60 mL x 2). The combined organic layer was washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted with 0-5% MeOH in DCM) to obtain U4 (2.67 g, 87% yield) as a yellow oil. LC / MS (ESI) m / z: 326 (M+H) + .

[0285] Step 4: Synthesis of U5 A mixture of U4 (2.67 g, 8.21 mmol) and AcOH (4.7 ml, 82.1 mmol) in EtOH (30 mL) and THF (60 mL) was mixed with (1-ethoxycyclopropoxy)trimethylsilane (4.95 ml, 24.62 mmol) and NaBH3CN (1.55 g, 24.62 mmol). The resulting mixture was stirred at 80°C for 6 hours under an N2 atmosphere. The mixture was then concentrated under reduced pressure until dry. The residue was dissolved in DCM (80 mL) and basicized with saturated NaHCO3 (aqueous solution) to adjust the pH to 8. The mixture was then extracted with DCM (60 mL x 2), the combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted with 0-3% MeOH in DCM) to obtain U5 (2.6 g, 87% yield) as a yellow oil. LC / MS (ESI) m / z: 366 (M+H) + .

[0286] Step 5: Synthesis of U6 A solution of U5 (2.6 g, 7.12 mmol) in TFA (30 mL) was stirred at 80°C for 4 hours under an N2 atmosphere. The mixture was then cooled and concentrated under reduced pressure until dry to obtain crude U6 (1.53 g, 99% yield) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 216 (M+H) + .

[0287] V5 synthesis [ka] Step 1: Synthesis of V1 To a solution of U1 (50.5 g, 231.6 mmol) in DCM (900 mL), TEA (46.7 g, 463.2 mmol) and acetic anhydride (28.3 g, 277.9 mmol) were added at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (1200 mL) and extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-8% MeOH in DCM) to obtain V1 (55.0 g, 91% yield) as a white solid. LC / MS (ESI) m / z: 261 (M+H) + .

[0288] Step 2: Synthesis of V2 A solution of V1 (55.0 g, 211.5 mmol) in HCl / dioxane (700 mL, 4 M) was stirred at room temperature under an N2 atmosphere for 2 hours. The mixture was then concentrated under reduced pressure until dry to obtain crude V2 (33.8 g, 99% yield) as a white solid, which was used directly in the next step without further purification. LC / MS(ESI) m / z: 161(M+H) + .

[0289] Step 3: Synthesis of V3 NaOAc (51.9 g, 633.6 mmol) and AcOH (38.0 g, 633.6 mmol) were added to a mixture of V2 (33.8 g, 211.2 mmol) and 2,4-dimethoxybenzaldehyde (35.0 g, 221.2 mmol) in DCM (1200 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0°C, and NaBH(OAc)3 (89.5 g, 422.4 mmol) was added to the mixture in portions. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure until dry. The residue was dissolved in DCM (600 mL) and basicized with saturated NaHCO3 solution to adjust the pH to 8. The mixture was then extracted with DCM (1000 mL x 5). The combined organic layer was washed with brine (1200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted with 0-5% MeOH in DCM) to obtain V3 (55.6 g, 85% yield) as a yellow oil. LC / MS(ESI) m / z: 311(M+H) + .

[0290] Step 4: Synthesis of V4 A mixture of V3 (55.6 g, 179.3 mmol) and AcOH (107.6 g, 1793 mmol) in EtOH (400 mL) and THF (1600 mL) was mixed with (1-ethoxycyclopropoxy)trimethylsilane (93.6 g, 537.9 mmol) and NaBH3CN (22.5 g, 35.8 mmol). The resulting mixture was stirred at 80°C for 6 hours under an N2 atmosphere. The mixture was then concentrated under reduced pressure until dry. The residue was dissolved in DCM (1000 mL) and basicized with saturated NaHCO3 (aqueous solution) to adjust the pH to 8. The mixture was then extracted with DCM (1000 mL x 4), the combined organic layer was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted with 0-5% MeOH in DCM) to obtain V4 (58.4 g, 93.1% yield) as a yellow oil. LC / MS(ESI) m / z: 351(M+H) + .

