Small molecule inhibitors of mammalian SLC6A19 function

Abstract

Compounds, compositions, and methods are disclosed that are useful for treating or preventing diseases or disorders associated with more than amino acid levels by modulating SLC6A19 transport.

Description

Technical Field

[0001] (Related Application) This application claims priority to U.S. Provisional Patent Application No. 63 / 389,246, filed on July 14, 2022.

Background Art

[0002] Phenylketonuria (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 and plasma levels of phenylalanine become abnormally high. Humans with PKU have abnormally high blood levels of phenylalanine, which, if untreated, can cause irreversible nerve damage and various complications such as intellectual disability, seizures, neurodevelopmental disorders, and behavioral disorders. PKU is difficult to treat because blood levels of phenylalanine are directly related to diet. Patients must adhere to a strict diet therapy throughout their lives, which affects all aspects of the patient's life. Current standard treatments are enzyme cofactor therapy and enzyme replacement therapy, but these therapies are not effective for all patients and carry the potential risk of adverse events.

[0003] The enzyme that metabolizes phenylalanine and thereby plays a role in maintaining phenylalanine homeostasis is phenylalanine hydroxylase (PAH). Loss-of-function (LOF) mutations in the PAH gene on chromosome 12q23.2 are known to affect most forms of PKU. These LOF mutations that cause PKU can be diagnosed as classical PKU (the most severe form), and relatively 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 responsible for the synthesis of a cofactor necessary for PAH activity, can also cause an increase in phenylalanine levels. In addition to diet, blood amino acid levels, including phenylalanine levels, are regulated by SLC6A19. SCL6A19 is located in the proximal renal tubules of the kidney and plays a role in reabsorbing amino acids and returning them to the bloodstream.

Summary of the Invention

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

[0005] Another aspect of the present invention relates to a compound of formula (I):

Chemical formula

[0006] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder associated with a gene deletion of phenylalanine hydroxylase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I).

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

[0008] Another aspect of the present invention relates to a method for regulating SLC6A19 transport in a subject in need of regulation, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0010] Other features, objects, and advantages of the present invention will be apparent from the detailed description and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

[0012] (DETAILED DESCRIPTION) Definition For the sake of brevity, before further description of the present invention, some terms used in this specification, the examples, and the appended claims are gathered herein. These definitions should be read in light of the remainder of the disclosure and should be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0013] For the present invention to be more easily understood, some terms and phrases are defined below and throughout this specification.

[0014] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0015] The phrase "and / or" as used in this specification and the claims should be understood to mean "either" or "both" of the connected elements, i.e., elements that may exist conjunctively in some cases and disjunctively in other cases. Multiple elements listed together with "and / or" should likewise be construed as "one or more" of the connected elements. Other elements other than those specifically identified by the "and / or" clause may exist as appropriate, whether or not related to those specifically identified elements. Thus, by way of non-limiting example, a reference to "A and / or B", when used in conjunction with a non-limiting term such as "comprising", may in one embodiment refer to only A (optionally including elements other than B); in another embodiment, it may refer to only B (optionally including elements other than A); and in yet another embodiment, it may refer to both A and B (optionally including other elements).

[0016] As used in this specification and 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 construed as inclusive, i.e., construed as including not only one inclusion, but also two or more inclusions, and optionally inclusions of items not in the additional list, of the number of elements or the list. Conversely, terms that clearly indicate a limitation, such as "only one of" or "exactly one of", or "consisting of" when used in the claims, will refer to the inclusion of exactly one element of the number of elements or the list. Generally, the term "or" as used in this specification should be construed only as referring to an exclusive alternative (i.e., "one or the other, but not both") when preceded by exclusive terms such as "either", "one of", "only one of", or "exactly one of". "Consisting essentially of", when used in the claims, shall have the ordinary meaning as used in the field of patent law.

[0017] As used in this specification and the claims, the phrase "at least one" in reference to a list of one or more elements means at least one element selected from any one or more of the elements in the list of those elements, and is not necessarily intended to include at least one of each and every element specifically recited in the list of those elements, nor to exclude any combinations of elements in the list of those elements. This definition is to be understood to permit the presence, as appropriate, of elements other than those specifically identified within the list of elements referred to by "at least one", whether or not related to those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B" or equivalently, "at least one of A and / or B") in one embodiment refers to at least one (optionally including two or more) A, where B is not present (optionally including elements other than B); in another embodiment, it refers to at least one (optionally including two or more) B, where A is not present (optionally including elements other than A); and in yet another embodiment, it refers to at least one (optionally including two or more) A and at least one (optionally including two or more) B (optionally including other elements).

[0018] Unless otherwise specified, in any claimed method that includes two or more steps or acts, it should also be understood that the order of the steps or acts in the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0019] In the claims, as well as in the above specification, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "composed of", etc. shall be construed to be non-limiting, i.e., to mean including but not limited to. As defined in Section 2111.03 of the Patent Examination Manual of the United States Patent and Trademark Office, only the transitional phrases "consisting of" and "consisting essentially of" shall be construed to be limiting or semi-limiting, respectively.

[0020] Some of the compounds included in the compositions of the present invention may exist in the form of specific geometric or stereoisomers. Further, the polymers of the present invention may also be optically active. The present invention includes all such compounds, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures, and other mixtures, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present within substituents such as alkyl groups. All of these isomers, as well as their mixtures, are considered to be included in the present invention.

[0021] "Geometric isomers" means isomers in which the arrangement of substituent atoms is different with respect to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) bonded to each side of a carbon-carbon double bond may be in the E (substituents are on the opposite side of the carbon-carbon double bond) or Z (substituents are arranged on the same side) configuration. "R", "S", "S * ", "R *", "E", "Z", "cis", and "trans" indicate the configuration relative to the core molecule. Some of the disclosed compounds may exist in "atropisomeric" forms or as "atropisomers". Atropisomers are stereoisomers resulting from the hindrance of rotation around a single bond when the steric hindrance to rotation is high enough to allow isolation of the conformers. The compounds of the present invention may be prepared as individual isomers by enantioselective synthesis or by separation from a mixture of isomers. Conventional resolution techniques include forming salts of the free bases of each isomer of an isomer pair using an optically active acid (subsequently followed by fractional crystallization and regeneration of the free base), forming salts of the acid form of each isomer of an isomer pair using an optically active amine (subsequently followed by fractional crystallization and regeneration of the free acid), forming the respective esters or amides of the isomers of an isomer pair using an optically pure acid, amine, or alcohol (subsequently followed by chromatographic separation and removal of the chiral auxiliary), or separating any mixture of isomers of the starting material or final product using various well-known chromatographic methods.

[0022] For example, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis or by induction using a chiral auxiliary, if desired. The resulting mixture of diastereomers is separated, and the auxiliary group is cleaved to obtain the pure desired enantiomer. As another method, when the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed using an appropriate optically active acid or base, and then the diastereomers thus formed are resolved by means such as fractional crystallization or chromatography well known in the art, and thereafter the pure enantiomer is recovered.

[0023] As used herein, the term "tautomer" means a structural isomer that exists in an equilibrium state resulting from the migration of a hydrogen atom. For example, two tautomers of 2-pyrimidinone are listed below. A single tautomer may be provided in the structural representation of a given compound. However, the present invention contemplates all such tautomers of a given compound.

Chemical formula

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

[0025] The disclosed compounds are depicted by name or structure without indicating stereochemistry, and when a compound has at least one chiral center, the name or structure is understood to encompass the enantiomer of the compound without the corresponding optical isomers, the racemic mixture of the compound, or a mixture enriched in one enantiomer as compared to the corresponding optical isomers thereof. When the disclosed compounds are depicted by name or structure without indicating stereochemistry and have two or more chiral centers, the name or structure is understood to encompass a diastereomer without other diastereomers, a number of diastereomers without other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers where one diastereomer is rich as compared to other diastereomer(s), or a mixture of diastereomers where one or more diastereomers are rich as compared to other diastereomers. The present invention encompasses all of these forms.

[0026] The structures illustrated herein are meant to include also compounds that differ only in that one or more isotope - rich atoms are present. For example, replacement of hydrogen by deuterium or tritium, or replacement of carbon by 13 C or 14 C - rich carbon gives rise to compounds that are within the scope of the present invention.

[0027] The term "prodrug" as used herein encompasses compounds that are converted to a therapeutically active agent under physiological conditions. One common method of preparing a prodrug is to include a selected moiety that is hydrolyzed under physiological conditions to yield the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

[0028] The phrases "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier", as used herein, mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid diluent, filler, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject chemical substance from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient and substantially nonpyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical formulations. In some embodiments, the pharmaceutical compositions of the invention are nonpyrogenic, i.e., do not induce a significant increase in temperature when administered to a patient.

[0029] The term "pharmaceutically acceptable salt" refers to addition salts of a compound(s) with relatively non-toxic inorganic and organic acids. These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the thus formed salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, etc. (see, e.g., Berge et al. (1977) "Pharmaceutical salts", J. Pharm. Sci. 66:1-19).

[0030] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and can thus form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these cases refers to addition salts of the compound(s) with relatively non-toxic inorganic and organic bases. These salts can likewise 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 hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary or tertiary organic amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, e.g., Berge et al., supra).

[0031] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with small molecules.

[0032] The "therapeutically effective amount" (or "effective amount") of a compound, from the perspective of use in treatment, refers to the amount of the compound in a preparation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), for example, at a reasonable benefit / risk ratio applicable to any medical treatment, alleviates symptoms, improves the condition, or delays the onset of the disease condition, in accordance with clinically acceptable standards for the disease or condition being treated or for cosmetic purposes.

[0033] The terms "preventive" or "therapeutic" treatment are recognized in the art and include administration of one or more of the subject compositions to a host. If it is administered prior to the clinical symptoms of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is preventive (i.e., it protects the host from the onset of the undesirable condition), while if it is administered after the onset of the undesirable condition, the treatment is therapeutic (i.e., it reduces, improves, or stabilizes the existing undesirable condition or its side effects).

[0034] The term "patient" or "subject" refers to a mammal in need of a particular treatment. In some embodiments, the patient is a primate, dog, cat, or horse. In some embodiments, the patient is a human.

[0035] The aliphatic chain includes the classes of alkyl, alkenyl, and alkynyl as defined below. The aliphatic straight chain is limited to an unbranched carbon chain moiety. As used herein, the term "aliphatic group" refers to a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, including saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0036] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms, or up to 30 carbon atoms if unspecified. For example, alkyl containing 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and moieties that are positional isomers of these moieties. Examples of alkyl containing 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In some embodiments, the straight-chain or branched-chain alkyl has 30 or fewer carbon atoms (e.g., C1 - C 30 straight-chain, C3 - C 30 branched-chain) in its backbone, and more preferably 20 or fewer. The alkyl group may be substituted or unsubstituted.

[0037] As used herein, the term "heteroalkyl" refers to an alkyl moiety as previously defined that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom.

[0038] As used herein, the term "haloalkyl" refers to an alkyl group as previously defined that is substituted with at least one halogen.

[0039] As used herein, the term "hydroxyalkyl" refers to an alkyl group as previously defined that is substituted with at least one hydroxyl.

[0040] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, for example, 2 to 12 carbon atoms, and having two points of attachment to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. The alkylene group can be a cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0041] "Cycloalkyl" means a monocyclic or bicyclic, or bridged or spirocyclic, or polycyclic saturated carbon ring, each having 3 to 12 carbon atoms. Preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably, have 3 to 6 carbons in their ring structure. The cycloalkyl group may be substituted or unsubstituted.

[0042] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above, which is substituted with at least one halogen.

[0043] "Cycloheteroalkyl" refers to a cycloalkyl moiety as defined above, which contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have 4 to 8 carbon atoms and heteroatoms in their ring structure, and more preferably, have 4 to 6 carbons and heteroatoms in their ring structure. The cycloheteroalkyl group may be substituted or unsubstituted.

[0044] Unless otherwise specified, the "lower alkyl" used in this specification is an alkyl group as defined above, but in its skeletal structure, it has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, 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, the preferred alkyl group is lower alkyl. In some embodiments, the substituent designated as alkyl herein is lower alkyl.

[0045] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the specified number of carbon atoms, or up to 26 carbon atoms if no upper limit on the number of carbon atoms is specified; and having one or more double bonds in that moiety. Examples of alkenyl having 6 to 26 carbon atoms include hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl, which are in various isomeric forms, and the unsaturated bond(s) can be at any position in that moiety and can take either the (Z) or (E) configuration with respect to the double bond(s).

[0046] "Alkynyl" refers to a hydrocarbyl moiety within the range of alkenyl, but having one or more triple bonds in that moiety.

[0047] As used herein, the term "aryl" refers to a substituted or unsubstituted monocyclic aromatic group having 3 to 12 members, wherein each atom of the ring is carbon (i.e., a carbocyclic aryl) or one or more atoms are heteroatoms (i.e., a heteroaryl). Preferably, the aryl group includes a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic ring systems having two or more rings, in which two or more carbons are common to two adjacent rings, where at least one of the rings is aromatic, and for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. The heteroaryl group includes a substituted or unsubstituted aromatic 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, more preferably a 5- to 10-membered ring, and these ring structures contain 1 to 4 heteroatoms. Examples of heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0048] As used herein, the terms "halo", "halide", or "halogen" mean halogen and include, for example, but not limited to, fluoro, chloro, bromo, iodo, etc., and include both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0049] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, and these ring structures contain 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, such as azetidinone and pyrrolidinone, sultam, sultone, and the like. The heterocyclic ring can be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, etc.

