Small molecule inhibitors against the function of mammalian SLC6A19

Abstract

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

Description

Technical Field

[0001] (Related Application) This application claims the priority of U.S. Provisional Patent Application No. 63 / 389,244, filed on July 14, 2022.

Background Art

[0002] Phenylketonuria (PKU) is an inborn error of metabolism 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 the 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 the blood levels of phenylalanine are directly related to diet. Patients must adhere to a strict diet therapy throughout their disorder, 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 are associated with a 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 required for PAH activity, can also cause an increase in phenylalanine levels. In addition to diet, blood amino acid levels, including phenylalanine levels, are controlled 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 blood.

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 compounds of formula (Ia) or (Ib)

Chemical formula

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

[0007] Another aspect of the present invention relates to a method of 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 thereof, the method comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0008] Another aspect of the invention relates to a method of modulating SLC6A19 transport in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[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 invention will be apparent from the detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

[0012] (DETAILED DESCRIPTION) Definition For convenience, before further description of the invention, some terms used herein in the specification, examples, and appended claims are gathered here. These definitions should be read in light of the remainder of the disclosure and should be understood by those of ordinary skill 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 sake of easier understanding of the present invention, several terms and phrases are defined below and apply 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 is to be understood to mean "either" or "both" of the associated elements, i.e., elements that may exist conjunctively in some cases and disjunctively in other cases. The plurality of elements recited together with "and / or" are to be construed in the same manner, i.e., as "one or more" of the associated elements. Other elements other than those specifically identified by the clause "and / or" may exist as appropriate, whether or not they are 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 interpreted as inclusive, i.e., as including not only at least one of the elements or items in the list, but also two or more of the elements or items in the list, and optionally additional items not in the list. Conversely, terms that clearly indicate a limitation, such as "only one of" or "exactly one of", or when used in the claims, "consisting of", will refer to the inclusion of exactly one of the elements or items in the list or group. Generally, the term "or" as used in this specification should be interpreted as referring to an exclusive alternative (i.e., "one or the other but not both") only 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 as permitting 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 those other elements are 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") means, in one embodiment, at least one (optionally including two or more) A and no B (optionally including elements other than B); in another embodiment, at least one (optionally including two or more) B and no A (optionally including elements other than A); and in yet another embodiment, 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, the order of the steps or acts in that method is not necessarily limited to the order in which the steps or acts of that method are recited.

[0019] In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed, respectively, as defined in the U.S. Patent and Trademark Office's Patent Examining Manual Section 2111.03.

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

[0021] "Geometric isomer" means an isomer that differs in the orientation of substituent atoms relative to a carbon-carbon double bond, relative to a cycloalkyl ring, or relative to a bridged bicyclic ring system. The atoms (other than H) attached to each side of a carbon-carbon double bond may be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are on the same side) orientation. "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 hindered 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 enantiomeric 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 enantiomeric pair using an optically active amine (subsequently followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each isomer of an enantiomeric 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, if desired, by asymmetric synthesis or by derivation using a chiral auxiliary, and 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 subsequently, the diastereomers thus formed are resolved by means such as fractional crystallization or chromatography well-known in the art, and then 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 mole ratio of the enantiomer (or diastereomer), or the mole of the enantiomer (or diastereomer), to the mole of the optical isomer added to the mole of the enantiomer (or diastereomer). When the stereochemistry of the disclosed compound is named or depicted by structure, the named or depicted 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 depicted by structure, the named or depicted 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 depicted by structure, the named or depicted 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 one enantiomer-rich mixture 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 the diastereomer without other diastereomers, multiple 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 also meant to include compounds that differ only in that one or more isotope-rich atoms are present. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 replacement of carbon by carbon-rich

[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 prodrugs is to include selected moieties that are 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 phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier", as used herein, means 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 are: (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., they 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 a 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 salt, sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt, 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 therapy, is that amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human), alleviates symptoms, ameliorates the condition, or delays the onset of the disease condition, according to clinically acceptable standards applicable to any medical treatment, for the disease or condition to be treated or for cosmetic purposes, with a reasonable benefit / risk ratio.

[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 an undesirable condition, the treatment is therapeutic (i.e., it reduces, ameliorates, 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] Aliphatic chains include the classes of alkyl, alkenyl, and alkynyl as defined below. Aliphatic straight chains are limited to unbranched carbon chain moieties. 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 alkyl groups, alkenyl groups, or alkynyl groups.

[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 not specified. 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 defined above 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 defined above that is substituted with at least one halogen.

[0039] As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above 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, e.g., 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, bicyclic, or bridged or spirocyclic, or polycyclic saturated carbon ring having 3 to 12 carbon atoms each. Preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably 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 4 to 6 carbons and heteroatoms in their ring structure. The cycloheteroalkyl group may be substituted or unsubstituted.

[0044] Unless otherwise specified, "lower alkyl" as used herein is an alkyl group as defined above, but having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, in its backbone structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, 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. Illustrative alkenyls having from 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 can be in various isomeric forms, and the unsaturated bond(s) can be at any position in that moiety and can assume 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" means a 3- to 12-membered substituted or unsubstituted monocyclic aromatic group, including those in which each atom of the ring is carbon (i.e., carbocyclic aryl) or those in which one or more atoms are heteroatoms (i.e., 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, etc. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0048] As used herein, the term "halo", "halide", or "halogen" means halogen and includes, for example, but not limited to, fluoro, chloro, bromo, iodo, etc., and includes 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, etc. 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] As used herein, the term "substituted" refers to a moiety having a substituent that replaces a 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 (e.g., does not spontaneously convert by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In one broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in an organic compound. 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 an aromatic or heteroaromatic moiety. In a preferred embodiment, the substituent on the substituted alkyl is selected from C 1~6 alkyl, C 3~6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In a more preferred embodiment, the substituent on the substituted alkyl is selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that, where appropriate, the substituent itself may be substituted. Unless stated otherwise as "unsubstituted", references herein to the chemical portions are understood to include substituted variants as well. 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 more than once in any structure, its definition at other sites in the same structure shall be independent of that at other sites.