[0291] Step 5: Synthesis of V5 A solution of V4 (58.4 g, 166.8 mmol) in TFA (500 mL) was stirred at 80°C for 4 hours under an N2 atmosphere. The mixture was then concentrated under reduced pressure until dry. The residue was dissolved in DCM (1000 mL) and basicized with saturated NaHCO3 (aqueous solution) to adjust the pH to 8. The mixture was then extracted with DCM (1000 mL x 6), the combined organic layer was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-5% MeOH in DCM) to obtain V5 (29.2 g, 87% yield) as a yellow oil. LC / MS (ESI) m / z: 201 (M+H) + .

[0292] Synthesis of W2 / Example 107 [ka] Step 1: Synthesis of W1 To a solution of N5 (48.8 g, 166 mmol) in THF (800 mL), CDI (29.6 g, 182.6 mmol) was added in portions at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (700 mL) and extracted with ethyl acetate (600 mL x 3). The combined organic layer was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-72% ethyl acetate in PE) to obtain W1 (52 g, 80.7% yield) as a yellow oil. LC / MS (ESI) m / z: 389 (M+H) + .

[0293] Step 2: Synthesis of W2 W1 (28.8 g, 134 mmol) was added at 0°C to a mixture of U6 (52 g, 134 mmol) and TEA (27.1 g, 268 mmol) in THF (900 mL). The resulting mixture was stirred at 50°C for 16 hours under an N2 atmosphere. The mixture was then diluted with H2O (800 mL) and extracted with SiO2 (800 mL x 2). The combined organic layer was washed with brine (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-90% SiO2 in PE) to obtain W2 (43.9 g, 61% yield) as a yellow oil. LC / MS (ESI) m / z: 418 (M+H-118) + .

[0294] Step 3: Synthesis of W3 / Example 107 To a solution of W2 (43.9 g, 82 mmol) in DMF (800 mL), ethane-1,2-diamine (29.5 g, 492 mmol) and a solution of TBAF in THF (246 mL, 1 M) were added. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The mixture was then diluted with RINKAN (1.5 L) and washed with H2O (600 mL × 8). The organic layer was separated, washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified via prep-HPLC (C18, H2O / MeCN (10-40%) / 0.1% NH4HCO3) to obtain Example 107 (18.2 g, 54% yield) as a pale yellow solid. LC / MS (ESI) m / z: 406 (M + H) + . 1H NMR (400 MHz, MeOD) δ 7.45 (d, J = 7.9 Hz, 1H), 7.28 (dd, J = 8.2, 2.5 Hz, 1H), 7.14 - 7.07 (m, 1H), 7.02 (dd, J = 11.1, 3.9 Hz, 1H), 4.57 - 4.36 (m, 3H), 4.34 - 4.25 (m, 1H), 3.88 - 3.67 (m, 2H), 3.21 - 3.09 (m, 1H), 2.73 - 2.63 (m, 4H), 2.56 - 2.45 (m, 1H), 2.40 - 2.18 (m, 2H), 0.92 (d, J = 6.0 Hz, 2H), 0.83 - 0.69 (m, 2H). 19 F NMR (376 MHz, MeOD) δ -180.46 (s), -182.15 (s).

[0295] Synthesis of X2 / Example 108 [ka] Step 1: Synthesis of X1 To a solution of U6 (1.53 g, 7.08 mmol) in THF (50 mL), TEA (2.7 mL, 19.3 mmol) and S6 (2.5 g, 6.44 mmol) were added dropwise at 0°C. The resulting mixture was stirred at 60°C for 16 hours under an N2 atmosphere. The mixture was then diluted with water (100 mL) and extracted with SiO2 (60 mL x 3). The combined organic layer was washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-50% SiO2 in PE) to obtain X1 (3.2 g, 93% yield) as a yellow solid. LC / MS (ESI) m / z: 418 (M+H-118) + .