[0050] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of a backbone. It will be understood that "substituted" or "substituted with" includes the implicit condition that such substitution follows the valences of the atoms being substituted and the substituent and results in a stable compound (i.e., is not spontaneously converted, such as by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to include all acceptable substituents of organic compounds. In one broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. Acceptable substituents can be one or more and can be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of that heteroatom. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituents on the substituted alkyl are selected from C 1~6 alkyl, C 3~6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In a more preferred embodiment, the substituents on the substituted alkyl are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that, where appropriate, the substituents themselves may be substituted. Unless stated otherwise as "unsubstituted," references to the chemical portions of this specification are understood to include substituted variants. For example, a reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0051] As used herein, when each expression, such as the definitions of alkyl, m, n, etc., appears two or more times in any structure, its definition in other parts of the same structure shall be independent of that in other parts.

[0052] As used herein, "low molecular weight" refers to an organic or inorganic low molecule having a molecular weight of less than about 3,000 Daltons. Generally, the low molecules useful for the present invention have a molecular weight of less than 3,000 Daltons (Da). The low molecules can have, for example, a molecular weight of at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2500 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 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0053] In some embodiments, "low molecular weight" refers to an organic, inorganic, or organometallic compound that typically has a molecular weight of less than about 1000. In some embodiments, the low molecule is an organic compound on the order of 1 nm in size. In some embodiments, the low molecular weight agents of the present invention include oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0054] "Effective amount" means an amount that is beneficial or sufficient to achieve a desired result. For example, a therapeutically effective amount is an amount that achieves a desired therapeutic effect. This amount may or may not be the same as a prophylactically effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount may be administered by one or more administrations, applications, or dosings. The therapeutically effective amount of a composition depends on the composition selected. The composition may be administered from more than once a day to more than once a week, including once every other day. One of ordinary skill in the art will recognize that several factors, including but not limited to, the severity of the disease or disorder, past treatments, the overall health and / or age of the subject, and other diseases present, can affect the dosage and frequency required to effectively treat the subject. Further, treatment of a subject with a therapeutically effective amount of a composition as described herein may include a single treatment or a series of treatments.

[0055] The terms "reducing," "decreasing," "decreased," "decrease," "reduction," and "inhibiting" are all used herein generally to mean a statistically significant decrease in amount as compared to a reference value. However, to avoid misunderstanding, "reduce," "reduction," or "decrease" or "inhibit" typically means a decrease of at least 10% as compared to a reference, and may include, for example, 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%, at least about 99% decrease, and up to, for example, a complete absence of a given entity or parameter as compared to a reference level, or any decrease from 10-99% as compared to the case where a given treatment is not performed.

[0056] The terms "increased", "increase", "enhanced", or "activated" are all generally used to mean an increase in a statistically significant amount; to avoid misunderstanding, the terms "increased", "increase", "improved", or "activated" mean an increase of at least 10%, for example 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% compared to a reference level, or at most, a 100% increase, or any increase from 10 to 100% compared to the reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold increase, or any increase from 2-fold to 10-fold or more compared to the reference level.

[0057] As used herein, the term "modulate" includes upregulation and downregulation, e.g., includes enhancing or inhibiting a response.

[0058] As defined herein, "radiopharmaceutical" refers to a pharmaceutical containing at least one radiation-emitting radioisotope. Radiopharmaceuticals are commonly used in nuclear medicine for the diagnosis and / or therapy of various diseases. A radiolabeled pharmaceutical, e.g., a radiolabeled antibody, contains a radioisotope (RI) that functions as a radiation source. As intended herein, the term "radioisotope" includes metallic and non-metallic radioisotopes. The radioisotope is selected based on the medical application of the radiolabeled pharmaceutical. When the radioisotope is a metallic radioisotope, a chelating agent is typically used to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly or via a linker to the rest of the molecule.

[0059] For the purposes of the present invention, chemical elements are identified according to the front and back covers of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986 - 87.

[0060] Compound of the present invention One aspect of the present invention relates to a compound of formula (I): [Chem.] or a pharmaceutically acceptable salt thereof [wherein: L1 is absent or is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH2-; L3 is absent or is -C(O)-; X1 and X2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkyl-cycloalkyl, heterocyclyl, and aryl; provided that both X1 and X2 are not -H; Y1 is selected from aryl and heteroaryl; Y2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH(Y2’), and -N(Y2’’)2; Y2’ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; Y2’’ is each independently alkyl or both together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclyl; Y3, Y3’, Y4, Y4’, Y5, and Y5’ are each independently selected from -H, alkyl, haloalkyl, heteroalkyl, halo, hydroxyl, alkoxy, -N(Z’), and -N(Z’’)2; or Y3 and Y4, or Y3’ and Y4’, together with the carbon atom to which they are attached, form an optionally substituted fused C3-C6 cycloalkyl; or Y4 and Y5, or Y4’ and Y5’, together with the carbon atom to which they are attached, form an optionally substituted fused C3-C6 cycloalkyl; provided that the compound contains only one optionally substituted fused C3-C6 cycloalkyl; Z’ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; and Z’’ is each independently alkyl or both, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl].

[0061] In certain embodiments, Y3 and Y4, or Y3’ and Y4’, together with the carbon atom to which they are attached, form an optionally substituted fused cyclopropyl.

[0062] In certain embodiments, Y3 and Y4, or Y3’ and Y4’, together with the carbon atom to which they are attached, form an optionally substituted fused cyclopropyl.

[0063] In certain embodiments, the compound has the structure:

Chemical formula

[0064] In certain embodiments, the compound has the structure:

Chemical formula

[0065] In certain embodiments, the compound has the structure:

Chemical formula

[0066] In certain embodiments, Y6 and Y7 are independently selected from -H, F, -CH2OH, -CH2CH2OH, -CH2CO2H, -CH2NH2, and -CH2CH2NH2.

[0067] In certain embodiments, Y6 and Y7 are each -H. In other embodiments, Y6 and Y7 are each alkyl. In other embodiments, Y6 and Y7 are each halo.

[0068] In certain embodiments, one of Y6 and Y7 is -H; the other of Y6 and Y7 is not -H.

[0069] In other embodiments, the compound has the structure:

Chemical formula

Chemical formula

[0070] In certain embodiments, one of X1 and X2 is -H; the other of X1 and X2 is selected from C1-C4 alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, and heterocyclyl.

[0071] In one embodiment, one of X1 and X2 is -H; the other of X1 and X2 is -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, and the structure: [Chemical formula] selected from.

[0072] In one embodiment, X1 is -H and X2 is -CH3, or X2 is -H and X1 is -CH3.

[0073] In one embodiment, X1 is -H and X2 has the structure: [Chemical formula] or X2 is -H and X1 has the structure: [Chemical formula] .

[0074] In one embodiment, L1 is absent.

[0075] In one embodiment, L1 is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH2-.

[0076] In one embodiment, L1 is selected from -CH2-, -C(H)(CH3)-, -CH2CH2-, and -C(H)(OH)CH2-.

[0077] In one embodiment, L1 has the structure: [Chemical formula] In other embodiments, L1 has the structure: [Chemical formula] selected from.

[0078] In one embodiment, L1 has the structure:

Chemical formula

[0079] In one embodiment, the compound has the structure:

Chemical formula

[0080] In one embodiment, the compound has the structure:

Chemical formula

[0081] In one embodiment, the compound has the structure:

Chemical formula

Chemical formula

[0082] In one embodiment, Y1 is unsubstituted aryl.

[0083] In one embodiment, Y1 is selected from unsubstituted phenyl and unsubstituted naphthyl.

[0084] In one embodiment, Y1 is substituted aryl.

[0085] In one embodiment, Y1 has the structure:

Chemical formula

[0086] In certain embodiments, R1, R2, R3, R4, and R5 are independently -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -OCH3, -OCF3, -OCHF2, and the structure:

Chemical formula

[0087] In certain embodiments, R1, R2, R3, R4, and R5 are independently -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCF3, and the structure:

Chemical formula

[0088] In certain embodiments, two of R1, R2, R3, R4, and R5 are not -H.

[0089] In certain embodiments, three of R1, R2, R3, R4, and R5 are not -H.

[0090] In certain embodiments, Y1 is the structure:

Chemical formula

[0091] In certain embodiments, Y1 is unsubstituted heteroaryl.

[0092] In certain embodiments, Y1 is the structure: [Chemical formula] selected from the following.

[0093] In certain embodiments, Y1 is a substituted heteroaryl.

[0094] In certain embodiments, Y1 has the structure: [Chemical formula] selected from the following; R6, R7, R8, and R9 are each independently selected from -H, halogen, -CN, -OCF3, -OCHF2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, and heteroaryl; provided that at least one of R6, R7, R8, and R9 is not -H.

[0095] In certain embodiments, L3 is absent.

[0096] In certain embodiments, L3 is -C(O)-.

[0097] In certain embodiments, the compound has the structure: [Chemical formula] selected from the following structures.

[0098] In certain embodiments, the compound has the structure: [Chemical formula] selected from the following structures.

[0099] In certain embodiments, the compound has the structure: [Chemical formula] selected from the following structures.

[0100] In certain embodiments, Y2 is an unsubstituted heteroaryl.

[0101] In one embodiment, Y2 has the structure:

Chemical formula

[0102] In one embodiment, Y2 has the structure:

Chemical formula

[0103] In one embodiment, Y2 is a substituted heteroaryl.

[0104] In one embodiment, Y2 has the structure:

Chemical formula

[0105] In one embodiment, R 10 、R 11 、and R 12is independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -OCH3, -OCF3, -OCHF2, -OAc, -NH2, -NHCH3, -NHAc, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, -C(O)NHSO2CH3, -C(O)NHSO2CH2CH3, -CO2H, phenyl, cyclopropyl, cyclobutyl, imidazolyl, and tetrazolyl.

[0106] In certain embodiments, R 10 and R 12 are each -H; R 11 is -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, and the structures:

Chemical formula

[0107] In certain embodiments, R 11 and R 12 are each -H; R 10 is -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, and the structures:

Chemical formula

[0108] In certain embodiments, R 10 and R 11 are each -H; R 12 is -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, and the structures:

Chemical formula

[0109] In one embodiment, Y2 has the structure:

Chemical formula

[0110] In one embodiment, R 16 is -CN, -CH3, -CF3, -C(O)NH2, -CO2CH2CH3, and the structure:

Chemical formula

[0111] In one embodiment, Y2 has the structure:

Chemical formula

[0112] In certain embodiments, R 17 R 18 R 19 R 20 and R 21 are independently selected from -H, -CN, -CH3, and -OCH3.

[0113] In certain embodiments, Y2 is of the structure:

Chemical formula

[0114] In certain embodiments, the compound is of the structure:

Chemical formula

[0115] In certain embodiments, the compound is of the structure:

Chemical formula

[0116] In certain embodiments, the compound is of the structure:

Chemical formula

[0117] In certain embodiments, Y2 is unsubstituted cycloalkyl or heterocyclyl.

[0118] In one embodiment, Y2 has the structure:

Chemical formula

[0119] In one embodiment, Y2 has the structure:

Chemical formula

[0120] In one embodiment, Y2 is a substituted cycloalkyl or heterocyclyl.

[0121] In one embodiment, Y2 has the structure:

Chemical formula

[0122] In one embodiment, Y2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, and hydroxyalkyl.

[0123] In one embodiment, Y2 is selected from -CH3, -CH2CH(CH3)2, -CH2CH2C≡CH, -CH2CH2OCH3, -C(H)(CH3)CH2OCH3, -OCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, and -CH2OCH3.

[0124] In one embodiment, Y2 is an unsubstituted heteroaryl or heteroaryl substituted with alkyl.

[0125] In one embodiment, Y2 has the structure:

Chemical formula

[0126] In one embodiment, Y2 is a substituted heteroaryl.

[0127] In one embodiment, Y2 has the structure:

Chemical formula

[0128] In one embodiment, Y2 is selected from the structures:

Chemical formula

[0129] In certain embodiments, Y2 has the structure:

Chemical formula

[0130] In certain embodiments, R 22 、R 23 、R 24 、and R 25 is independently selected from -H and -CH3 for each occurrence.

[0131] In certain embodiments, Y2 is selected from unsubstituted pyridonyl, unsubstituted pyrimidinoyl, unsubstituted pyrazinonyl, unsubstituted triazinonyl, and unsubstituted quinazolinonyl.

[0132] In certain embodiments, Y2 has the structure: [Chemical formula] and is selected from:

[0133] In certain embodiments, Y2 is selected from substituted pyridonyl, substituted pyrimidinoyl, substituted pyrazinonyl, substituted triazinonyl, and substituted quinazolinonyl.

[0134] In certain embodiments, Y2 has the structure: [Chemical formula] wherein: R6 and R7 are independently selected from -H, halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino, and cycloalkyl, provided that at least one of R6 and R7 is not -H; or R6 and R7 together with the carbon atom to which they are attached form an unsubstituted or substituted fused C5-C7 cycloalkyl; or Y2 has the structure: [Chemical formula] wherein: R7 and R8 are independently selected from -H, halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino, and cycloalkyl, provided that at least one of R7 and R8 is not -H; or R7 and R8 together with the carbon atom to which they are attached form an unsubstituted or substituted fused C5-C7 cycloalkyl; or Y2 has the structure: [Chemical formula] wherein: R6 and R9 are independently selected from -H, halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino, and cycloalkyl; provided that at least one of R6 and R9 is not -H; or Y2 has the structure:

Chemical formula

Chemical formula

[0135] In certain embodiments, Y2 has the structure:

Chemical formula

[0136] In certain embodiments, Y2 is N-substituted pyridonyl, N-substituted pyrimidinoyl, N-substituted pyrazinonyl, N-substituted triazinonyl, or N-substituted quinazolinonyl.

[0137] In certain embodiments, Y2 is N-alkyl-substituted pyridonyl, N-alkyl-substituted pyrimidinoyl, N-alkyl-substituted pyrazinonyl, N-alkyl-substituted triazinonyl, or N-alkyl-substituted quinazolinonyl.

[0138] In certain embodiments, Y2 has the structure:

Chemical formula

[0139] In one embodiment, Y2 is -NH(Y2') or Y2 is -N(Y2'')2.