[0052] As used herein, "low molecule" 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 molecule" refers to an organic, inorganic, or organometallic compound, typically having 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 drugs 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 can be the same as, or different from, a prophylactically effective amount that is necessary to prevent the onset of a disease or disease symptom. An effective amount can be administered by one or more administrations, applications, or dosages. The therapeutically effective amount of a composition depends on the composition selected. The composition can 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 can include a single treatment or a series of treatments.

[0055] The terms "lowering," "decreasing," "decreased," "decrease," "reduce," and "inhibit" are all used herein generally to mean a statistically significant amount of decrease compared to a reference value. However, to avoid misunderstanding, "lower," "reduce," or "decrease" or "inhibit" typically means a decrease of at least 10% compared to a reference, 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 can include, at most, for example, a complete absence of a given entity or parameter compared to a reference level, or a decrease of any amount from 10 - 99% 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 a statistically significant amount of increase; 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 the 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. Radio-labeled pharmaceuticals, e.g., radio-labeled antibodies, contain 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 radio-labeled 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] Compounds of the present invention One aspect of the present invention relates to a compound of formula (Ia) or (Ib):

Chemical formula

[0061] In some embodiments, the compound has the structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0062] In some embodiments, Y3 and Y4 are each -H. In other embodiments, Y3 and Y4 are each alkyl. In other embodiments, Y3 and Y4 are each halo.

[0063] In some embodiments, one of Y3 and Y4 is -H; the other of Y3 and Y4 is not -H.

[0064] In some 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.

[0065] In some embodiments, one of X1 and X2 is -H; the other of X1 and X2 is -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, and the structure:

[0066] In some embodiments, one of X1 and X2 is -H; the other of X1 and X2 is -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, and the structure: [ka] is selected from.

[0067] In some embodiments, X1 is -H and X2 is -CH3, or X2 is -H and X1 is -CH3.

[0068] In some embodiments, X1 is -H and X2 has the structure: [ka] or X2 is -H and X1 has the structure: [ka] is.

[0069] In some embodiments, L1 is absent.

[0070] In some embodiments, L1 is chosen from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH2-.

[0071] In some embodiments, L1 is selected from -CH2-, -C(H)(CH3)-, -CH2CH2-, and -C(H)(OH)CH2-.

[0072] In some embodiments, L1 has the structure: [ka] is.

[0073] In some embodiments, L1 has the structure: [ka] is selected from.

[0074] In some embodiments, L1 has the structure: [Chemistry] selected from

[0075] In some embodiments, the compound has the structure: [Chemistry] [Chemistry] and has a structure selected from

[0076] In some embodiments, Y1 is unsubstituted aryl.

[0077] In some embodiments, Y1 is selected from unsubstituted phenyl and unsubstituted naphthyl.

[0078] In some embodiments, Y1 is substituted aryl.

[0079] In some embodiments, Y1 has the structure: [Chemistry] wherein; R1, R2, R3, R4, and R5 are each independently selected from -H, halogen, -CN, -CF3, -CHF2, -CF2CH3, -OCF3, -OCHF2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, provided that at least one of R1, R2, R3, R4, and R5 is not -H.

[0080] In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -OCH3, -OCF3, -OCHF2, and the structure: [Chemistry] selected from

[0081] In some embodiments, R1, R2, R3, R4, and R5 are independently -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCF3, and the structure:

Chemical formula

[0082] In some embodiments, two of R1, R2, R3, R4, and R5 are not -H.

[0083] In some embodiments, three of R1, R2, R3, R4, and R5 are not -H.

[0084] In some embodiments, Y1 has the structure:

Chemical formula

[0085] In some embodiments, Y1 is unsubstituted heteroaryl.

[0086] In some embodiments, Y1 has the structure:

Chemical formula

[0087] In some embodiments, Y1 is substituted heteroaryl.

[0088] In some embodiments, Y1 has the structure:

Chemical formula

[0089] In some embodiments, L2 is absent.

[0090] In some embodiments, L2 is -CH2-.

[0091] In some embodiments, L3 is absent.

[0092] In some embodiments, L3 is -C(O)-.

[0093] In some embodiments, the compound has a structure:

Chemical formula

[0094] In some embodiments, Y2 is unsubstituted heteroaryl.

[0095] In some embodiments, Y2 has a structure:

Chemical formula

[0096] In some embodiments, Y2 has a structure:

Chemical formula

[0097] In some embodiments, Y2 is substituted heteroaryl.

[0098] In some embodiments, Y2 has a structure: [Chemistry] and; R 10 R 11 and R 12 are independently selected from -H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 -CO2R 15 and -C(O)NHSO2R 15 provided that at least one of R 10 R 11 and R 12 is not -H; R 13 R 14 and R 15 are independently selected from -H, alkyl, aryl, and heteroaryl each time they appear.

[0099] In some embodiments, R 10 R 11 and R 12 are 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.

[0100] In some 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 structure: [Chemical formula] selected from the following.

[0101] In some 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 structure: [Chemical formula] selected from the following.

[0102] In some 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 structure: [Chemical formula] selected from the following.

[0103] In some embodiments, Y2 has the structure: [Chemical formula] selected from the following; R 16 is, independently for each occurrence, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , -CO2R 15 selected from the following; R 13 R 14 and R 15is independently selected, for each occurrence, from -H, alkyl, aryl, and heteroaryl.

[0104] In some embodiments, R 16 is -CN, -CH3, -CF3, -C(O)NH2, -CO2CH2CH3, and the structure:

Chemical formula

[0105] In some embodiments, Y2 is the structure:

Chemical formula

[0106] In some embodiments, R 17 , R 18 , R 19 , R 20 , and R 21 are independently selected from -H, -CN, -CH3, and -OCH3.

[0107] In some embodiments, Y2 has the structure: [ka] is selected from.