[0296] Step 2: Synthesis of X2 / Example 108 Ethylenediamine (2.4 mL, 35.84 mmol) and TBAF (4.68 g, 17.92 mmol) were added to a solution of X1 (3.2 g, 5.97 mmol) in DMF (50 mL). The resulting mixture was stirred at 80°C for 3 hours under an N2 atmosphere. The mixture was then diluted with water (100 mL) and extracted with  (60 mL × 3). The combined organic layer was washed with saturated NH4Cl solution (100 mL × 3) and brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted with 0-5% MeOH in DCM) to obtain Example 108 (1.1 g, 45% yield) as a white solid. LC / MS (ESI) m / z: 406 (M+H) + . 1 H NMR (400 MHz, MeOD) δ 7.25 (dd, J = 8.8, 4.5 Hz, 1H), 7.10 (dd, J = 9.9, 2.5 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.27 (s, 1H), 4.57 - 4.45 (m, 3H), 4.40 (dd, J = 10.4, 5.2 Hz, 1H), 4.29 (dd, J = 12.5, 2.0 Hz, 1H), 3.84 (dd, J = 12.8, 1.5 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.15 (dd, J = 12.5, 11.5 Hz, 1H), 2.74 - 2.61 (m, 4H), 2.55 - 2.48 (m, 1H), 2.31 (dd, J = 14.3, 8.0 Hz, 2H), 0.93 (d, J = 5.8 Hz, 2H), 0.78 (d, J = 3.5 Hz, 2H). 19 F NMR (377 MHz, MeOD) δ -127.96 (s), -182.11 (s).

[0297] Synthesis of Y2 / Example 109 [ka] Step 1: Synthesis of Y1 To a solution of V6 (29.2 g, 146.0 mmol) in THF (800 mL), TEA (29.4 g, 292.0 mmol) and R6 (56.6 g, 146.0 mmol) were added, and the resulting mixture was stirred at 60°C for 16 hours under an N2 atmosphere. The mixture was then diluted with water (700 mL) and extracted with SiO2 (600 mL x 3). The combined organic layer was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-77% SiO2 in PE) to obtain Y1 (56.7 g, 74.7% yield) as a yellow solid. LC / MS (ESI) m / z: 403 (M+H-118) + .

[0298] Step 2: Synthesis of Y2 / Example 109 Ethylenediamine (39.2 g, 654.2 mmol) and TBAF (85.3 g, 327.1 mmol) were added to a solution of Y1 (56.7 g, 109.0 mmol) in DMF (1000 mL). The resulting mixture was stirred at 80°C for 4 hours under an N2 atmosphere. The mixture was then diluted with water (3000 mL) and extracted twice with siRNA (2000 mL). The combined organic layer was washed with brine (700 mL x 6), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (eluted by 0-5% MeOH in DCM) to obtain Example 109 (20.2 g, 47.5% yield) as a white solid. LC / MS (ESI) m / z: 391 (M+H) + . 1H NMR (400 MHz, MeOD) δ 7.28 - 7.20 (m, 1H), 7.10 (dd, J = 9.9, 2.5 Hz, 1H), 6.84 -6.75 (m, 1H), 6.27 (s, 1H), 4.79 - 4.71 (m, 0.6H), 4.67 - 4.33 (m, 3.7H), 4.17 - 4.08 (m, 0.4H), 3.90 - 3.76 (m, 1H), 3.66 - 3.54 (m, 0.5H), 3.13 - 2.98 (m, 1H), 2.60 - 2.47 (m, 1.7H), 2.45 - 2.23 (m, 2H), 2.15 - 2.10 (m, 3H), 1.00 - 0.89 (m, 2H), 0.86 - 0.69 (m, 2H). 19 F NMR (377 MHz, MeOD) δ -127.01 - -128.90 (m), -181.97 (d, J = 8.8 Hz), -182.43 (d, J = 8.6 Hz).