[0140] In one embodiment, Y2' is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

[0141] In one embodiment, Y2' is selected from -H, -OCH3, -CH3, -CH2CH3, -CH2OH, and -CH2CH2OH.

[0142] In one embodiment, Y2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

[0143] In one embodiment, Y2' is -H, -OH, -OCH3, -CH3, -CH2CH2OCH3, and the structure:

Chemical formula

[0144] In one embodiment, Y2' is H. In other embodiments, Y2' is -CH3. In other embodiments, Y2' is -CH2CH3. In other embodiments, Y2' is -OCH3. In other embodiments, Y2' is -CH2OH. In other embodiments, Y2' is -CH2CH2OH.

[0145] In one embodiment, each of Y2'' is -CH3.

[0146] In one embodiment, Y2'', together with the nitrogen atom to which they are attached, forms morpholinyl.

[0147] In one embodiment, L1 is selected from -alkyl-, -cycloalkyl-, and -heteroaryl-CH2-; L3 is absent or is -C(O)-; X1 is -H; X2 is cycloalkyl; Y1 is selected from aryl and heteroaryl; Y2 is selected from alkyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, and -NH(Y2'); Y2' is selected from -H, alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl.

[0148] In certain embodiments, X2 has the structure:

Chemical Structure

[0149] In certain embodiments, L1 is -CH2-.

[0150] In certain embodiments, L1 has a structure selected from:

Chemical Structure

[0151] In certain embodiments, L1 has a structure selected from:

Chemical Structure

[0152] In certain embodiments, Y1 is phenyl.

[0153] In certain embodiments, Y1 has the structure:

Chemical Structure

[0154] In certain embodiments, two of R1, R2, R3, R4, and R5 are not -H.

[0155] In certain embodiments, three of R1, R2, R3, R4, and R5 are not -H.

[0156] In certain embodiments, the structure:

Chemical formula

[0157] In certain embodiments, L3 is absent.

[0158] In certain embodiments, L3 is -C(O)-.

[0159] In certain embodiments, Y2 has the structure:

Chemical formula

[0160] In certain embodiments, Y2 is selected from alkyl, hydroxyalkyl, and haloalkyl.

[0161] In certain embodiments, Y3 is selected from -CH3 and -CH2OH.

[0162] In certain embodiments, Y2 is -NH(Y2’); Y2’ is -H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2OH, -CH2CF3, -CH3, and the structure:

Chemical formula

[0163] In certain embodiments, Y3, Y3’, Y4, Y4’, Y5, and Y5’ are each -H.

[0164] In one embodiment, both Y3 and Y3' are -F; Y4, Y4', Y5, and Y5' are each -H.

[0165] In one embodiment, both Y4 and Y4' are -F; Y3, Y3', Y5, and Y5' are each -H.

[0166] In one embodiment, one of Y3 and Y3' is selected from -F, -CF3, -OH, and -OCH3, and the other is -H.

[0167] In one embodiment, one of Y4 and Y4' is selected from -F, -CF3, -OH, and -OCH3, and the other is -H.

[0168] In one embodiment, Y3 and Y4, or Y3' and Y4', together with the carbon atom to which they are attached, form an optionally substituted fused C3 - C4 cycloalkyl; or Y4 and Y5, or Y4' and Y5', together with the carbon atom to which they are attached, form an optionally substituted fused C3 - C6 cycloalkyl; provided that the compound contains only one optionally substituted fused C3 - C4 cycloalkyl.

[0169] In one embodiment, Y3 and Y4, or Y3' and Y4', or Y3' and Y4, or Y3 and Y4' together with the carbon atom to which they are attached, form an optionally substituted fused C5 - C6 cycloalkyl; or Y4 and Y5, or Y4' and Y5', or Y4' and Y5, or Y4 and Y5' together with the carbon atom to which they are attached, form an optionally substituted fused C5 - C6 cycloalkyl; provided that the compound contains only one optionally substituted fused C5 - C4 cycloalkyl.

[0170] In some embodiments, the compound is selected from Table 1 below.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

[0171] In some embodiments, the compound is an atropisomer. Additionally, unless otherwise specified, the structures depicted herein are intended to also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds made by replacing hydrogen with deuterium or tritium, or by replacing carbon with 13 C or 14 C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents described in the present invention. For example, the variable group R 1In the case of, (C1-C4) alkyl or -O(C1-C4) alkyl can be suitably deuterated (e.g., -CD3, -OCD3).

[0172] Any compound of the present invention can also be radiolabeled for use in preparing radiopharmaceuticals.

[0173] Treatment method One aspect of the present invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal amino acid levels by modulating SLC6A19 transport.

[0174] Another aspect of the present invention relates to a method of modulating SLC6A19 transport in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0175] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder associated with a gene deletion of phenylalanine hydroxylase in a subject in need of treatment or prevention, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0176] In some embodiments, the present invention relates to a method for treating or preventing phenylketonuria in a subject in need of treatment or prevention, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0177] In some embodiments, the present invention relates to a method for treating or preventing hyperphenylalaninemia in a subject in need of treatment or prevention, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0178] In some embodiments, the compound reduces the systemic phenylalanine level in the subject.

[0179] In some embodiments, the present invention relates to a method of treating or preventing tyrosinemia (type I, II, or III) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0180] In some embodiments, the compound decreases the systemic glycine levels in the subject.

[0181] In some embodiments, the present invention relates to a method of treating or preventing isovaleric academia, methylmalonic academia, propionic academia, maple syrup urine disease, DNAJC12 deletion, urea cycle disorder, or hyperammonemia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I).

[0182] In some embodiments of any one of the disclosed methods, the compound modulates SLC6A19 in the subject.

[0183] In some embodiments of any one of the disclosed methods, the compound inhibits SLC6A19 in the subject.

[0184] In some embodiments of any one of the disclosed methods, the compound modulates SLC6A19 transport in the subject.

[0185] In some embodiments of any one of the disclosed methods, the compound inhibits SLC6A19 transport in the subject.

[0186] In some embodiments, the compound decreases the systemic levels of a certain amino acid in the subject.

[0187] 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.

[0188] In some embodiments of any one of the disclosed methods, the compound of formula (I) is defined as follows: [Chemical formula] [Wherein, L1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH2-; L3 is absent or is -C(O)-; X1 and X2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkyl-cycloalkyl, heterocyclyl, and aryl; provided that both X1 and X2 are not -H; Y1 is selected from aryl and heteroaryl; Y2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH(Y2’), and -N(Y2’’)2; Y2’ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; Y2’’ are each independently alkyl or both together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl; Y3, Y3’, Y4, Y4’, Y5, and Y5’ are independently selected from -H, alkyl, haloalkyl, heteroalkyl, halo, hydroxyl, alkoxy, NH(Z’), and N(Z’’)2; or Y3 and Y4, or Y3’ and Y4’ together with the carbon atom to which they are attached form an optionally substituted fused C3-C6 cycloalkyl; or Y4 and Y5, or Y4’ and Y5’ together with the carbon atom to which they are attached form an optionally substituted fused C3-C6 cycloalkyl; provided that the compound contains only one optionally substituted fused C3-C6 cycloalkyl; Z’ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; and Z’’ is each independently alkyl or both together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl] or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments of any one of the disclosed methods, the compound is selected from the structure of any one of the compounds listed in Table 1.

[0190] Pharmaceutical composition, administration route, and dosage In one embodiment, the present invention is directed to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0191] In one embodiment, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent in addition to the compound of the present invention. The at least one additional pharmaceutically active agent can be an agent useful for the treatment of ischemia-reperfusion injury.

[0192] The pharmaceutical composition 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.

[0193] As described above, "effective amount" refers to any amount that is sufficient to achieve the desired biological effect. In combination with the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned by selecting from various active compounds and weighting factors, such as potency, relative bioavailability, patient body weight, severity of side effects, and mode of administration, which does not cause substantially unwanted toxicity and is still effective in treating a particular subject. The effective amount for any particular use can vary depending on factors such as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agents without undue experimentation required. The maximum dose, i.e., the maximum safe dose according to some medical judgment, may be used. Multiple administrations per day may be contemplated to achieve an appropriate systemic level of the compound. The appropriate systemic level can be determined, for example, by measuring the peak or sustained plasma level of the drug in the patient. "Dose" and "dosage" are used interchangeably herein.

[0194] In some embodiments, intravenous administration of the compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0195] Generally, the oral dosage of the compound will be about 0.01 mg / kg / day to 1000 mg / kg / day for human subjects. Oral dosages in the range of 0.5 to 50 mg / kg are expected to result in therapeutic outcomes when administered one or more times per day. The dosage may be appropriately adjusted according to the mode of administration to achieve the desired drug level locally or systemically. For example, intravenous administration is expected to be in dosages that are one to several orders of magnitude lower per day. If the response of the subject is inadequate at such dosages, additional dosages (or effective multiple dosages by different, more local delivery routes) may be used to the extent tolerated by the patient. Multiple administrations per day are expected to achieve the appropriate systemic level of the compound.

[0196] For any of the compounds described herein, a therapeutically effective amount can be determined in advance from animal models. A therapeutically effective dosage can also be determined from human data of compounds tested in humans and compounds known to exhibit similar pharmacological activity, such as other related active agents. More dosages may be required for parenteral administration. The dosages applied can be adjusted based on the relative bioavailability and potency of the compound being administered. Adjusting the dosage to achieve maximum efficiency based on the above methods and other methods well known in the art is well within the ability of those skilled in the art.

[0197] The formulations of the present invention can be administered in a pharmaceutically acceptable solution, which may usually contain salts, buffers, preservatives, compatible carriers, adjuvants at pharmaceutically acceptable concentrations, and may optionally contain other therapeutic components.

[0198] For use in therapy, an effective amount of the compound can be administered to a subject by any mode of delivering the compound to the desired surface. Administration of the pharmaceutical composition may be achieved by any means well known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into a tumor or abscess), mucosal (e.g., topically to the eye), inhalation, and topical.

[0199] For intravenous and other parenteral routes of administration, the compounds of the present invention can be formulated as lyophilized dry formulations, as lyophilized formulations of the active compound inserted or encapsulated in liposomes, as lipid complexes in aqueous suspensions, or as salt complexes. Lyophilized formulations are generally reconstituted immediately prior to administration in a suitable aqueous solution, such as sterile water or saline.

[0200] For oral administration, the compounds can be readily formulated by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated. Pharmaceutical formulations for oral use can be obtained as solid excipients, and the appropriately obtained mixture is comminuted and, if desired, after adding suitable auxiliaries, the granule mixture is processed to obtain the core of tablets or dragees. Suitable excipients specifically include sugars containing fillers such as lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or their salts, such as sodium alginate, may be added. The oral formulations may be appropriately formulated in physiological saline or buffer solutions, such as EDTA for neutralizing internal acidity, or may be administered without a carrier.

[0201] Oral dosage forms of the above component(s) are also specifically contemplated. The above component(s) may be chemically modified such that oral delivery of the derivative is effective. Generally, the chemical modification contemplated is one in which at least one moiety binds to the molecule of the component itself, the moiety being capable of (a) inhibiting acid hydrolysis; and (b) enabling transfer from the stomach or intestine into the bloodstream. Also desirable is an improvement in the overall stability of the above component(s) and an extension of the in vivo circulation time. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-189 (1982). Other polymers that may be used are poly-1,3-dioxolane and poly-1,3,6-trioxocane. For pharmaceutical use, as described above, polyethylene glycol moieties are suitable.

[0202] For the component (or derivative), the site of release is the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art have access to formulations that do not dissolve in the stomach but release the substance in the duodenum or other intestine. Preferably, the release avoids adverse events in the gastric environment by protecting the compound (or derivative) of the invention or by releasing the biologically active substance beyond the gastric environment, e.g., in the intestine.

[0203] To ensure complete resistance to the stomach, at least a pH 5.0 impermeable coating is essential. Examples of more common inert ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP50, HPMCP55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as a mixed film.

[0204] A single coating or a mixture of coatings may also be used for tablets, which are not intended to protect from the stomach. This may include a sugar coating or a coating that makes the tablet easier to swallow. Capsules may consist of a hard shell (e.g., gelatin) for the delivery of dry therapeutic agents (e.g., powders); a soft gelatin shell may be used for liquid dosage forms. The shell material of cachets may be thick starch or other edible paper. For pills, lozenges, molded powder tablets (s), wet granulation methods may be used.

[0205] The therapeutic agent may be included in the formulation as fine multiparticulates in the dosage form of granules or pellets with a particle size of about 1 mm. The formulation of the material for capsule administration may be a powder, a lightly compressed plug, or a tablet. The therapeutic agent may be prepared by compression.

[0206] All coloring agents and flavoring agents may be included. For example, the compounds (or derivatives) of the present invention may be formulated (e.g., by capsule filling of liposomes or microspheres), and then further included in an edible product, such as a refrigerated beverage containing coloring agents and flavoring agents.

[0207] It may be diluted with an inert substance or the volume of the therapeutic agent may be increased. These diluents may include carbohydrates, especially mannitol, lactose, lactose anhydrous, cellulose, sucrose, modified dextran and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0208] Disintegrants may be included when formulating the therapeutic agent into a solid dosage form. Materials used as disintegrants include, but are not limited to, starches including the commercially available starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethyl cellulose, ultraamylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all also be used. Other forms of disintegrants are insoluble cation exchange resins. Powder gums may be used as disintegrants and as binders, and these may include, for example, agar, karaya gum or tragacanth gum as powder gums. Alginate and its sodium salts are also useful as disintegrants.

[0209] Binders may be used to hold the therapeutic agent together to form hard tablets and may include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methylcellulose (MC), ethylcellulose (EC) and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) may both be used in an alcohol solution to granulate the therapeutic agent.