[0108] In some embodiments, the compound has the structure: [ka] The compound has a structure selected from:

[0109] In some embodiments, Y2 is unsubstituted cycloalkyl or heterocyclyl.

[0110] In some embodiments, Y2 has the structure: [ka] is selected from.

[0111] In some embodiments, Y2 has the structure: [ka] is selected from.

[0112] In some embodiments, Y2 is substituted cycloalkyl or heterocyclyl.

[0113] In some embodiments, Y2 has the structure: [ka] is selected from.

[0114] In some embodiments, Y2 is chosen from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, and hydroxyalkyl.

[0115] In some embodiments, Y2 is selected from -CH3, -CH2CH(CH3)2, -CH2CH2C≡CH, -CH2CH2OCH3, -C(H)(CH3)CH2OCH3, -OCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, and -CH2OCH3.

[0116] In some embodiments, Y2 is unsubstituted heteroaryl or heteroaryl substituted with alkyl.

[0117] In some embodiments, Y2 has the structure:

Chemical formula

[0118] In some embodiments, Y2 is substituted heteroaryl.

[0119] In some embodiments, Y2 has the structure:

Chemical formula

[0120] In some embodiments, Y2 has the structure: [Chemical formula] selected from; R 17 、R 18 、R 19 、R 20 、and R 21 are, each occurrence independently, -H, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 、and -CO2R 15 selected from; R 13 、R 14 、and R 15 are, each occurrence independently, -H, alkyl, aryl, and heteroaryl, provided that at least one of R 17 、R 18 、R 19 、R 20 、and R 21 is not -H.

[0121] In some embodiments, Y2 has the structure: [Chemical formula] selected from; R 22 、R 23 、R 24 and R 25 are, each occurrence independently, -H, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 、and -CO2R 15 selected from; R 13 、R 14 、and R 15is independently selected from -H, alkyl, aryl, and heteroaryl for each occurrence, provided that R 22 R 23 R 24 and R 25 at least one of which is not -H.

[0122] In some embodiments, R 22 R 23 R 24 and R 25 are independently selected from -H and -CH3 for each occurrence.

[0123] In some embodiments, Y2 is selected from unsubstituted pyridonyl, unsubstituted pyrimidinoyl, unsubstituted pyrazinonyl, unsubstituted triazinonyl, and unsubstituted quinazolinonyl.

[0124] In some embodiments, Y2 has the structure:

Chemical formula

[0125] In some embodiments, Y2 is selected from substituted pyridonyl, substituted pyrimidinoyl, substituted pyrazinonyl, substituted triazinonyl, and substituted quinazolinonyl.

[0126] In some embodiments, Y2 has the structure:

Chemical formula

Chemical formula

[0127] In some embodiments, Y2 has the structure selected from: [Chemical formula] [[ID=%54]]

[0128] ​In some embodiments, Y2 is N-substituted pyridonyl, N-substituted pyrimidinoyl, N-substituted pyrazinonyl, N-substituted triazinonyl, or N-substituted quinazolinonyl.

[0129] In some embodiments, Y2 is N-alkyl-substituted pyridonyl, N-alkyl-substituted pyrimidinoyl, N-alkyl-substituted pyrazinonyl, N-alkyl-substituted triazinonyl, or N-alkyl-substituted quinazolinonyl.

[0130] In some embodiments, Y2 has the structure:

Chemical formula

[0131] In some embodiments, Y2 is -NH(Y2') or Y2 is -N(Y2'')2.

[0132] In some embodiments, Y2' is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

[0133] In some embodiments, Y2' is selected from -H, -OCH3, -CH3, and -CH2CH2OH.

[0134] In some embodiments, Y2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

[0135] In some embodiments, Y2' is selected from -H, -OH, -OCH3, -CH3, -CH2CH2OCH3, and the structure:

Chemical formula

[0136] In some embodiments, each of Y2'' is -CH3.

[0137] In some embodiments, Y2’’ together with the nitrogen atom to which they are attached form a morpholinyl.

[0138] In some embodiments, the compound has the structure:

Chemical formula

[0139] In some embodiments, the compound has the structure:

Chemical formula

[0140] In some embodiments, L1 is selected from -alkyl-, -cycloalkyl-, and -heteroaryl-CH2-; L2 is absent; L3 is absent or -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, and hydroxyalkyl.

[0141] In some embodiments, X2 has the structure:

Chemical formula

[0142] In some embodiments, L1 is -CH2-. In other embodiments, L1 has the structure:

Chemical formula

Chemical formula

[0143] In some embodiments, Y1 has the structure: [ka] and; R1, R2, R3, R4, and R5 are independently selected from -H, halogen, -CN, -CF3, -CHF2, -CF2CH3, -OCF3, and -OCHF2, provided that at least one of R1, R2, R3, R4, and R5 is not -H.

[0144] In some embodiments, two of R1, R2, R3, R4, and R5 are not -H.

[0145] In some embodiments, the structure: [ka] is selected from.

[0146] In some embodiments, L3 is absent. In other embodiments, L3 is -C(O)-.

[0147] In some embodiments, Y2 has the structure: [ka] is.

[0148] In some embodiments, Y2 is alkyl or hydroxyalkyl.

[0149] In some embodiments, Y2 is selected from -CH3 and -CH2OH.

[0150] In some embodiments, Y2 is -NH(Y2'); Y2' is -H or -CH3.

[0151] In some embodiments, the compound is selected from Table 1 below.

Table 1

Table 2

Table 3

[0152] In some embodiments, the compound is an atropisomer. In addition, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, compounds produced by replacing hydrogen with deuterium or tritium, or by replacing carbon with 13 C or 14 C-rich carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes for biological assays, or as therapeutic agents associated with the present invention. For example, in the case of the variable group R1, (C1-C4) alkyl or -O(C1-C4) alkyl can be appropriately deuterated (e.g., CD3, OCD3).

[0153] Any compound of the present invention can also be radiolabeled for the preparation of radiopharmaceuticals.