[0299] The compounds listed in the table below were prepared according to the method described above.

[0300] [Table 3-1] [Table 3-2]

[0301] Embedding by reference All U.S. patents and U.S. and PCT patent application publications cited herein are incorporated herein by reference.

[0302] Equal portions Those skilled in the art will recognize, or can confirm by mere ordinary experimentation, many equivalents to the specific embodiments of the present invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. Compound of formula (I): 【Chemistry 1】 (In the formula, L １ It is -alkyl-; X １ and X ２ is independently selected from -H and cycloalkyl groups; however, X １ and X ２ Not all of them are -H; Y １ is an arbitrarily substituted 5,6-condensed bicyclic heteroaryl; Y ２ is selected from -NH(Y ２ '), -OY ２ '', alkyl, and hydroxyalkyl; Y ２ ' is selected from -H, alkyl, and -O-alkyl; Y ２ '' is alkyl; Y ３ (Selected from -H, hydroxyalkyl, and halogen) or a pharmaceutically acceptable salt thereof.

2. X １ and X ２ One of them is -H; X １ and X ２ The other side is, 【Chemistry 2】 The compound according to claim 1.

3. X １ is -H; X ２ teeth, 【Transformation 3】 The compound according to claim 2.

4. L １ is, -C １ -C ４ A compound according to any one of claims 1 to 3, wherein it is alkyl-.

5. L １ is, -CH ２ - The compound according to claim 4.

6. Y １ The compound according to any one of claims 1 to 5, wherein is an unsubstituted 5,6-condensed bicyclic heteroaryl.

7. Y １ teeth, 【Chemistry 4】 A compound according to claim 6, selected from the above.

8. Y １ teeth, 【Transformation 5】 A compound according to claim 6, selected from the above.

9. Y １ The compound according to any one of claims 1 to 5, wherein is a substituted 5,6-condensed bicyclic heteroaryl.

10. Y １ teeth, 【Transformation 6】 And; R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently of; Z is H or alkyl; however, R １ , R ２ , R ３ , R ４ , R ５ The compound according to claim 9, wherein at least one of , and Z is not -H.

11. R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, alkyl, cycloalkyl, halogen, -CN, -CF ３ , and -OCF ３ Selected independently from; Z is -H; however, R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 10, wherein at least one of them is not -H.

12. R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, -Cl, -Br, -F, -CH ３ , 【Transformation 7】 -CF ３ , and -OCF ３ Selected independently of; however, R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 11, wherein at least one of them is not -H.

13. Y １ teeth, 【Transformation 8】 A compound according to any one of claims 10 to 12, selected from the above.

14. R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 13, wherein each of them is a halogen.

15. R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 14, wherein each of them is -F.

16. Y １ teeth, 【Chemistry 9】 And; R ６ , R ７ , R ８ , and R ９ The presence of each of these is -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently of; however, R ６ , R ７ , R ８ , and R ９ The compound according to claim 9, wherein at least one of them is not -H.

17. R ６ 、 R ７ 、 R ８ 、 and R ９ each presence of, -H, -Cl, -Br, -F, -CH ３ , 【Chemistry 10】 -CF ３ and -OCF ３ is independently selected from; provided that R ６ , R ７ , R ８ , and R ９ at least one of which is not -H, the compound according to claim 16.

18. Y １ teeth, 【Chemistry 11】 A compound according to claim 16 or 17, selected from the above.

19. Y １ teeth, 【Chemistry 12】 And; R １０ , R １１ , R １２ , and R １３ The presence of each of these is -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently of; however, R ６ , R ７ , R ８ , and R ９ The compound according to claim 9, wherein at least one of them is not -H.

20. R １０ , R １１ , R １２ , and R １３ The presence of each of these is -H, -Cl, -Br, -F, -CH ３ , 【Chemistry 13】 -CF ３ , and -OCF ３ Selected independently of; however, R ６ , R ７ , R ８ , and R ９ The compound according to claim 19, wherein at least one of them is not -H.