[0210] An anti-friction material may be included in the formulation of the therapeutic agent to prevent sticking during the formulation process. A lubricant may be used as a layer between the therapeutic agent and the die wall, and these may include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000, and 6000 may also be used.

[0211] A flow promoter may be added to improve the flow properties of the drug during formulation and assist in rearrangement during compression. Flow promoters may include starch, talc, calcined silica, and hydrated aluminosilicates.

[0212] To assist in the dissolution of the therapeutic agent into the aqueous environment, a surfactant may be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may be used and may include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glyceryl 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 alone or as mixtures in different ratios.

[0213] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft-sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient in a mixture with a bulking agent such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Further, a stabilizer may be added. Microsphere formulations for oral administration may also be used. Such microspheres are well-defined in the art. All formulations for oral administration should be in an appropriate dosage for their administration.

[0214] For buccal administration, the composition may be in the form of tablets or lozenges formulated by conventional methods.

[0215] 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 those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

[0216] For administration by inhalation, the compounds for use according to the invention may be conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator may be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0217] Lung delivery of the compounds (or salts thereof) disclosed herein is also contemplated herein. The compounds are delivered to the lungs of a mammal while inhaling and reach the bloodstream across the pulmonary epithelial lining. As other reports of inhaled molecules, Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13 (suppl.5):143-146 (1989) (1-antitrypsin); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, ‘‘Aerosolization of Proteins’’, Proceedings of Symposium on Respiratory Drug Delivery 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 Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference) may be mentioned. Methods and compositions for lung delivery of agents for systemic effects are described in U.S. Patent No. 5,451,569 issued to Wong et al. on September 19, 1995 (incorporated by reference).

[0218] A wide variety of mechanical devices designed for the lung delivery of therapeutic agent products are contemplated for use in the practice of the present invention and include, but are not limited to, nebulizers, metered dose inhalers, and powder inhalers, all of which are well known to those skilled in the art.

[0219] Some specific examples of commercially available devices suitable for the practice of the present invention are the Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhale powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0220] All such devices require the use of formulations suitable for the dispensing of the compounds of the present invention. Typically, each formulation is specific to the type of device used and may require the use of suitable propellant materials in addition to normal diluents, adjuvants, and / or carriers useful in therapy. The use of liposomes, microcapsules, or microparticles, inclusion complexes, or other types of carriers is also contemplated. Chemically modified compounds of the present invention may be formulated in different formulations depending on the type of chemical modification or the type of device used.

[0221] Formulations suitable for use with either a jet or ultrasonic nebulizer will typically contain the compound (or derivative) of the present invention dissolved in water at a concentration of about 0.1 to 25 mg of bioactive compound per mL of solution. The formulation may also contain buffers and simple sugars (e.g., for stabilization of the inhibitor and adjustment of osmotic pressure). Nebulizer formulations may also contain surfactants to reduce or prevent surface induced aggregation of the compounds of the present invention caused by atomization of the solution in forming the aerosol.

[0222] Formulations for use in metered-dose inhaler devices will generally comprise micronized powders containing the compound (or derivative) of the invention suspended in a propellant, with the aid of a surfactant. The propellant can be any conventional material used 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.

[0223] Formulations for dispensing from powder inhaler devices comprise micronized dry powders containing the compound (or derivative) of the invention, and may also include bulking agents such as lactose, sorbitol, sucrose, or mannitol, in an amount that promotes dispersion of the powder from the device, for example, 50 to 90% by weight of the formulation. The compound (or derivative) of the invention should preferably be prepared in particulate 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 lung.

[0224] Transnasal delivery of the pharmaceutical compositions of the invention is also contemplated. Transnasal delivery allows the pharmaceutical compositions of the invention to pass into the bloodstream immediately after administration of the therapeutic agent product to the nose and does not require deposition of the product in the lungs. Formulations for transnasal delivery include those having dextran or cyclodextran.

[0225] For nasal delivery, a useful device is a small rigid bottle with a metered spray attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition solution of the present invention into a chamber of defined volume, the chamber having an aperture sized to aerosolize and an aerosol formulation that forms a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In certain embodiments, the chamber is a piston arrangement. Such devices are commercially available.

[0226] Alternatively, a plastic squeeze bottle having an aperture or opening sized to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is typically found at the upper end of the bottle, which is tapered to fit partially into the nasal cavity for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a defined amount of aerosol formulation for administering a measured dose of the drug.

[0227] The compounds may be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion, when it is desirable to deliver them systemically. Injectable formulations may be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. The composition may be in the form of a suspension, solution, or emulsion, etc. in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents.

[0228] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound may be prepared as suitable oily suspension injections. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous suspension injections may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension may also optionally contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions.

[0229] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0230] The compound may be formulated in rectal or vaginal compositions, such as suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides.

[0231] In addition to the preparations described above, the compound may also be formulated as a depot preparation. Such long-acting preparations may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion-exchange resin, or as a poorly soluble derivative, such as a poorly soluble salt.

[0232] The pharmaceutical composition may also include a suitable solid or gel layer carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0233] Suitable forms of the pharmaceutical preparation, which may be liquid or solid, are, for example, aqueous solutions or saline solutions for inhalation, microencapsulated in microscopic gold particles, encochleated, coated, contained in liposomes, sprayed, an aerosol, pellets for implantation into the skin, or dried on a sharp object for rubbing into the skin. The pharmaceutical composition includes granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with long-term release of the active compound, in which excipients such as disintegrants, binders, coating agents, swelling agents, lubricants, fragrances, sweeteners, or solubilizers, as well as additives and / or adjuvants are usually used as described above. The pharmaceutical composition is suitable for use in various drug delivery systems. For a brief reference to methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[0234] The compounds of the present invention and optionally other therapeutic agents may be administered per se (pure) or in the form of a pharmaceutically acceptable salt or co-crystal. When used in medicine, the salt or co-crystal should be pharmaceutically acceptable, but pharmaceutically unacceptable salts or co-crystals may be advantageously used to prepare pharmaceutically acceptable salts or their co-crystals. 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 carboxylic acid groups.

[0235] Suitable buffers 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).

[0236] The pharmaceutical composition of the present invention contains an effective amount of the compound described herein and may optionally contain a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid diluents, extenders, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" means a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate its use. The components of the pharmaceutical composition can be mixed with the compound of the present invention and with each other in such a way that there is no interaction that substantially impairs the desired pharmaceutical efficiency.

[0237] The therapeutic agent(s) may include, but is not limited to, specifically the compounds of the present invention and may be provided in particles. As used herein, particles mean nanoparticles or microparticles (or in some examples larger particles), and all or part of which may be composed of the compounds of the present invention or other therapeutic agent(s) described herein. The particles may contain the therapeutic agent(s) within a core surrounded by a coating (including, but not limited to, enteric coatings). The therapeutic agent(s) may be dispersed throughout the particles. The therapeutic agent(s) may be incorporated into the particles. The particles may have any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. The particles may contain, in addition to the therapeutic agent(s), any material commonly used in the fields of pharmacy and medicine, including, but not limited to, erodible materials, non-erodible materials, biodegradable materials, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the compounds of the present invention in solution or semi-solid state. The particles may be substantially of any shape.

[0238] Both non-biodegradable and biodegradable polymer materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period during which release is desired. Of particular interest as bioadhesive polymers are the biodegradable hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, gluten, polyanhydrides, polyacrylic acid, alginic acid, 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).

[0239] 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 means and profile of drug release from the formulation are controlled. This refers to both immediate 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 referred to as "extended release") is used in its conventional meaning and refers to a drug formulation that provides a slow release of the drug over a long period of time, preferably, but not necessarily, resulting in a substantially constant blood drug level over a long period of time. The term "delayed release" is used in its conventional meaning and refers to a drug formulation in which there is a time delay between the administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not be accompanied by a slow release of the drug over a long period of time, and thus may or may not be "sustained release".

[0240] The use of long-term sustained release implants may be particularly suitable for the treatment of chronic conditions. "Long-term" release, as used herein, means that the implant is configured and arranged to deliver a therapeutically active ingredient at a therapeutic level 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 above-described release systems.

[0241] Other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, taking into account the 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 relevant art. Although the invention has been described in detail heretofore, the invention will be more clearly understood by reference to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the invention.

Examples

[0242] The present invention is further described in the following examples, which do not limit the scope of the invention as described in the claims.

[0243] Example 1: SLC6A19 Isoleucine Transport Assay Generation and Maintenance of Cell Lines The Flp-In™ T-REx™ 293 cell line was purchased from Thermo Fisher Scientific. Using this cell line, a stable cell line was generated that inductively expresses human SLC6A19 with a C-terminal V5 tag and stably expresses human TMEM27 (also known as collectrin) with a C-terminal myc-DDK tag. The stable cell line was generated by transfecting SLC6A19- and TMEM27-encoding plasmids using standard protocols, followed by antibiotic selection. The stable cells were maintained in DMEM / F12 supplemented with Glutamax, 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, 200 μg / mL hygromycin, 10 μg / mL blasticidin, and 300 μg / mL neomycin (Thermo Fisher).

[0244] Assay: Isoleucine Transport Assay in 96-Well Format On day 0, stable cell lines were seeded at a density of 35,000 cells per well in a poly-D-lysine-coated 96-well cell culture treatment plate. On day 1, expression of SLC6A19 was induced by dispensing tetracycline at a final concentration of 1 μg / mL using a Tecan D300e digital dispenser. On day 2, a transport assay was performed. The medium was removed from the plate using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio), and the cells were washed with 175 μL of live cell imaging solution (Thermo Fisher) using the Blue Washer. Following the wash, the cells were treated with 70 μL of either DMSO, positive control, or compound 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) at room temperature. After 20 - 60 minutes, 13 C6, 15 30 μL of a 3.3 mM solution of N-L-isoleucine (Cambridge Isotope Laboratories) was added. After incubation with the isoleucine substrate for 20 minutes at room temperature, the cells were washed with 175 μL of live cell imaging solution using the Blue Washer. The cells were then lysed in 150 μL of 15 μM D-leucine-d10 (CDN Isotopes) in ultrapure water. To facilitate lysis, the plate was placed on a shaker at 700 rpm for a minimum of 40 minutes. After lysis, 13 C6, 15 A standard dilution curve of N-L-isoleucine was added to wells containing lysates of untreated cells. The plate was returned to the shaker for a minimum of 2 minutes to ensure proper mixing of the standard curve. The plate was then centrifuged at 4000 rpm for 5 minutes to pellet cell debris. The supernatant was diluted 1:10 with acetonitrile + 0.1% formic acid on a polypropylene plate.

[0245] Assay: Isoleucine transport assay in 384-well format On day 0, stable cell lines were seeded at a density of 20,000 cells per well into poly-D-lysine-coated 384-well cell culture treated plates in medium containing 1 μg / mL of tetracycline using a Viaflo 384-well pipette. The transport assay was performed the next day (day 1). Using the GentleSpin setting of the Centrifugal Blue Washer (Blue Cat Bio), the medium was removed from the plates, 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 20 μL of either DMSO, positive control, or compound 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) using a TECAN liquid handler. After incubation at room temperature for 20 - 60 minutes, 13 C6, 15 8.6 μL of a 3.3 mM solution of N-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 the Blue Washer. Then, the cells were lysed in 80 μL of 15 μM D-leucine-d10 (CDN Isotopes) in ultrapure water. To facilitate lysis, the plates were placed on a shaker at 700 rpm for at least 2 hours. After lysis, 13 C6, 15 A standard dilution curve of N-L-isoleucine was added to the wells containing lysates of untreated cells. To ensure proper mixing of the standard curve, the plates were returned to the shaker for at least 5 minutes. Then, the plates were centrifuged at 4000 rpm for 10 minutes to pellet and precipitate cell debris. The supernatant was diluted 1:10 with acetonitrile + 0.1% formic acid on a polypropylene plate.

[0246] 13 C6, 15The N-L-isoleucine analysis was performed using a RapidFire365-QTOF 6545 (Agilent). For quantitative sample analysis, automated solid-phase extraction (HILIC H6 cartridge) was utilized prior to mass spectrometry injection. The sample was loaded using 95% acetonitrile and 0.1% formic acid, eluted from the cartridge in 5% acetonitrile and 0.1% formic acid, and subjected directly to ESI-MS (electrospray ionization) analysis. Quantification of the analyte was performed using Agilent Masshunter Quant software from high-resolution full-scan data.

[0247] Example 2: Preparation of Exemplary Compounds General procedure A

Chemical Structure

[0248] Step 1 To a solution of A1 (1 equivalent) and DIPEA (1.1 equivalents) in DCM (0.1 M), solid 2-nitrobenzenesulfonyl chloride (1.05 equivalents) was added portionwise. The reaction mixture was stirred at ambient temperature for 15 minutes, after which TFA (10 equivalents) was added slowly. The reaction mixture was stirred at room temperature for an additional 2 hours and then concentrated under reduced pressure using a rotary evaporator. The residue of the crude product was then resuspended in DCM (0.1 M), and DIPEA (1.8 equivalents), 2,4-dimethoxybenzaldehyde (0.95 equivalents), and sodium triacetoxyborohydride (2.5 equivalents) were added to this solution. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then washed with 1 M NaOH, after which the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The residue of the crude product was purified by flash column chromatography to obtain A2.

[0249] Step 2 To a solution of A2 (1 equivalent) in THF / EtOH (2:1, 0.05 M), 1-ethoxy-1-trimethylsiloxysilane (2.5 equivalents), sodium cyanoborohydride (3.5 equivalents), and acetic acid (15 equivalents) were added. The reaction mixture was stirred at 80 °C overnight, then cooled to room temperature and concentrated under reduced pressure using a rotary evaporator. Subsequently, the residue was dissolved in ethyl acetate and washed with 1 M NaOH and brine. Then, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure using a rotary evaporator to obtain A3, which was used in the next step without further purification.