[0154] Treatment method One aspect of the present invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with amino acid level abnormalities by modulating SLC6A19 transport.

[0155] Another aspect of the present invention relates to a method of modulating SLC6A19 transport in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0156] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder associated with a genetic defect in 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 (Ia) or (Ib).

[0157] 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 (Ia) or (Ib).

[0158] 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 (Ia) or (Ib).

[0159] In some embodiments, the compound reduces the systemic phenylalanine level in the subject.

[0160] In some embodiments, the present invention relates to a method for treating or preventing tyrosinemia (type I, II, or III) in a subject in need of treatment or prevention, the method comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0161] In some embodiments, the compound reduces the systemic glycine level in the subject.

[0162] In some embodiments, the present invention relates to a method for 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 of treatment or prevention, the method comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0163] In some embodiments of any one of the disclosed methods, the compound modulates the SLC6A19 of the subject.

[0164] In some embodiments of any one of the disclosed methods, the compound inhibits the SLC6A19 of the subject.

[0165] In some embodiments of any one of the disclosed methods, the compound modulates the SLC6A19 transport of the subject.

[0166] In some embodiments of any one of the disclosed methods, the compound inhibits the SLC6A19 transport of the subject.

[0167] In some embodiments, the compound reduces the systemic amino acid level in the subject.

[0168] 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.

[0169] In some embodiments of any one of the disclosed methods, the compound of formula (Ia) or (Ib) is defined as follows: The following structure, or a pharmaceutically acceptable salt thereof

Chemical formula

[0170] In some embodiments of any one of the disclosed methods, the compound is selected from the structure of any one of the compounds described in Table 1.

[0171] Pharmaceutical composition, route of administration, and dosage In some embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0172] In some embodiments, 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 a drug useful for the treatment of ischemic reperfusion injury.

[0173] 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 combining one or more additional pharmaceutically active agents.

[0174] As described above, "effective amount" refers to any amount 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 undesirable 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 present 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 present invention and / or other therapeutic agent 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 expected 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.

[0175] 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.

[0176] 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 a therapeutic outcome when administered one or more times a day. The dosage may be appropriately adjusted according to the mode of administration to achieve the desired drug level, either 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 insufficient 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.

[0177] For any compound described herein, a therapeutically effective amount can be determined in advance from animal models. Therapeutically effective dosages can also be determined from human data for 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 efficacy of the compound being administered. Adjusting the dosage to achieve maximum efficiency is well within the capabilities of those skilled in the art based on the above methods and other methods well known in the art.

[0178] The formulations of the present invention can be administered in a pharmaceutically acceptable solution, which may typically contain salts, buffers, preservatives, compatible carriers, adjuvants at pharmaceutically acceptable concentrations, and may optionally contain other therapeutic components.

[0179] 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 can 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., locally to the eye), inhalation, and topical.

[0180] For intravenous and other parenteral routes of administration, the compounds of the invention can be formulated as lyophilized dry formulations, as lyophilized formulations of the active compound inserted into 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.

[0181] 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 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 mixtures obtained as appropriate are comminuted, and if desired, after adding suitable adjuvants, the granule mixtures are processed to obtain cores 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, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinyl pyrrolidone, 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.

[0182] 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, and the moiety (a) inhibits acid hydrolysis; and (b) enables transfer from the stomach or intestine into the bloodstream. Improvement in the overall stability of the above component(s) and extension of the in vivo circulation time are also desirable. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, 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 4:185-9 (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.

[0183] For the component (or derivative), the location of release is the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. One of ordinary skill in the art has access to formulations that do not dissolve in the stomach and release the substance in the duodenum or other intestine. Preferably, release avoids adverse events in the gastric environment by protecting the compound (or derivative) of the present invention or by releasing the biologically active substance beyond the gastric environment, e.g., in the intestine.

[0184] 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.

[0185] A single coating or a mixture of coatings may also be used in tablets, which are not intended to protect from the stomach. This may include a sugar coating or a coating to make 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.

[0186] The therapeutic agent may be included in the formulation as fine multi-particles 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.

[0187] 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 encapsulation in liposomes or microspheres), and then further included in an edible product, such as a refrigerated beverage containing coloring agents and flavoring agents.

[0188] 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.

[0189] 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.

[0190] 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 alcoholic solutions to granulate the therapeutic agent.

[0191] An anti-friction material may be included in the formulation of a 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.

[0192] 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.

[0193] To assist in the dissolution of the therapeutic agent into an 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 alone or as mixtures in different ratios in the formulation of the compounds or derivatives of the present invention.

[0194] 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 can 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 a dosage appropriate for their administration.

[0195] For buccal administration, the composition may be in the form of tablets or lozenges formulated by conventional methods.

[0196] 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, and those designed for transdermal, transmucosal, oral or pulmonary administration.

[0197] For administration by inhalation, the compounds for use according to the present 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.

[0198] 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).

[0199] 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.

[0200] 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.

[0201] 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 appropriate propellant materials in addition to conventional 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 into different formulations depending on the type of chemical modification or the type of device used.

[0202] 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 a buffer and a monosaccharide (e.g., for stabilization of the inhibitor and adjustment of osmotic pressure). Nebulizer formulations may also contain a surfactant to reduce or prevent surface induced aggregation of the compounds of the present invention caused by atomization of the solution in forming the aerosol.

[0203] 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, assisted by 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 soybean lecithin. Oleic acid may also be useful as a surfactant.

[0204] Formulations for dispensing from a powder inhaler device comprise a micronized dry powder containing the compound (or derivative) of the invention and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol, in an amount that promotes dispersion of the powder from the device, for example, 50 - 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 - 5 μm, for optimal delivery to the deep lung.

[0205] Transnasal delivery of the pharmaceutical compositions of the invention is also contemplated. Transnasal delivery allows the pharmaceutical composition 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.

[0206] 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 defined volume chamber, which chamber has holes 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 in a piston arrangement. Such devices are commercially available.

[0207] Alternatively, a plastic squeeze bottle having holes or openings 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.