21. Y １ teeth, 【Chemistry 14】 A compound according to claim 19 or 20, selected from the above.

22. Y １ teeth, 【Chemistry 15】 Selected from; R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, halogen, alkyl, alkoxy, cyclopropyl, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently of; however, R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 9, wherein at least one of them is not -H.

23. R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, -Cl, -Br, -F, -CH ３ , 【Chemistry 16】 -CF ３ , and -OCF ３ Selected independently of; however, R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 22, wherein at least one of them is not -H.

24. Y １ teeth, 【Chemistry 17】 A compound according to claim 22 or 23, selected from the above.

25. Y １ teeth, [Chemistry 18] Selected from; R １ , R ２ , R ３ , and R ４ The presence of each of these is -H, alkyl, alkoxy, cyclopropyl, halogen, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently of; however, R １ , R ２ , R ３ , and R ４ The compound according to claim 9, wherein at least one of them is not -H.

26. R １ , R ２ , R ３ , and R ４ The presence of each of these is -H, -Cl, -Br, -F, -CH ３ , 【Chemistry 19】 -CF ３ , and -OCF ３ Selected independently of; however, R １ , R １ , R ２ , R ３ , and R ４ The compound according to claim 25, wherein at least one of them is not -H.

27. Y １ teeth, 【Chemistry 20】 A compound according to claim 25 or 26, selected from the above.

28. Y １ teeth, 【Chemistry 21】 Selected from; R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, alkyl, alkoxy, cycloalkyl, halogen, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently of; Z is H or alkyl; however, R １ , R ２ , R ３ , R ４ , R ５ The compound according to claim 9, wherein at least one of , and Z is not -H.

29. R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, alkyl, cycloalkyl, halogen, -OH, -CN, -CF ３ , -OCHF ２ , and -OCF ３ Selected independently from; Z is -H; however, R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 28, wherein at least one of them is not -H.

30. R １ , R ２ , R ３ , R ４ , and R ５ The presence of each of these is -H, -Cl, -Br, -F, -CH ３ , 【Chemistry 22】 -CF ３ , and -OCF ３ Selected independently from; Z is -H; however, R １ , R ２ , R ３ , R ４ , and R ５ The compound according to claim 29, wherein at least one of them is not -H.