[0250] Step 3 A3 (1 equivalent) was dissolved in TFA (0.2 M), and then Et3SiH (3.5 equivalents) was added. The resulting mixture was heated to 80 °C. After 4 hours, an additional portion of triethylsilane (3.5 equivalents) was added to suppress the formation of dimethoxytolyl cation. Then, the reaction mixture was stirred overnight. Subsequently, the reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the residue of the crude product was dissolved in ethyl acetate. The organic layer was washed with 3 M NaOH and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure using a rotary evaporator. Then, the residue of the crude product was dissolved in diethyl ether, and a 2.0 M hydrochloric acid solution in diethyl ether was slowly added dropwise. The product was filtered from the solution to obtain A4 as the hydrochloride salt.

[0251] Example - Synthesis of (3R)-N-cyclopropyl-1-(2-nitrophenyl)sulfonyl-piperidin-3-amine

Chemical formula

[0252] Step 1 A solution of tert-butyl N-[(3R)-3-piperidyl]carbamate (10 g, 49.93 mmol, A1) and DIPEA (7.10 g, 54.92 mmol, 9.57 mL) in DCM (500 mL) was added solid 2-nitrobenzenesulfonyl chloride (11.62 g, 52.43 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 15 minutes, then TFA (56.93 g, 499.31 mmol, 38.47 mL) was added slowly. The reaction mixture was stirred at ambient temperature for a further 2 hours and then concentrated under reduced pressure using a rotary evaporator. The residue of the crude product was then resuspended in 500 mL of DCM and to this solution was added DIPEA (11.29 g, 87.38 mmol, 15.22 mL), 2,4-dimethoxybenzaldehyde (7.88 g, 47.43 mmol), and sodium triacetoxyborohydride (26.46 g, 124.83 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then washed with 1 M NaOH (500 mL), then the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The residue of the crude product was purified by flash column chromatography (DCM:MeOH, 100:0 to 96:4) to give (3R)-N-[(2,4-dimethoxyphenyl)methyl]-1-(2-nitrophenyl)sulfonyl-piperidin-3-amine (7.94 g, 18.23 mmol, 36.52% yield, A2).

[0253] Step 2 To a solution of (3R)-N-[(2,4-dimethoxyphenyl)methyl]-1-(2-nitrophenyl)sulfonyl-piperidin-3-amine (7.93 g, 18.21 mmol, A2) in THF (240 mL) and EtOH (120 mL) were added 1-ethoxy-1-trimethylsilyloxycyclopropane (7.94 g, 45.52 mmol, 9.15 mL), sodium cyanoborohydride (4.01 g, 63.73 mmol), and acetic acid (16.40 g, 273.14 mmol, 15.62 mL). The reaction mixture was stirred at 80 °C overnight, then cooled to room temperature and concentrated under reduced pressure using a rotary evaporator. The residue was then dissolved in ethyl acetate (250 mL), washed with 1 M NaOH (250 mL) and brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to give (3R)-N-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-1-(2-nitrophenyl)sulfonyl-piperidin-3-amine (8.58 g, 18.04 mmol, 99.08% yield, A3), which was used in the next step without further purification.

[0254] Step 3 (3R)-N-Cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-1-(2-nitrophenyl)sulfonyl-piperidin-3-amine (8.58 g, 18.04 mmol, A3) was dissolved in TFA (100 mL), and then Et3SiH (7.28 g, 62.61 mmol, 10 mL) was added. The resulting mixture was heated to 80 °C. After 4 hours, an additional portion of triethylsilane (7.28 g, 62.61 mmol, 10 mL) was added to suppress the formation of dimethoxytolyl cation. Then, the reaction mixture was stirred overnight. Thereafter, the reaction mixture was concentrated under reduced pressure by a rotary evaporator, and the residue of the crude product was dissolved in 200 mL of ethyl acetate. The organic layer was washed with 3 M NaOH (ca. 200 mL) and brine (ca. 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by a rotary evaporator. Then, the residue of the crude product was dissolved in 100 mL of diethyl ether, and a 2.0 M hydrochloric acid solution (2.0 M, 9.02 mL) was slowly added dropwise in diethyl ether. The product was filtered from the solution, and (3R)-N-cyclopropyl-1-(2-nitrophenyl)sulfonyl-piperidin-3-amine (5.5 g, 15.20 mmol, yield 84.25%, HCl, A4) was obtained as a yellowish brown solid.

[0255] General procedure B [Chemical formula]

[0256] Step 1 At 0 °C under a nitrogen atmosphere, Ac2O (3 equivalents) was added dropwise to a mixture of A4 (1 equivalent) and TEA (2 equivalents) in DCM, and the resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with PE / EtOAc) to obtain B1.

[0257] Step 2 Under a nitrogen atmosphere, PhSH (4 equivalents) was added to a MeCN mixture of B1 (1 equivalent) and K2CO3 (4 equivalents), and the resulting mixture was stirred at 50 °C for 12 hours. Then, the mixture was concentrated under reduced pressure to obtain the crude product of B2, which was used in the next step without further purification.

[0258] Example - Synthesis of (R)-N-cyclopropyl-N-(piperidin-3-yl)acetamide

Chemical formula

[0259] Step 1 Under a nitrogen atmosphere at 0 °C, Ac2O (376 mg, 3.69 mmol) was added dropwise to a DCM (12 mL) mixture of A4 (400 mg, 1.23 mmol) and TEA (248 mg, 2.46 mmol), and the resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water (30 mL) and extracted with DCM (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with 0 - 40% PE / EtOAc) to obtain B1 (370 mg, yield 82%) as a colorless oily substance. LC / MS (ESI) m / z: 368 (M + H) + .

[0260] Step 2 Under a nitrogen atmosphere, PhSH (500 mg, 4.03 mmol) was added to a MeCN (20 mL) mixture of B1 (370 mg, 1.01 mmol) and K2CO3 (556 mg, 4.03 mmol), and the resulting mixture was stirred at 50 °C for 12 hours. Then, the mixture was concentrated under reduced pressure to obtain the crude product of B2 (172 mg, yield 94%), which was used in the next step without further purification. LC / MS (ESI) m / z: 183 (M + H) + .

[0261] General procedure C

Chemical formula

[0262] Project 1 At 0 °C under a nitrogen atmosphere, trimethylsilyl isocyanate (2.5 equivalents) was added dropwise to a mixture of A4 (1 equivalent) and TEA (3 equivalents) in anhydrous DCM, and the resulting mixture was stirred at room temperature for 20 hours. Then, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with DCM / MeOH) to obtain C1.

[0263] Project 2 At 0 °C under a nitrogen atmosphere, PhSH (1.5 equivalents) was added to a mixture of C1 (1 equivalent) and K2CO3 (2 equivalents) in MeCN, and the resulting mixture was stirred at 50 °C for 4 hours. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of C2, which was used in the next step without further purification.

[0264] Synthesis of Example - 1 - cyclopropyl - 1 - ((3R,5S) - 5 - fluoropiperidin - 3 - yl)urea [Chemical formula]

[0265] Project 1 At 0 °C under a nitrogen atmosphere, trimethylsilyl isocyanate (148 mg, 1.010 mmol) was added dropwise to a mixture of A4 (139 mg, 0.405 mmol) and TEA (123 mg, 0.232 mmol) in DCM (10 mL), and the resulting mixture was stirred at room temperature for 20 hours. Then, the mixture was diluted with water (30 mL) and extracted with DCM (15 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with 1 - 5% MeOH / DCM) to obtain C1 (122 mg, yield 78%) as a yellow solid. LC / MS: m / z 387 (M + H) + .

[0266] Process 2 At 0 °C under a nitrogen atmosphere, PhSH (60 mg, 0.474 mmol) was added to a mixture of C1 (122 mg, 0.316 mmol) and K2CO3 (88 mg, 0.631 mmol) in MeCN (10 mL). The resulting mixture was stirred at 50 °C for 4 hours. Thereafter, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of C2 (40 mg) as a yellow oily substance, which was used in the next step without further purification. LC / MS: m / z 202 (M+H) + .

[0267] General procedure D

Chemical Structure

[0268] Processes 1 and 2 At 0 °C under a nitrogen atmosphere, CDI (1.1 equivalents) was added dropwise to a solution of D1 (1 equivalent) in anhydrous THF. The resulting mixture was stirred at room temperature for 30 minutes until it was completely converted to D2. Thereafter, under a nitrogen atmosphere at room temperature, a mixture of A4 (1 equivalent) and TEA (3 equivalents) in anhydrous MeCN was added dropwise, and the resulting mixture was stirred at 80 °C for 2 hours. Thereafter, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with DCM / MeOH) to obtain D3.

[0269] Process 3 PhSH (5 equivalents) was added to a solution of D3 (1 equivalent) and K2CO3 (3 equivalents) in MeCN. The resulting mixture was stirred at 70 °C for 16 hours. Thereafter, the mixture was filtered, and the filtrate was concentrated to obtain the crude product of D4, which was used in the next step without further purification.

[0270] Example - Synthesis of (R)-1-Cyclopropyl-3-methyl-1-(piperidin-3-yl)urea

Chemical Structure

[0271] Projects 1 and 2 At 0 °C under a nitrogen atmosphere, CDI (423 mg, 2.61 mmol) was added dropwise to a solution of methylamine * HCl (160 mg, 2.37 mmol) in anhydrous THF (8 mL). The resulting mixture was stirred at room temperature for 30 minutes until completely converted to D2. Then, at room temperature under a nitrogen atmosphere, a mixture of A4 (771 mg, 2.37 mmol) and TEA (720 mg, 7.11 mmol) in anhydrous MeCN (12 mL) was added dropwise, and the resulting mixture was stirred at 80 °C for 2 hours. Then, the mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluted with DCM / MeOH) to obtain D3 (310 mg, yield 34%). LC / MS (ESI) m / z: 383 (M + H) + .

[0272] Project 3 PhSH (447 mg, 4.05 mmol) was added to a solution of D3 (310 mg, 0.81 mmol) and K2CO3 (336 mg, 2.43 mmol) in MeCN (16 mL). The resulting mixture was stirred at 70 °C for 16 hours. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of D4 (150 mg, yield 94%), which was used in the next step without further purification. LC / MS (ESI) m / z: 198 (M + H) + .

[0273] General procedure E

Chemical formula

[0274] Project 1 - Method A At 0 °C under a nitrogen atmosphere, E1 (2 equivalents) was added dropwise to a DCM mixture of A4 (1 equivalent) and DIEA (3 equivalents). The resulting mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with PE / EtOAc) to obtain E3.

[0275] Step 1 - Method B HATU (1.3 equivalents) was added to a DMF mixture of E2 (1.2 equivalents) and DIEA (3 equivalents). Before adding A4, the resulting mixture was stirred at room temperature for 5 - 10 minutes. The reaction mixture was stirred for 15 minutes. Thereafter, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with PE / EtOAc) to obtain E3.

[0276] Step 2 Under a nitrogen atmosphere, PhSH (4 equivalents) was added to a MeCN mixture of E3 (1 equivalent) and K2CO3 (4 equivalents). The resulting mixture was stirred at 50 °C for 12 hours. Thereafter, the mixture was concentrated under reduced pressure to obtain the crude product of E4, which was used in the next step without further purification.

[0277] Example - Synthesis of Ethyl (R)-2-(Cyclopropyl(piperidin-3-yl)amino)-2-oxoacetate [Chemical formula]

[0278] Step 1 At 0 °C under a nitrogen atmosphere, E1 (250 mg, 1.84 mmol) was added dropwise to a mixture of A4 (300 mg, 0.92 mmol) and DIEA (357 mg, 2.77 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water (30 mL) and extracted with DCM (15 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with 10 - 50% PE / EtOAc) to obtain E3 (270 mg, 69% yield) as a colorless oily substance. LC / MS (ESI) m / z: 426 (M + H) + .

[0279] Step 2 Under a nitrogen atmosphere, PhSH (315 mg, 2.54 mmol) was added to a mixture of E3 (270 mg, 0.64 mmol) and K2CO3 (353 mg, 2.54 mmol) in MeCN (20 mL). The resulting mixture was stirred at 50 °C for 12 hours. Then, the mixture was concentrated under reduced pressure to obtain the crude product of E4 (130 mg), which was used in the next step without further purification. LC / MS (ESI) m / z: 241 (M + H) + .

[0280] General procedure F

Chemical formula

[0281] Step 1 At 0 °C, 2,4 - dichloropyrimidine (1.5 equivalents) was added to a DMF solution of A4 (1 equivalent) and K2CO3 (1.5 equivalents). The resulting mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered, diluted with water, and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluted with PE / EtOAc) to obtain F1.

[0282] Step 2 At 0 °C under a nitrogen atmosphere, PhSH (1.5 equivalents) was added to a mixture of F1 (1 equivalent) and K2CO3 (2.0 equivalents), and the resulting mixture was stirred at 50 °C for 2 hours. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of F2, which was used in the next step without further purification.

[0283] Example - Synthesis of (R)-2-chloro-N-cyclopropyl-N-(piperidin-3-yl)pyrimidin-4-amine

Chemical Structure

[0284] Step 1 At 0 °C, 2,4-dichloropyrimidine (206 mg, 1.38 mmol) was added to a mixture of A4 (300 mg, 0.92 mmol) and K2CO3 (191 mg, 1.38 mmol) in DMF (12 mL), and the resulting mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with PE:EtOAc = 100:1 to 30:1) to obtain F1 (230 mg, yield 57%) as a yellow solid. LC / MS: m / z 438 (M+H) + .

[0285] Step 2 At 0 °C under a nitrogen atmosphere, PhSH (99 mg, 0.79 mmol) was added to a mixture of F1 (230 mg, 0.52 mmol) and K2CO3 (145 mg, 1.05 mmol) in MeCN (15 mL), and the resulting mixture was stirred at 50 °C for 2 hours. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of F2 as a yellow oily substance, which was used in the next step without further purification. LC / MS: m / z 253 (M+H) + .