[0208] The compounds may be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion, when it is desirable to deliver them systemically. Injectable formulations may be provided in unit dosage forms, e.g., in ampoules or multi-dose containers, with added preservatives. The composition may be in a dosage form such as a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents.

[0209] 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 appropriately contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions.

[0210] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0211] 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.

[0212] In addition to the above-described preparations, the compound may also be formulated as a depot preparation. Such long-acting preparations may be formulated together with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or may be formulated as poorly soluble derivatives, such as poorly soluble salts.

[0213] The pharmaceutical composition may also include a suitable solid-phase 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.

[0214] Suitable forms of the pharmaceutical preparation in liquid or solid form are, for example, an aqueous solution or saline solution for inhalation, microencapsulated in microscopic gold particles, encochleated, coated, contained in liposomes, sprayed, an aerosol, a pellet for implantation in the skin, or dried on a sharp object for rubbing into the skin. The pharmaceutical composition also 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).

[0215] 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 can also be prepared as alkali metal salts or alkaline earth metal salts such as sodium, potassium, or calcium salts of carboxylic acid groups.

[0216] 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).

[0217] 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.

[0218] 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 include, 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 any shape.

[0219] 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).

[0220] 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 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".

[0221] 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.

[0222] 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 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

[0223] The present invention will be described in more detail in the following examples, which do not limit the scope of the present invention described in the claims.

[0224] Example 1: SLC6A19 Isoleucine Transport Assay

[0225] <H 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 the SLC6A19-encoding plasmid and the TMEM27-encoding plasmid 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).

[0226] 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 poly-D-lysine-coated 96-well cell culture-treated plates. On day 1, SLC6A19 expression was induced by dispensing tetracycline at a final concentration of 1 μg / mL using a Tecan D300e digital dispenser. On day 2, transport assays were performed. Media was removed from the plates using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio), and cells were washed with 175 μL of live cell imaging solution (Thermo Fisher) using the Blue Washer. After washing, 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 CaCl, 1.2 mM MgCl, 11 mM HEPES, 10 mM glucose, pH 7.4) at room temperature. After 20–60 min, 3.3 mM 13 C6, 15 30 μL of NL-isoleucine (Cambridge Isotope Laboratories) solution was added. After 20 minutes of incubation with the isoleucine substrate at room temperature, the cells were washed with 175 μL of live cell imaging solution using a Blue Washer. The cells were then lysed in 150 μL of D-leucine-d10 (CDN Isotopes) in ultrapure water (15 μM). 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 NL-isoleucine was added to wells containing untreated cell lysate. The plate was placed back on 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 and sediment cell debris. The supernatant was diluted in acetonitrile + 0.1% formic acid (1:10) in a polypropylene plate.

[0227] Assay: Isoleucine Transport Assay in 384-Well Format On day 0, a stable cell line was seeded at a density of 20,000 cells per well in a medium containing 1 μg / mL of tetracycline in a 384-well cell culture-treated plate coated with poly-D-lysine using a Viaflo 384-well pipette. The next day (day 1), the transport assay was performed. Using the GentleSpin setting of the Centrifugal Blue Washer (Blue Cat Bio), the medium was removed from the plate, 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 and diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1. 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, 8.6 μL of 13 C6, 15 a solution (3.3 mM) of N-L-isoleucine (Cambridge Isotope Laboratories) was added. After incubation at room temperature with the isoleucine substrate for 20 minutes, the cells were washed with 80 μL of live cell imaging solution using the Blue Washer. Then, the cells were dissolved in 80 μL of an ultrapure aqueous solution (15 μM) of D-leucine-d10 (CDN Isotopes). To facilitate dissolution, it was placed on a shaker at 700 rpm for at least 2 hours. After dissolution, 13 C6, 15The standard dilution curve of N-L-isoleucine was added to the wells containing the lysate of untreated cells. To ensure proper mixing of the standard curve, the plate was returned to the shaker for at least 5 minutes. Then, the plate was centrifuged at 4000 rpm for 10 minutes to pellet and precipitate the cell debris. The supernatant was diluted with acetonitrile + 0.1% formic acid (1:10) on a polypropylene plate.

[0228] Using RapidFire365-QTOF 6545 (Agilent), 13 C6, 15 the analysis of N-L-isoleucine was performed. For the analysis of quantitative samples, automated solid-phase extraction (HILIC H6 cartridge) before injection into the mass spectrometry was utilized. The samples were loaded using 95% acetonitrile, 0.1% formic acid and eluted from the cartridge in 5% acetonitrile, 0.1% formic acid and directly analyzed by ESI-MS (electrospray ionization). Quantification of the detected substances was carried out from high-resolution full-scan data using Agilent Masshunter Quant software.

[0229] Example 2: Preparation of Exemplary Compounds

[0230]

Chemical Structure

[0231] Step 2 Et2Zn (56 mL, 55.98 mmol) was added to a solution of A2 (8.7 g, 37.32 mmol) in anhydrous DCE (100 mL) at 0 °C under a N2 atmosphere, and the resulting mixture was stirred at 0 °C for 15 minutes. Then, CH2I2 (4.51 mL, 55.98 mmol) was added dropwise at 0 °C under a N2 atmosphere, 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 (eluted with 0 - 50% EtOAc / PE) to obtain A3 (7.1 g, yield 77%) as a yellow oil. LC / MS (ESI) m / z: 248 (M + H) + .

[0232] Step 3 10% Pd / C (1.4 g) and (Boc)₂O (7.53 g, 34.49 mmol) were added to a solution of A3 (7.1 g, 28.74 mmol) in EtOAc (100 mL) under N₂ conditions. The resulting suspension was degassed under vacuum and purged several times with H₂. Then, the mixture was stirred at room temperature in a H₂ atmosphere for 4 hours. Subsequently, the mixture was filtered through a Celite® pad, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 - 50% EtOAc / PE) to obtain A4 (5.5 g, 90% yield) as a yellow oily substance. LC / MS (ESI) m / z: 214 (M + H) + .