31. Y １ teeth, 【Chemistry 23】 A compound according to any one of claims 28 to 30, selected from the above.

32. Y １ teeth, 【Chemistry 24】 A compound according to any one of claims 9 to 31, selected from the above.

33. Y １ teeth, 【Chemistry 25】 A compound according to any one of claims 13 to 15, selected from the above.

34. Y ２ is -NH(Y ２ The compound according to any one of claims 1 to 33, which is ').

35. Y ２ ' is C １ -C ４ The compound according to claim 34, wherein it is alkyl.

36. Y ２ ' is, -CH ３ The compound according to claim 35.

37. Y ２ The compound according to claim 34, wherein ' is -H.

38. Y ２ The compound according to claim 34, wherein ' is an -O-alkyl group.

39. Y ２ ' is -O-(C １ -C ４ The compound according to claim 38, wherein it is alkyl.

40. Y ２ ' is, -OCH ３ The compound according to claim 39.

41. Y ２ is, -OY ２ The compound according to any one of claims 1 to 33, which is ''.

42. Y ２ '' is C １ -C ４ The compound according to claim 41, wherein it is alkyl.

43. Y ２ '' is -CH ３ The compound according to claim 42.

44. Y ２ The compound according to any one of claims 1 to 33, wherein is an alkyl group.

45. Y ２ C １ -C ４ The compound according to claim 44, wherein it is alkyl.

46. Y ２ is, -CH ３ or -CH ２ CH ３ A compound according to claim 45, selected from the above.

47. Y ２ The compound according to any one of claims 1 to 33, wherein is a hydroxyalkyl group.

48. Y ２ is, (C １ -C ４ The compound according to claim 47, wherein it is alkyl)-OH.

49. Y ２ is, -CH ２ OH, -CH ２ CH ２ OH and -CH ２ CH ２ CH ２ The compound according to claim 48, selected from OH.

50. Y ３ The compound according to any one of claims 1 to 49, wherein is -H.

51. Y ３ The compound according to any one of claims 1 to 49, wherein is a hydroxyalkyl group.

52. Y ３ is, (C １ -C ４ The compound according to claim 51, wherein it is alkyl)-OH.

53. Y ３ is, -CH ２ The compound according to claim 52, wherein it is an OH group.

54. Y ３ The compound according to any one of claims 1 to 49, wherein is a halogen.

55. Y ３ The compound according to claim 54, wherein is -F. 【Request Item 56】 【Chemistry 26】 The compound according to claim 1, having a structure selected from the above. 【Request Item 57】 【Chemistry 27】 The compound according to claim 30, having a structure selected from the above.

58. L １ It is -alkyl-; X １ and X ２ is independently selected from -H and cyclopropyl; however, X １ and X ２ Neither of them is -H; Y １ is an arbitrarily substituted indolyl; Y ２ is -NH(Y ２ ') and Y ２ ' is alkyl; Y ３ is -H or halogen. The compound according to claim 1, 56, or 57; or a pharmaceutically acceptable salt thereof.

59. L １ It is -alkyl-; X １ and X ２ is independently selected from -H and cyclopropyl; however, X １ and X ２ Neither of them is -H; Y １ is an arbitrarily substituted indolyl; Y ２ It is alkyl; Y ３ is -H or halogen. The compound according to claim 1, 56, or 57; or a pharmaceutically acceptable salt thereof.

60. Y ３ The compound according to claim 58 or 59, wherein is a halogen.

61. Y ３ The compound according to claim 60, wherein is -F. 【Request Item 62】 【Chemistry 28-1】 【Chemistry 28-2】 【Chemistry 28-3】 【Chemistry 28-4】 【Chemistry 28-5】 【Chemistry 28-6】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure selected from the above. 【Request Item 63】 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure selected from the above. 【Request Item 64】 【Chemistry 30】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure selected from the above.

65. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64, and a pharmaceutically acceptable excipient.

66. A method for treating or preventing a disease or disorder related to a gene defect in phenylalanine hydroxylase, comprising administering an effective amount of a compound according to any one of claims 1 to 64 to a subject in need thereof.

67. A method for treating or preventing phenylketonuria, comprising administering an effective amount of a compound according to any one of claims 1 to 64 to a subject in need thereof.

68. A method for treating or preventing hyperphenylalaninemia, comprising administering an effective amount of a compound according to any one of claims 1 to 64 to a subject in need thereof.

69. The method according to any one of claims 66 to 68, wherein the compound reduces the systemic phenylalanine level in a subject.

70. A method for treating or preventing tyrosinemia (type I, II, or III), comprising administering an effective amount of a compound according to any one of claims 1 to 64 to a subject in need thereof.

71. The method according to claim 70, wherein the compound reduces systemic tyrosine levels in a subject.

72. A method for treating or preventing nonketotic hyperglycinemia, comprising administering an effective amount of a compound according to any one of claims 1 to 64 to a subject in need thereof.

73. The method according to claim 72, wherein the compound reduces the systemic glycine level in the subject.

74. A method for treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNA JC12 deficiency, urea cycle disorder, or hyperammonemia, comprising administering an effective amount of any one of claims 1 to 64 to a subject in need thereof.

75. A method for treating or preventing diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome, obesity-related disorders, or neurodevelopmental and autism spectrum disorders, comprising administering an effective amount of any one of claims 1 to 64 to a subject in need thereof.

76. The method according to any one of claims 66 to 75, wherein the compound inhibits SLC6A19 in the target.

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