[0286] General procedure G [Chemical]

[0287] Step 1 At room temperature, DIEA (3.0 equivalents) was added to a DMSO mixture of G1 (1 equivalent) and 4-(tert-butoxy)-2-chloropyrimidine (1.1 equivalents), and the resulting mixture was stirred at 120 °C for 5 hours under a nitrogen atmosphere. Subsequently, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc) to obtain G2.

[0288] Step 2 At 0 °C, Cu(OAc)2 (3 equivalents) and cyclopropylboronic acid (3 equivalents) were added to a MeCN mixture of G2 (1 equivalent) and DMAP (6 equivalents), and the resulting mixture was stirred at 80 °C for 5 days under an oxygen atmosphere. After cooling to room temperature, the mixture was quenched with a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with DCM / MeOH) to obtain G3.

[0289] Step 3 At 0 °C, TFA (TFA:DCM = 1 / 4, V / V) was added dropwise to a DCM solution of G3 (1 equivalent), and the resulting mixture was stirred at room temperature for 1 hour. Subsequently, the mixture was concentrated under reduced pressure to obtain the crude product of G4, which was used in the next step without further purification.

[0290] Example - Synthesis of (R)-4-(cyclopropyl(piperidin-3-yl)amino)pyrimidin-2-ol [Chemical]

[0291] Step 1 At room temperature, DIEA (1.93 g, 14.98 mmol) was added to a DMSO (25 mL) mixture of G1 (1.0 g, 4.99 mmol) and 4-(tert-butoxy)-2-chloropyrimidine (1.02 g, 5.49 mmol). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 5 hours. Then, the mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 10 - 50% EtOAc / PE) to obtain G2 (570 mg, yield 33%) as a yellow oily substance. LC / MS (ESI) m / z: 295 (M - 56 + H) + .

[0292] Step 2 At 0 °C, Cu(OAc)2 (820 mg, 4.11 mmol) and cyclopropylboronic acid (354 mg, 4.11 mmol) were added to a MeCN (25 mL) mixture of G2 (480 mg, 1.37 mmol) and DMAP (1.0 g, 8.22 mmol). The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 5 days. Then, the mixture was diluted with saturated aqueous NH4Cl solution (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 to dryness. The residue was purified by flash column chromatography (100% DCM) to obtain G3 (380 mg, yield 71%) as a yellow oily substance. LC / MS (ESI) m / z: 291 (M - 100 + H) + .

[0293] Step 3 At 0 °C, TFA (2 mL) was added dropwise to a DCM (8 mL) solution of G3 (380 mg, 0.974 mmol). The resulting mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated under reduced pressure to obtain the crude product of G4 (460 mg), which was used in the next step without further purification. LC / MS (ESI) m / z: 235 (M + H) + .

[0294] General procedure H

Chem.

[0295] Project 1 At 0 °C, 3,6-dichloropyridazine (1.5 equiv) was added to a mixture of H1 (1 equiv) and DIPEA (1.5 equiv) in n-butanol, and the resulting mixture was stirred at 100 °C for 17 h. After cooling to room temperature, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with PE / EA) to give H2.

[0296] Project 2 Cu(OAc)2 (2 equiv), 2,2'-bipyridine (2 equiv) and cyclopropylboronic acid (3 equiv) were added to a mixture of H2 (1 equiv) and Na2CO3 (2 equiv) in DCE, and the resulting mixture was stirred at 80 °C under an oxygen atmosphere for 5 days. Then, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by column silica gel chromatography (eluted with PE / EtOAc) to give H3.

[0297] Project 3 Under nitrogen conditions, Pd / C (10%, w / w) was added to a solution of H3 (1 equiv) in MeOH, and the resulting suspension was degassed under vacuum and purged several times with hydrogen. Then, the mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. Then, the mixture was filtered through a Celite® pad and concentrated under reduced pressure to obtain the crude product of H4, which was used in the next step without further purification.

[0298] Synthesis of Project 4:5 At 0 °C under a nitrogen atmosphere, TFA was added to a DCM solution of 4 (1 equivalent), and the resulting mixture was stirred at room temperature for 4 hours. Thereafter, the mixture was concentrated under reduced pressure to obtain a crude product of H5, which was used in the next step without further purification.

[0299] Example - Synthesis of (R)-N-cyclopropyl-N-(piperidin-3-yl)pyridazin-3-amine

Chemical formula

[0300] Step 1 At 0 °C, 3,6-dichloropyridazine (1.12 g, 7.49 mmol) was added to a mixture of H1 (1.00 g, 4.99 mmol) and DIPEA (968 mg, 7.49 mmol) in n-butanol (20 mL), and the resulting mixture was stirred at 100 °C for 17 hours. After cooling to room temperature, the mixture was filtered, the filtrate was diluted with water (50 mL), and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with PE:EtOAc = 100:1 to 3:1) to obtain H2 (210 mg, yield 13%) as a white solid. LC / MS: m / z 313 (M+H) + .

[0301] Step 2 Cu(OAc)2 (244 mg, 1.34 mmol), 2,2'-bipyridine (210 mg, 1.34 mmol) and cyclopropylboronic acid (173 mg, 2.01 mmol) were added to a DCE (25 mL) mixture of H2 (210 mg, 0.671 mmol) and Na2CO3 (142 mg, 1.34 mmol). The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 5 days. Then, the mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (PE:EtOAc = 100:1~3:1) to obtain H3 (123 mg, 52% yield) as a white solid. LC / MS: m / z 353 (M + H) + .

[0302] Step 3 Pd / C (24 mg, 10% Pd / activated carbon) was added to a MeOH (20 mL) solution of H3 (123 mg, 0.35 mmol). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. Then, the mixture was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure to obtain the crude product of H4 (110 mg, 99% yield), which was used in the next step without further purification. LC / MS: m / z 319 (M + H) + .

[0303] Step 4 At 0 °C under a nitrogen atmosphere, TFA (2 mL) was added to a DCM (8 mL) solution of H4 (110 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 4 hours. Then, the mixture was concentrated under reduced pressure to obtain the crude product of H5 as a yellow oily substance, which was used in the next step without further purification. LC / MS: m / z 219 (M + H) + .

[0304] General procedure I

Chemical Structure

[0305] Project 1 At -78 °C, NaBH4 (7.2 g, 189.39 mmol) was added to a mixture of I1 (12.0 g, 126.26 mmol) and NaHCO3 (9.54 g, 113.64 mmol) in MeOH (100 mL). The resulting mixture was stirred at -78 °C for 20 minutes. Then, at -78 °C under a nitrogen atmosphere, CbzCl (35.5 mL, 252.52 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was quenched with water (150 mL) and extracted twice with DCM (100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 60% EtOAc / PE) to obtain pure I2 (8.7 g, yield 35%) as a yellow oily substance. LC / MS (ESI) m / z: 234 (M+H) + .

[0306] Project 2 At 0 °C under a nitrogen atmosphere, Et2Zn (56 mL, 55.98 mmol) was added to a solution of I2 (8.7 g, 37.32 mmol) in anhydrous DCE (100 mL). The resulting mixture was stirred at 0 °C for 15 minutes. Then, at 0 °C under a nitrogen atmosphere, CH2I2 (4.51 mL, 55.98 mmol) was added dropwise, and the resulting mixture was stirred at room temperature overnight. Then, the mixture was quenched with water (150 mL) and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 50% EtOAc / PE) to obtain I3 (7.1 g, yield 77%) as a yellow oily substance. LC / MS (ESI) m / z: 248 (M+H) + .

[0307] Project 3 Under nitrogen conditions, 10% Pd / C (1.4 g) and (Boc)2O (7.53 g, 34.49 mmol) were added to a solution of I3 (7.1 g, 28.74 mmol) in EtOAc (100 mL). The resulting suspension was degassed under vacuum and purged several times with hydrogen. Then, the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. Thereafter, the mixture was filtered through a Celite® pad, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 50% EtOAc / PE) to obtain I4 (5.5 g, 90% yield) as a yellow oily substance. LC / MS (ESI) m / z: 214 (M + H) + .

[0308] Step 4 TEA (3.0 g, 29.1 mmol) and DPPA (4.8 g, 17.46 mmol) were added to a solution of I4 (3.1 g, 14.55 mmol) in toluene (60 mL). The resulting mixture was stirred at 120 °C for 18 hours. Then, the mixture was diluted with water (120 mL) and extracted with EtOAc (60 mL × 2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product of I5 (3.5 g, 99% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 239 (M + H) + .

[0309] Step 5 PPh3 (7.71 g, 29.42 mmol) was added to a solution of I5 (3.5 g, 14.71 mmol) in THF (40 mL) and H2O (10 mL). The resulting mixture was stirred at 45 °C for 18 hours. Then, the mixture was concentrated under reduced pressure to obtain the crude product of I6 (3.1 g, 99% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 213 (M + H) + .

[0310] Step 6 At 0 °C, 2,4-dimethoxybenzaldehyde (2.67 g, 16.08 mmol) and NaBH(OAc)3 (7.75 g, 36.55 mmol) were added to a solution of I6 (3.1 g, 14.62 mmol) and AcOH (8 drops) in MeOH (60 mL). The resulting mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Then, the mixture was quenched with water (80 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH / DCM) to give I7 (3.2 g, 60% yield) as a yellow oil. LC / MS (ESI) m / z: 363 (M + H) + .

[0311] Step 7 At 0 °C, (1-ethoxycyclopropoxy)trimethylsilane (2.31 g, 13.26 mmol) and NaBH3CN (1.11 g, 17.68 mmol) were added to a mixture of I7 (3.2 g, 8.84 mmol) and AcOH (5.06 mL, 88.4 mmol) in THF (60 mL) and EtOH (30 mL). The resulting mixture was stirred at 80 °C for 18 h under a nitrogen atmosphere. Then, the mixture was quenched with water (80 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (0 - 10% MeOH / DCM) to give I8 (2.9 g, 82% yield) as a yellow oil. LC / MS (ESI) m / z: 403 (M + H) + .

[0312] Step 8 At 0 °C, TFA (4 mL) was added to a solution of I8 (1.2 g, 2.99 mmol) in DCM (16 mL). The resulting mixture was stirred at room temperature for 2 h. Then, the mixture was concentrated under reduced pressure to give the crude product of I9 (820 mg, 91% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 303 (M + H) + .

[0313] Step 9 At 0 °C, TEA (0.35 mL, 2.485 mmol) and NsCl (132 mg, 0.596 mmol) were added to a solution of I9 (150 mg, 0.497 mmol) in DCM (8 mL), and the resulting mixture was stirred at room temperature for 2 h. Then, the mixture was diluted with water (20 mL) and extracted with DCM (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH / DCM) to give I10 (240 mg, 96% yield) as a yellow solid. LC / MS (ESI) m / z: 488 (M + H) + .

[0314] Step 10 I10 (240 mg, 0.506 mmol) was dissolved in TFA (5 mL), and the resulting solution was stirred at 80 °C for 3 h. Then, the mixture was concentrated under reduced pressure to give the crude product of I11 (170 mg, 99% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 338 (M + H) + .

[0315] General procedure J

Chemical Structure

[0316] Step 1 At - 30 °C, dichlorotrimethyl carbonate (0.5 equiv) was added to a toluene solution of J1 (1 equiv), and the resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product of J2, which was used in the next step without further purification.

[0317] Synthesis of Steps 2 - 4 At 0 °C, a solution of J2 (1 equivalent) in anhydrous DCM was added dropwise to a solution of J3 (1 equivalent) and DIEA (3 equivalents) in anhydrous DCM, and the resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with saturated aqueous NaHCO3 and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by preparative HPLC to obtain J4.

[0318] Synthesis of Example-(1)

Chemical formula

[0319] Step 1 At -30 °C, a solution of triphosgene (71 mg, 0.239 mmol) in anhydrous toluene (1 mL) was added dropwise to a solution of J1 (100 mg, 0.478 mmol) in toluene (10 mL), and the resulting mixture was stirred at 120 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product of J2 (101 mg) as a colorless oily substance, which was used in the next step without further purification.

[0320] Step 2 At 0 °C under a nitrogen atmosphere, a solution of J2 (43 mg, 0.179 mmol) in DCM (1 mL) was added dropwise to a mixture of J3 (36 mg, 0.179 mmol) and DIEA (70 mg, 0.539 mmol) in DCM (5 mL), and the resulting mixture was stirred at room temperature for 30 minutes. Then, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to obtain 1 (7.0 mg, yield 9%) as a white solid. LC / MS: m / z 436 (M+H) + . 11H NMR (400 MHz, MeOD) δ 7.44 (t, J = 8.5 Hz, 1H), 7.08 (t, J = 8.8 Hz, 2H), 4.60 - 4.44 (m, 1H), 4.42 - 4.34 (m, 2H), 4.32 - 4.22 (m, 1H), 3.90 - 3.80 (m, 1H), 3.78 - 3.68 (m, 1H), 3.30 - 3.20 (m, 1H), 2.81 - 2.67 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 (s, 3H), 1.00 - 0.91 (m, 2H), 0.89 - 0.81 (m, 2H). 19 19F NMR (377 MHz, MeOD) δ -59.78 (s), -117.19(s), -182.18 (s).

[0321] Synthesis of Example-(2)

Chemical Structure

[0322] Step 1 At -30 °C, a solution of triphosgene (43 mg, 0.14 mmol) in anhydrous toluene (1 mL) was added dropwise to a solution of J1 (50 mg, 0.29 mmol) in toluene (8 mL). The resulting mixture was stirred at 120 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product of J2 as a colorless oily substance, which was used directly in the next step without further purification.