[0233] Step 4 TEA (3.0 g, 29.1 mmol) and DPPA (4.8 g, 17.46 mmol) were added to a solution of A4 (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 A5 (3.5 g, 99% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 239 (M + H) + .

[0234] Step 5 PPh₃ (7.71 g, 29.42 mmol) was added to a solution of A5 (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 A6 (3.1 g, 99% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 213 (M + H) + .

[0235] Step 6 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 A6 (3.1 g, 14.62 mmol) and AcOH (8 drops) in MeOH (60 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 18 h under a N2 atmosphere. The mixture was then 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 A7 (3.2 g, 60% yield) as a yellow oil. LC / MS (ESI) m / z: 363 (M + H) + .

[0236] Step 7 (1-Ethoxycyclopropoxy)trimethylsilane (2.31 g, 13.26 mmol) and NaBH3CN (1.11 g, 17.68 mmol) were added to a mixture of A7 (3.2 g, 8.84 mmol) and AcOH (5.06 mL, 88.4 mmol) in THF (60 mL) and EtOH (30 mL) at 0 °C, and the resulting mixture was stirred at 80 °C for 18 h under a N2 atmosphere. The mixture was then 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 (eluting with 0 - 10% MeOH / DCM) to give A8 (2.9 g, 82% yield) as a yellow oil. LC / MS (ESI) m / z: 403 (M + H) + .

[0237] Step 8 TFA (4 mL) was added to a solution of A8 (1.2 g, 2.99 mmol) in DCM (16 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give the crude product of A9 (820 mg, 91% yield), which was used in the next step without further purification. LC / MS (ESI) m / z: 303 (M + H)+ .

[0238]

Chem.

[0239] Project 2 DPPA (750.3 mg, 2.73 mmol) was added dropwise to a solution of B2 (530.0 mg, 2.49 mmol) and TEA (301.8 mg, 2.98 mmol) in THF (15 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 17 hours. Thereafter, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, concentrated, and B3 was obtained as a colorless oily substance and used in the next step without further purification. LC / MS (ESI) m / z: 183 (M - 56 + H) + .

[0240] Project 3 PPh3 (990.6 mg, 3.78 mmol) was added to a solution of B3 (450.0 mg, 1.89 mmol) in THF (20 mL) and H2O (10 mL), and the resulting mixture was stirred at room temperature for 17 hours. Then, the mixture was concentrated to obtain B4, which was used in the next step without further purification. LC / MS (ESI) m / z: 213 (M+H) + .

[0241] Step 4 AcOH (480.9 mg, 8.01 mmol) and 2,4-dimethoxybenzaldehyde (279.4 mg, 1.68 mmol) were added to a solution of B4 (340.0 mg, 1.60 mmol) in DCM (10 mL) at room temperature, and the resulting mixture was stirred for 1.5 hours before NaBH(OAc)3 (678.9 mg, 3.20 mmol) was added at 0 °C. Then, the reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous NaHCO3 (100 mL, water), and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain B5 (320.0 mg, 55% yield) as an oily substance. LC / MS (ESI) m / z: 363 (M+H) + .

[0242] Step 5 (1-Ethoxycyclopropoxy)trimethylsilane (384.7 mg, 2.21 mmol), NaBH3CN (138.7 mg, 2.21 mmol) and AcOH (530.2 mg, 8.83 mmol) were added to a solution of B5 (320.0 mg, 0.88 mmol) in THF (20 mL) and EtOH (10 mL) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3 solution (30 mL, water), and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM:MeOH = 100:1 to 20:1) to give B6 (350.0 mg, 98% yield) as an oily substance. LC / MS (ESI) m / z: 403 (M+H) + .

[0243] Step 6 TFA (5 mL) was added to a solution of B6 (350.0 mg, 0.87 mmol) in DCM (20 mL) at 0 °C under a N2 atmosphere. The resulting mixture was warmed to 20 °C and stirred for 4 h. Then, the reaction mixture was concentrated under reduced pressure to give B7 as an oily substance, which was used in the next step without further purification. LC / MS (ESI) m / z: 303 (M+H) + .

[0244]

Chemical formula

[0245]

Chemical formula

[0246] Step 1 - Method B HATU (1.3 equiv) was added to a DMF mixture of D2 (1.2 equiv) and DIEA (3 equiv), and the resulting mixture was stirred at room temperature for 5 - 10 minutes before adding A9. The reaction mixture was stirred for 15 minutes, 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 to give D3.

[0247] Synthesis of Ethyl 2-(4-(Cyclopropyl(3,4 - dimethoxybenzyl)amino)-2 - azabicyclo[4.1.0]heptan - 2 - yl)-2 - oxoacetate ​ DIEA (0.97 mL, 5.55 mmol) and D1 (302 mg, 2.22 mmol) were added to a solution of A9 (560 mg, 1.85 mmol) in DCM (20 mL) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with water (50 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 5% MeOH / DCM) to obtain D3 (650 mg, 87% yield) as a yellow oily substance. LC / MS (ESI) m / z: 403 (M + H) + .

[0248]

Chemical formula

[0249]

Chemical formula

[0250] Step 2 TEA (3 eq) and F2 (1.2 eq) were added to a MeCN solution of A9 (1 eq) at 0 °C, and the reaction mixture was stirred at 50 °C for 18 h. 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 to obtain F3.

[0251] Synthesis of 4-(cyclopropyl(3,4-dimethoxybenzyl)amino)-N-methyl-2-azabicyclo[4.1.0]heptane-2-carboxamide [Chemical formula] Step 1 CDI (233 mg, 1.44 mmol) was added dropwise to a solution of methylamine HCl (80.4 mg, 1.2 mmol) in anhydrous THF (4 mL) at 0 °C under a N2 atmosphere, and the resulting mixture was stirred at room temperature for 30 min until complete conversion. Then, the mixture was concentrated under reduced pressure to obtain the crude product of F2, which was used in the next step without further purification. *

[0252]

[0252] Step 2 TEA (0.42 mL, 3 mmol) and F2 (150 mg, 1.2 mmol) were added to a MeCN (10 mL) solution of A9 (302 mg, 1 mmol) at 0 °C, and the resulting mixture was stirred at 50 °C for 18 h. Then, the mixture was diluted with water (90 mL) and extracted twice with DCM (40 mL). 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 (eluted with 0 - 10% MeOH / DCM) to obtain F3 (350 mg, 97% yield) as a yellow oily substance. LC / MS (ESI) m / z: 360 (M + H) + .

[0253] [Chemical formula] TEA (0.9 mL, 6.45 mmol) and TMSNCO (297 mg, 2.58 mmol) were added to a solution of A9 (650 mg, 2.15 mmol) in THF (10 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 1 hour. Then, the mixture was diluted with water (100 mL) and extracted twice with DCM (50 mL). The combined organic layers were washed with brine (120 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 G1 (470 mg, 63% yield) as a yellow oily substance. LC / MS (ESI) m / z: 346 (M + H) + .

[0254]

Chemical Structure

[0255] Step 2 10% Pd / C (74 mg, 0.069 mmol) was added to a solution of H2 (284 mg, 0.69 mmol) in EtOAc (16 mL) and MeOH (4 mL) under nitrogen. The resulting suspension was degassed under vacuum, purged several times with H2, and stirred for 1 hour at room temperature under a H2 atmosphere. Subsequently, 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 - 6% MeOH / DCM) to give H3 (70 mg, 27% yield) as a yellow oily substance. LC / MS (ESI) m / z: 381 (M + H) + .

[0256]

Chemical formula

[0257] Synthesis of 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2-carboxamide

Chemical formula

[0258]

Chemical formula

[0259]

Chemical formula

[0260]

Chem.

[0261]

Chem.

[0262]

Chemical Structure

[0263] Step 2 TEA (5 eq) and L2 (1.2 eq) were added to a DCM solution of I2 (1 eq) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. 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 L3.

[0264]

Chemical formula

[0265] Step 3: Synthesis of 4-P1 TEA (0.2 mL, 1.45 mmol) and L5 (60 mg, 0.35 mmol) were added to a DCM (10 mL) solution of L6 (60 mg, 0.29 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. Then, the mixture was diluted with water (80 mL) and extracted twice with DCM (30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to obtain the racemic mixture (66 mg, yield 50%) as a white solid. LC / MS (ESI) m / z: 453 (M + H) + . Then, the mixture was further purified by SFC (Shimadzu E-UC; Chiralcel OZ 100 * 4.6 mm 5 μm; OZ-M-D-10-40) to obtain Compound 21 (18 mg, yield 27%, d.e. >98%). 1H NMR (400 MHz,MeOD) δ 7.27-7.21 (m,2H),7.14 (d,J = 8.1 Hz,2H),6.65 (d,J = 2.0 Hz,1H),3.98-3.80 (m,1H),3.39-3.31 (m,1H),3.05 (t,J = 11.7 Hz,1H),2.77 (s,3H),2.75-2.68 (m,1H),2.67-2.61 (m,1H),2.49-2.39 (m,2H),2.09-2.01 (m,2H),1.49-1.38 (m,1H),1.27-1.17 (m,2H),0.97-0.85 (m,3H),0.75-0.61 (m,2H),0.36-0.28 (m,1H); 19 F NMR (377 MHz, MeOD) δ -59.63 (s).

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

[0266] Incorporation by Reference All U.S. patents, as well as all U.S. and PCT patent application publications, cited in this specification are hereby incorporated by reference herein.

[0267] 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 several embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. The compound of formula (Ia) or (Ib): 【Chemical 1】 or a pharmaceutically acceptable salt thereof [wherein, L １ is absent or is selected from —alkyl—, —hydroxyalkyl—, —cycloalkyl—, and —heteroaryl—CH ２ —; L ２ is absent or is -CH ２ -; L ３ is absent or is -C(O)-; X １ and X ２ are each independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, heterocyclyl, aryl, and arylalkyl; 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 and Y ４ are each independently selected from -H, halo, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, and alkyl-CO ２ H].

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

3. Structure: 【Chemical Formula 3】 The compound according to claim 1, having

4. Y ３ and Y ４ The compound according to claim 2 or 3, wherein each of them is H.

5. 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 4

6. 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 as well as the structure: [Chemical Formula 4] The compound according to claim 5, selected from

7. 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 6

8. X １ is -H, and X ２ has the structure: 【Chemical Formula 5】 or X ２ is -H and X １ has the structure: 【Chemical Formula 6】 The compound according to claim 6, being

9. L １ The compound according to any one of claims 1 to 8, wherein L is absent.

10. L １ is - alkyl -, - hydroxyalkyl -, - cycloalkyl -, and - heteroaryl - CH ２ - selected from, a compound according to any one of claims 1 to 8.

11. L １ is -CH ２ -, -C(H)(CH ３ ), -CH ２ CH ２ -, and -C(H)(OH)CH ２ -, the compound according to claim 10, selected from

12. L １ has a structure: 【Chemical 7】 The compound according to claim 10, being

13. L １ has a structure: 【Chemical 8】 The compound according to claim 10, selected from

14. L １ has the structure: 【Chemical Formula 9】 The compound according to claim 10, selected from

15. Structure: 【Chemical 10】 【Chemical 11】 The compound according to any one of claims 9 to 14, having a structure selected from

16. Y １ The compound according to any one of claims 1 to 15, wherein Y is unsubstituted aryl.

17. Y １ The compound according to claim 16, wherein Y is selected from unsubstituted phenyl and unsubstituted naphthyl.

18. Y １ The compound according to any one of claims 1 to 17, wherein Y is a substituted aryl.

19. Y １ has a structure; 【Chemical Formula 12】 being, R １ 、R ２ 、R ３ 、R ４ 、and R ５ are each 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 18.