[0323] Step 2 At 0 °C under a nitrogen atmosphere, a solution of J2 (39 mg, 0.19 mmol) in anhydrous DCM (1 mL) was added dropwise to a mixture of J3 (50 mg, 0.19 mmol) and DIPEA (77 mg, 0.59 mmol) in DCM (8 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water (20 mL) and extracted twice with DCM (15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with DCM:MeOH = 100:1 to 20:1), and J4 (30 mg, yield 34%) was obtained as a white solid. LC / MS: m / z: 452 (M+H) + .

[0324] Step 3 At room temperature, DABCO (11 mg, 0.09 mmol) was added to a mixture of J4 (30 mg, 0.06 mmol) and K2CO3 (14 mg, 0.09 mmol) in dioxane (6 mL) and H2O (3 mL). The resulting mixture was stirred at 100 °C for 17 hours. After cooling to room temperature, the mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC, and 2 (6 mg, yield 21%) was obtained as a white solid. 1 H NMR (400 MHz, MeOD) δ 7.50 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 6.43 (d, J = 7.4 Hz, 1H), 4.42 (s, 2H), 4.23 - 4.13 (m, 1H), 4.10 - 4.00 (m, 2H), 3.26 - 3.18 (m, 1H), 2.85 - 2.75 (m, 1H), 2.68 - 2.58 (m, 1H), 2.35 - 2.26 (m, 4H), 2.08 - 1.98 (m, 1H), 1.84 - 1.74 (m, 1H), 1.60 - 1.48 (m, 1H), 1.07 - 1.01 (m, 2H), 0.92 - 0.82 (m, 1H), 0.80 - 0.70 (m, 1H). 1919F NMR (377 MHz, MeOD) δ -123.16 (s).

[0325] General procedure K

Chem.

[0326] Under a nitrogen atmosphere at 0 °C, CDI (1.0 equiv) was added portionwise to a THF solution of K1 (1.0 equiv), and the resulting mixture was stirred at room temperature for 1 hour. Then, a MeCN mixture of K2 (1.0 equiv) and TEA (3.0 equiv) was added, and the resulting mixture was stirred at 70 °C for 2 hours. Then, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to obtain K3.

[0327] Synthesis of Example-(3)

Chem.

[0328] At 0 °C under a nitrogen atmosphere, CDI (55 mg, 0.34 mmol) was added dropwise to a solution of K1 (80 mg, 0.31 mmol) in anhydrous THF (8 mL), and the resulting mixture was stirred at room temperature for 30 minutes. Then, at room temperature under a nitrogen atmosphere, a mixture of K2 (61 mg, 0.31 mmol) and TEA (94 mg, 0.93 mmol) in anhydrous MeCN (14 mL) was added dropwise, and the resulting mixture was stirred at 80 °C for 2 hours. Then, the mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to obtain 3 (14 mg, yield 9%) as a white solid. LC / MS (ESI) m / z: 482 (M + H) + . 11H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.42 - 7.36 (m, 1H), 6.76 (s, 1H), 4.56 - 4.46 (m, 2H), 4.08 - 3.98 (m, 1H), 3.96 - 3.88 (m, 1H), 3.74 - 3.63 (m, 1H), 3.25 - 3.18 (m, 1H), 2.75 (s, 3H), 2.74 - 2.66 (m, 1H), 2.49 - 2.41 (m, 1H), 2.20 - 2.06 (m, 1H), 1.90 - 1.78 (m, 1H), 1.74 - 1.64 (m, 1H), 1.62 - 1.46 (m, 1H), 0.95 - 0.86 (m, 2H), 0.78 - 0.67 (m, 2H). 19 19F NMR (377 MHz, MeOD) δ -59.79 (s).

[0329] General procedure L

Chemical formula

[0330] Step 1 At 0 °C, DPPA (1.1 eq) was added dropwise to a toluene solution of L1 (1 eq) and TEA (1.2 eq), and the resulting mixture was stirred at 120 °C for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product of L2, which was used in the next step without further purification.

[0331] Step 2 At 0 °C under a nitrogen atmosphere, L2 (1.0 eq) was added to a DCM mixture of L3 (1 eq) and DIEA (3 eq), and the resulting mixture was stirred at room temperature for 30 min. Then, the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to obtain L4 as a mixture of diastereomers, which was further purified by SFC.

[0332] Synthesis of Example-(4) [Chemical]

[0333] Project 1 At 0 °C, DPPA (108.7 mg, 0.445 mmol) was added dropwise to a toluene (10 mL) mixture of L1 (100 mg, 0.406 mmol) and TEA (49.3 mg, 0.487 mmol), and the resulting mixture was stirred at 120 °C for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product of L2 (100 mg, yield 99%) as a colorless oily substance, which was used in the next step without further purification.

[0334] Project 2 At 0 °C under a nitrogen atmosphere, L2 (87 mg, 0.359 mmol) was added to a DCM (10 mL) mixture of L3 (72 mg, 0.359 mmol) and DIPEA (139 mg, 1.080 mmol), and the resulting mixture was stirred at room temperature for 30 min. Then, the mixture was diluted with water and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to obtain a diastereomer mixture (48.0 mg, yield 30%) as a white solid. This mixture was further purified by SFC (Waters Thar 80 preparative SFC; (R,R)-Whelk-O1, 250 × 4.6 mm I.D. 5 μm; RRWO1_MeOH_DEA_40) to obtain 4 (14 mg, yield 29%, d.e. >99%). LC / MS: m / z 444 (M+H) + . 11H NMR (400 MHz, MeOD) δ 7.23 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 4.58 - 4.38 (m, 1H), 4.33 - 4.23 (m, 1H), 3.87 - 3.73 (m, 2H), 3.17 (t, J = 11.9 Hz, 1H), 2.78 - 2.66 (m, 3H), 2.36 - 2.26 (m, 2H), 2.22 (s, 3H), 2.08 - 1.98 (m, 1H), 1.23 - 1.15 (m, 2H), 1.00 - 0.92 (m, 2H), 0.88 - 0.78 (m, 2H); 19 19F NMR (377 MHz, MeOD) δ -59.63 (s), -182.18 (s).

[0335]

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

[0336] Incorporation by Reference Herein, all U.S. patents and U.S. patent application publications cited in this specification are incorporated by reference.

[0337] Equivalents One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. Formula (I): 【Chemical 1】 compound, or a pharmaceutically acceptable salt thereof wherein, L １ is absent or is selected from —alkyl—, —hydroxyalkyl—, —cycloalkyl—, and —heteroaryl—CH ２ —; L ３ is absent or is -C(O)-; X １ and X ２ are each independently selected from -H, alkyl, haloalkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkyl-cycloalkyl, heterocyclyl, and aryl; provided that neither １ X ２ nor X is -H; Y １ is selected from aryl and heteroaryl; Y ２ is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH(Y ２ '), and -N(Y ２ '') ２ ; and is selected from Y ２ ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; Y ２ ’’ are each independently alkyl or both together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl; Y ３ , Y ３ ', Y ４ , Y ４ ', Y ５ , and Y ５ ' is independently -H, alkyl, haloalkyl, heteroalkyl, halo, hydroxyl, alkoxy, -NH(Z'), and -N(Z''). ２ or Y ３ and Y ４ , or Y ３ ' and Y ４ ', taken together with the carbon atom to which they are attached, represent an optionally substituted fused C ３ ~C ６ forms a cycloalkyl; or Y ４ and Y ５ , or Y ４ ' and Y ５ ', taken together with the carbon atom to which they are attached, represent an optionally substituted fused C ３ ~C ６ cycloalkyl; provided that the compound is an optionally substituted fused C ３ ~C ６ Contains only one cycloalkyl; Z ２ ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; and Z ２ ’’ are each independently alkyl, or both together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl].

2. Structure: 【Chemical 2】 The compound according to claim 1, having

3. Structure: [Chemical Formula 3] or Structure: [Chemical Formula 4] The compound according to claim 1, having [wherein, Y ６ and Y ７ are independently selected from -H, halo, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, and alkyl-CO ２ H].

4. Structure: 【Chemical Formula 5】 The compound according to claim 3, having

5. Y ６ and Y ７ The compound according to claim 3 or 4, wherein each of them is H.

6. X １ and X ２ one of which is -H; X １ and X ２ the other of which is C １ -C ４ alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, and heterocyclyl, a compound according to any one of claims 1 to 5

7. X １ and X ２ one of which is -H; X １ and X ２ the other of which is -CH ３ , -CH ２ CH ３ , -CH ２ CF ３ , -CH ２ CH ２ CH ３ and the structure: 【Chemical Formula 6】 The compound according to claim 6, selected from

8. X １ is -H, and X ２ is -CH ３ or X ２ is -H, and X １ is -CH ３ The compound according to claim 7

9. X １ is -H, and X ２ has the structure: 【Chemical Formula 7】 or X ２ is -H, and X １ has the structure: 【Chemical Formula 8】 The compound according to claim 7, which is

10. L １ The compound according to any one of claims 1 to 9, wherein L is absent.

11. L １ is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH ２ - and is a compound according to any one of claims 1 to 9.

12. L １ is -CH ２ -, -C(H)(CH ３ ), -, -CH ２ CH ２ -, and -C(H)(OH)CH ２ -, and is selected from the group consisting of: the compound according to claim 11.

13. L １ has a structure: 【Chemical Formula 9】 The compound according to claim 11, which is

14. L １ has a structure: 【Chemical Formula 10】 and Structure: 【Chemical Formula 11】 The compound according to claim 11, selected from

15. L １ has the structure: 【Chemical 12】 The compound according to claim 11, selected from

16. Structure: 【Chemical 13】 The compound according to any one of claims 10 to 15, having a structure selected from

17. Structure: 【Chemical Formula 14】 The compound according to claim 10, having a structure selected from

18. Structure: 【Chemical Formula 15】 The compound according to any one of claims 10 to 15, having a structure selected from [Wherein, L １ is -CH ２ -, -CH ２ CH ２ -, and the structure: 【Chemical 16】 selected from ]].

19. Y １ The compound according to any one of claims 1 to 18, wherein Y is unsubstituted aryl.

20. Y １ The compound according to claim 19, wherein Y is selected from unsubstituted phenyl and unsubstituted naphthyl.

21. Y １ The compound according to any one of claims 1 to 18, wherein Y is a substituted aryl.

22. Y １ has the structure: 【Chemical 17】 which is; R １ 、R ２ 、R ３ 、R ４ 、and R ５ are independently selected from -H, halogen, -CN, -CF ３ 、-CHF ２ 、-CF ２ CH ３ 、-OCF ３ 、-OCHF ２ 、alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; provided that at least one of R １ 、R ２ 、R ３ 、R ４ 、and R ５ is not -H, the compound according to claim 21.

23. R １ 、R ２ 、R ３ 、R ４ 、and R ５ are independently, -H, -F, -Cl, -Br, -CN, -CH ３ 、-CH ２ CH ３ 、-CF ３ 、-CHF ２ 、-CF ２ CH ３ 、-OCH ３ 、-OCF ３ 、-OCHF ２ 、and structure: 【Chemical Formula 18】 The compound according to claim 22, selected from

24. R １ 、R ２ 、R ３ 、R ４ 、and R ５ are independently, -H, -F, -Cl, -Br, -CN, -CH ３ 、-CH ２ CH ３ 、-OCF ３ 、and structure: 【Chemical Formula 19】 The compound according to claim 23, selected from

25. R １ 、R ２ 、R ３ 、R ４ 、and R ５ wherein two of them are not -H, a compound according to any one of claims 22 to 24.

26. R １ 、R ２ 、R ３ 、R ４ 、and R ５ wherein three of them are not -H, a compound according to any one of claims 22 to 24.

27. Y １ has a structure: 【Chemical 20】 The compound according to claim 24, selected from

28. Y １ The compound according to any one of claims 1 to 18, wherein Y is an unsubstituted heteroaryl.

29. Y １ has the structure: 【Chemical 21】 The compound according to claim 28, selected from

30. Y １ The compound according to any one of claims 1 to 18, wherein Y is a substituted heteroaryl.

31. Y １ has the structure: 【Chemical 22】 selected from; R ６ , R ７ , R ８ , and R ９ is independently, for each occurrence, -H, halogen, -CN, -OCF ３ , -OCHF ２ , alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, and heteroaryl; provided that at least one of R ６ , R ７ , R ８ , and R ９ is not -H, the compound according to claim 30.

32. L ３ The compound according to any one of claims 1 to 31, wherein L is absent.

33. L ３ The compound according to any one of claims 1 to 31, wherein L is -C(O)-.

34. Structure: 【Chemical 23】 The compound according to claim 32, having a structure selected from

35. Structure: 【Chemical 24】 The compound according to claim 32, having a structure selected from

36. Y ２ The compound according to claim 32 or 33, wherein Y is an unsubstituted heteroaryl.

37. Y ２ has a structure: 【Chemical 25】 The compound according to claim 36, selected from

38. Y ２ has a structure: 【Chemical 26】 The compound according to claim 37, which is

39. Y ２ The compound according to claim 34 or 35, wherein Y is a substituted heteroaryl.

40. Y ２ has a structure: 【Chemical 27】 which is; R １０ 、R １１ 、and R １２ are independently selected from -H, halogen, -CN, -OH, -NH ２ 、-OCF ３ 、-OCHF ２ 、-OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR １３ R １４ 、-CO ２ R １５ 、and -C(O)NHSO ２ R １５ ; provided that at least one of R １０ 、R １１ 、and R １２ is not -H; R １３ 、 R １４ 、 and R １５ each independently at each occurrence is selected from -H, alkyl, aryl, and heteroaryl, the compound according to claim 39.

41. R １０ 、R １１ 、and R １２ are independently selected from -H, -F, -Cl, -Br, -CN, -CH ３ 、-CH ２ CH ３ 、-CF ３ 、-CHF ２ 、-CF ２ CH ３ 、-OCH ３ 、-OCF ３ 、-OCHF ２ 、-OAc, -NH ２ 、-NHCH ３ 、-NHAc, -C(O)NH ２ 、-C(O)NHCH ３ 、-C(O)NHCH ２ CH ３ 、-C(O)NHSO ２ CH ３ 、-C(O)NHSO ２ CH ２ CH ３ 、-CO ２ H, phenyl, cyclopropyl, cyclobutyl, imidazolyl, and tetrazolyl, the compound according to claim 40.

42. R １０ and R １２ are each -H; R １１ is -CN, -CF ３ , -CH ３ , -OCH ３ , -NH ２ , -NHCH ３ , -NHAc, -CO ２ H, -C(O)NH ２ , -C(O)NHCH ３ , -C(O)NHCH ２ CH ３ as well as the structure: 【Chemical Formula 28】 The compound according to claim 41, selected from

43. R １１ and R １２ are each -H; R １０ is -CN, -CF ３ , -CH ３ , -OCH ３ , -NH ２ , -NHCH ３ , -NHAc, -CO ２ H, -C(O)NH ２ , -C(O)NHCH ３ , -C(O)NHCH ２ CH ３ and the structure: 【Chemical 29】 The compound according to claim 41, selected from

44. R １０ and R １１ are each -H; R １２ is -CN, -CF ３ , -CH ３ , -OCH ３ , -NH ２ , -NHCH ３ , -NHAc, -CO ２ H, -C(O)NH ２ , -C(O)NHCH ３ , -C(O)NHCH ２ CH ３ and the structure: 【Chemical 30】 The compound according to claim 41, selected from

45. Y ２ has the structure: 【Chemical 31】 selected from; R １６ Each time R appears independently, halogen, -CN, -NH ２ , -OCF ３ , -OCHF ２ , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR １３ R １４ , -CO ２ R １５ is selected from; R １３ 、 R １４ 、 and R １５ is independently selected from -H, alkyl, aryl, and heteroaryl each time it appears, the compound according to claim 39.

46. R １６ is -CN, -CH ３ , -CF ３ , -C(O)NH ２ , -CO ２ CH ２ CH ３ and structure: 【Chemical 32】 The compound according to claim 45, selected from

47. Y ２ has a structure: 【Chemical 33】 selected from; R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ each occur independently, -H, halogen, -CN, -NH ２ 、-OCF ３ 、-OCHF ２ 、-OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR １３ R １４ 、and -CO ２ R １５ is selected from; provided that at least one of R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ is not -H; R １３ 、 R １４ 、 and R １５ each independently upon occurrence is selected from -H, alkyl, aryl, and heteroaryl, the compound according to claim 39.

48. R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ are each independently selected from -H, -CN, -CH ３ and -OCH ３ the compound according to claim 47

49. Y ２ has a structure: 【Chemical 34】 The compound according to claim 39, selected from

50. Structure: 【Chemical 35】 The compound according to claim 33, having a structure selected from

51. Structure: 【Chemical 36】 The compound according to claim 34, having a structure selected from:

52. Y ２ The compound according to claim 50 or 51, wherein Y is unsubstituted cycloalkyl or heterocyclyl.

53. Y ２ has a structure: 【Chemical 37】 The compound according to claim 52, selected from:

54. Y ２ has the structure: 【Chemical 38】 The compound according to claim 52, selected from:

55. Y ２ The compound according to claim 50 or 51, wherein Y is a substituted cycloalkyl or heterocyclyl.

56. Y ２ has a structure: 【Chemical Formula 39】 The compound according to claim 55, selected from:

57. Y ２ The compound according to claim 50 or 51, wherein Y is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, and hydroxyalkyl.

58. Y ２ is -CH ３ 、-CH ２ CH(CH ３ ) ２ 、-CH ２ CH ２ C≡CH, -CH ２ CH ２ OCH ３ 、-C(H)(CH ３ )CH ２ OCH ３ 、-OCH ３ 、-CH ２ OH、-CH ２ CH ２ OH、-C(CH ３ ) ２ OH、and -CH ２ OCH ３ selected from the group consisting of, the compound according to claim 57.

59. Y ２ The compound according to claim 50 or 51, wherein Y is unsubstituted heteroaryl or heteroaryl substituted with alkyl.

60. Y ２ has a structure: 【Chemical 40】 The compound according to claim 59, selected from:

61. Y ２ The compound according to claim 50 or 51, wherein Y is a substituted heteroaryl.

62. Y ２ has the structure: 【Chemical 41】 being; R １０ 、 R １１ 、 and R １２ are each independently selected from -H, halogen, -CN, -OH, -NH ２ 2, -OCF ３ 3, -OCHF ２ 2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR １３ R １４ ', and -CO ２ R １５ ; R １３ 、R １４ 、and R １５ is independently selected from -H, alkyl, aryl, and heteroaryl each time it appears, provided that at least one of R １０ 、R １１ 、and R １２ is not -H, the compound according to claim 61.

63. Y ２ has the structure: 【Chemical 42】 selected from: R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ each occur independently, -H, halogen, -CN, -NH ２ 、-OCF ３ 、-OCHF ２ 、-OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR １３ R １４ 、and -CO ２ R １５ is selected from; R １３ 、 R １４ 、 and R １５ is independently selected from -H, alkyl, aryl, and heteroaryl each time it appears, provided that at least one of R １７ 、 R １８ 、 R １９ 、 R ２０ 、 and R ２１ is not -H, the compound according to claim 61.

64. Y ２ has the structure: 【Chemical 43】 selected from: R ２２ 、 R ２３ 、 R ２４ 、 and R ２５ each occur independently, -H, halogen, -CN, -NH ２ 、 -OCF ３ 、 -OCHF ２ 、 -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR １３ R １４ 、 and -CO ２ R １５ is selected from; R １３ 、R １４ 、and R １５ is independently selected from -H, alkyl, aryl, and heteroaryl each time it appears, provided that at least one of R ２２ 、R ２３ 、R ２４ 、and R ２５ is not -H, The compound according to claim 61.

65. R ２２ 、R ２３ 、R ２４ 、and R ２５ each occur independently and are selected from -H and -CH ３ The compound according to claim 64,

66. Y ２ The compound according to claims 34, 35, 50, and 51, wherein Y is selected from unsubstituted pyridonyl, unsubstituted pyrimidinoyl, unsubstituted pyrazinonyl, unsubstituted triazinonyl, and unsubstituted quinazolinonyl.

67. Y ２ has the structure: 【Chemical 44】 The compound according to claim 66, selected from:

68. Y ２ The compound according to claims 34, 35, 50, and 51, wherein Y is selected from substituted pyridonyl, substituted pyrimidinoyl, substituted pyrazinonyl, substituted triazinonyl, and substituted quinazolinonyl.

69. Y ２ has a structure: 【Chemical 45】 being; R ６ and R ７ are each independently selected from -H, halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ , alkyl, alkoxy, alkylamino, and cycloalkyl, provided that at least one of R ６ and R ７ is not -H; or R ６ and R ７ together with the carbon atom to which they are attached form unsubstituted or substituted condensed C ５ -C ７ cycloalkyl; or Y ２ has a structure: 【Chemical Formula 46】 being; R ７ and R ８ are each independently selected from -H, halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ , alkyl, alkoxy, alkylamino, and cycloalkyl, provided that at least one of R ７ and R ８ is not -H; or R ７ and R ８ together with the carbon atom to which they are attached form unsubstituted or substituted condensed C ５ -C ７ -cycloalkyl; or Y ２ has the structure: 【Chemical 47】 being; R ６ and R ９ are each independently selected from -H, halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ , alkyl, alkoxy, alkylamino, and cycloalkyl, provided that at least one of R ６ and R ９ is not -H; or Y ２ has a structure: 【Chemical 48】 being R １０ is selected from halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ , alkyl, alkoxy, alkylamino, and cycloalkyl; or Y ２ has a structure: 【Chemical 49】 being; R １１ is halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ selected from alkyl, alkoxy, alkylamino, and cycloalkyl, the compound according to claim 68.

70. Y ２ has a structure: 【Chemical Formula 50】 The compound according to claim 68 or 69, selected from:

71. Y ２ The compound according to claim 34, 35, 50, or 51, wherein Y is N-substituted pyridonyl, N-substituted pyrimidinoyl, N-substituted pyrazinonyl, N-substituted triazinonyl, or N-substituted quinazolinonyl.

72. Y ２ The compound according to claim 71, wherein Y is N-alkyl-substituted pyridonyl, N-alkyl-substituted pyrimidinoyl, N-alkyl-substituted pyrazinonyl, N-alkyl-substituted triazinonyl, or N-alkyl-substituted quinazolinonyl.

73. Y ２ has the structure: 【Chemical 51】 The compound according to claim 72, selected from:

74. Y ２ is -NH(Y ２ '), or Y ２ is -N(Y ２ '' ２ ), a compound according to claim 50 or 51.

75. Y ２ The compound according to claim 74, wherein Y' is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

76. Y ２ ’ is -H, -OCH ３ , -CH ３ , -CH ２ CH ３ , -CH ２ OH, and -CH ２ CH ２ OH, and the compound according to claim 75, which is selected from

77. Y ２ The compound according to claim 76, wherein Y’ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

78. Y ２ ' is -H, -OH, -OCH ３ , -CH ３ , -CH ２ CH ２ OCH ３ , and structure: 【Chemical 52】 The compound according to claim 77, selected from:

79. Y ２ ’’ is each -CH ３ The compound according to claim 74, wherein is

80. Both Ys ２ The compound according to claim 74, wherein the ’’ together with the nitrogen atom to which they are attached forms a morpholinyl.

81. L １ is selected from -alkyl-, -cycloalkyl-, and -heteroaryl-CH ２ -; L ３ is absent or is -C(O)-; X １ is -H; X ２ is a cycloalkyl; Y １ is selected from aryl and heteroaryl; Y ２ is selected from alkyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, and -NH(Y ２ ') and; and Y ２ The compound according to any one of claims 1 to 4, wherein Y' is selected from -H, alkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl.

82. X ２ has a structure: 【Chemical Formula 53】 The compound according to claim 81, being:

83. L １ is -CH ２ - and is the compound according to claim 81 or 82.

84. L １ has the structure: 【Chemical 54】 The compound according to claim 81 or 82, selected from:

85. L １ has a structure: 【Chemical Formula 55】 The compound according to claim 81 or 82, selected from:

86. Y １ The compound according to any one of claims 81 to 85, wherein Y is phenyl.

87. Y １ has a structure: 【Chemical 56】 being; R １ 、R ２ 、R ３ 、R ４ 、and R ５ are independently selected from -H, halogen, -CN, -CF ３ 、-CHF ２ 、-CF ２ CH ３ 、-OCF ３ 、-OCHF ２ 、alkyl, alkoxy, and cycloalkyl; provided that at least one of R １ 、R ２ 、R ３ 、R ４ 、and R ５ is not -H. A compound according to any one of claims 81 to 85.

88. R １ 、R ２ 、R ３ 、R ４ 、and R ５ wherein two of R １ 、R ２ 、R ３ 、R ４ 、and R ５ are not -H, a compound according to claim 87.

89. R １ 、 R ２ 、 R ３ 、 R ４ 、 and R ５ where three of them are not -H, the compound according to claim 87.

90. Y １ has the structure: 【Chemical 57】 The compound according to any one of claims 87 to 89, selected from:

91. L ３ A compound according to any one of claims 81 to 90, wherein L is absent.

92. L ３ The compound according to any one of claims 81 to 90, wherein L is -C(O)-.

93. Y ２ has the structure: 【Chemical Formula 58】 The compound according to claim 91, selected from:

94. Y ２ The compound according to claim 92, wherein Y is selected from alkyl, hydroxyalkyl, and haloalkyl.

95. Y ３ is -CH ３ and -CH ２ OH, the compound according to claim 94, selected from

96. Y ２ is -NH(Y ２ '); Y ２ ' is -H, -OH, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH ２ , -CH ２ CF ３ , -CH ３ , and the structure: 【Chemical Formula 59】 The compound according to claim 92, selected from:

97. A compound or a pharmaceutically acceptable salt thereof having the structure of any of the compounds listed in Table 1.

98. A pharmaceutical composition comprising a compound according to any one of claims 1 to 97 and a pharmaceutically acceptable excipient.

99. A method for treating or preventing a disease or disorder associated with a gene deletion of phenylalanine hydroxylase, the method comprising administering to a subject in need of treatment or prevention an effective amount of a compound according to any one of claims 1 to 97.

100. A method for treating or preventing phenylketonuria, comprising administering to a subject in need of treatment or prevention an effective amount of the compound according to any one of claims 1 to 97.

101. A method for treating or preventing hyperphenylalaninemia, comprising administering to a subject in need of treatment or prevention an effective amount of the compound according to any one of claims 1 to 97.

102. The method according to any one of claims 99 to 101, wherein the compound reduces the systemic phenylalanine level in the subject.

103. A method for treating or preventing tyrosinemia (type I, II, or III), comprising administering to a subject in need of treatment or prevention an effective amount of the compound according to any one of claims 1 to 97.

104. The method according to claim 103, wherein the compound reduces the systemic tyrosine level in the subject.

105. A method for treating or preventing non-ketotic hyperglycinemia, comprising administering to a subject in need of treatment or prevention an effective amount of the compound according to any one of claims 1 to 97.

106. The method according to claim 105, wherein the compound reduces the systemic glycine level in the subject.

107. A method for treating or preventing isovaleric academia, methylmalonic academia, propionic academia, maple syrup urine disease, DNAJC12 deletion, urea cycle disorder, or hyperammonemia, comprising administering to a subject in need of treatment or prevention an effective amount of the compound according to any one of claims 1 to 97.

108. A method for treating or preventing diabetes, chronic kidney disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome, obesity-related disorders, or neurodevelopmental disorders and autism spectrum disorders, comprising administering to a subject in need of treatment or prevention an effective amount of the compound according to any one of claims 1 to 97.

109. The method according to any one of claims 99 to 108, wherein the compound inhibits SLC6A19 in the subject.

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