20. 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 13】 The compound according to claim 19, selected from

21. 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 14】 The compound according to claim 20, selected from

22. R １ 、R ２ 、R ３ 、R ４ 、and R ５ in which two of them are not -H, a compound according to any one of claims 19 to 21.

23. 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 19 to 21.

24. Y １ has the structure: 【Chemical Formula 15】 The compound according to claim 21, selected from

25. Y １ The compound according to any one of claims 1 to 15, wherein Y is an unsubstituted heteroaryl.

26. Y １ has a structure: 【Chemical 16】 The compound according to claim 25, selected from

27. Y １ The compound according to any one of claims 1 to 15, wherein Y is a substituted heteroaryl.

28. Y １ has the structure: 【Chemical 17】 selected from; R ６ 、 R ７ 、 R ８ 、 and R ９ are, independently for each occurrence, selected from -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 27.

29. L ２ The compound according to any one of claims 1 to 28, wherein L is absent.

30. L ２ is -CH ２ -, the compound according to any one of claims 1 to 28.

31. L ３ The compound according to any one of claims 1 to 28, wherein L is absent.

32. L ３ The compound according to any one of claims 1 to 28, wherein L is -C(O)-.

33. Structure: 【Chemical Formula 18】 The compound according to claim 31, having a structure selected from

34. Y ２ The compound according to claim 33, wherein Y is an unsubstituted heteroaryl.

35. Y ２ has a structure: 【Chemical Formula 19】 The compound according to claim 34, selected from

36. Y ２ has the structure: 【Chemical 20】 The compound according to claim 35, being

37. Y ２ The compound according to claim 33, wherein Y is a substituted heteroaryl.

38. Y ２ has the structure: 【Chemical 21】 being; R １０ 、R １１ 、and R １２ are each 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 is, independently for each occurrence, selected from -H, alkyl, aryl, and heteroaryl, the compound according to claim 37.

39. 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[[ID=4"]] ３ 、 -CO ２ H, phenyl, cyclopropyl, cyclobutyl, imidazolyl, and tetrazolyl, the compound according to claim 38.

40. 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 [[ID=2,2]]and -C(O)NHCH ２ CH ３ and the structure: It should be noted that there seems to be an issue with the text in this patent content. For example, the "R １０ " and other tags might be part of a specific format or notation in the original patent language that needs further context to be fully understood and accurately translated in a more comprehensive sense. Also, the "R １２ " and subsequent lines with "R" might be better presented in a more structured or clear way in the original patent document for a more seamless translation. The above translation is based on the literal replacement of the characters while trying to maintain the overall structure and the specific tags as required. 【Chemical 22】 The compound according to claim 39, selected from

41. 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 23】 The compound according to claim 39, selected from

42. 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 24】 The compound according to claim 39, selected from

43. Y ２ has a structure: 【Chemical Formula 25】 selected from; R １６ is, independently for each occurrence, 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 selected from; R １３ , R １４ , and R １５ is, independently for each occurrence, selected from -H, alkyl, aryl, and heteroaryl, the compound according to claim 37.

44. R １６ is -CN, -CH ３ , -CF ３ , -C(O)NH ２ , -CO ２ CH ２ CH ３ and structure: 【Chemical 26】 The compound according to claim 43, selected from

45. Y ２ has the structure: 【Chemical 27】 selected from; R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ are, independently for each occurrence, -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 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 are, for each occurrence independently, selected from -H, alkyl, aryl, and heteroaryl, the compound according to claim 37.

46. R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ are independently selected from -H, -CN, -CH ３ 、and -OCH ３ ; the compound according to claim 45

47. Y ２ has a structure: 【Chemical 28】 The compound according to claim 37, selected from

48. Structure: ​ The compound according to claim 32, having a structure selected from

49. Y ２ The compound according to claim 48, wherein Y is unsubstituted cycloalkyl or heterocyclyl.

50. Y ２ has the structure: 【Chemical 30】 The compound according to claim 49, selected from

51. Y ２ has a structure: 【Chemical 31】 The compound according to claim 48, selected from

52. Y ２ The compound according to claim 48, wherein Y is a substituted cycloalkyl or heterocyclyl.

53. Y ２ has a structure: 【Chemical 32】 The compound according to claim 52, selected from

54. Y ２ The compound according to claim 48, wherein Y is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, and hydroxyalkyl.

55. 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 54.

56. Y ２ The compound according to claim 48, wherein Y is unsubstituted heteroaryl or heteroaryl substituted with alkyl.

57. Y ２ has a structure: 【Chemical Formula 33】 The compound according to claim 56, selected from

58. Y ２ The compound according to claim 48, wherein Y is a substituted heteroaryl.

59. Y ２ has the structure: 【Chemical 34】 and; R １０ 、R １１ 、and R １２ are each 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 、and -CO ２ R １５ ; R １３ 、 R １４ 、 and R １５ are each independently selected, upon each occurrence, from -H, alkyl, aryl, and heteroaryl, provided that at least one of R １０ 、 R １１ 、 and R １２ is not -H, the compound according to claim 58.

60. Y ２ has a structure: 【Chemical Formula 35】 selected from R １７ 、R １８ 、R １９ 、R ２０ 、and R ２１ each occur independently and are selected from -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 ; R １３ 、 R １４ 、 and R １５ are each independently selected, upon each occurrence, from -H, alkyl, aryl, and heteroaryl, 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 67.

61. Y ２ has the structure: 【Chemical Formula 36】 selected from R ２２ , R ２３ , R ２４ , and R ２５ independently at each occurrence -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 Selected from: R １３ 、 R １４ 、 and R １５ are each independently selected from -H, alkyl, aryl, and heteroaryl, provided that at least one of R ２２ 、 R ２３ 、 R ２４ 、 and R ２５ is not -H, the compound according to claim 58.

62. R ２２ 、R ２３ 、R ２４ 、and R ２５ are, independently for each occurrence, selected from -H and -CH ３ and the compound according to claim 61.

63. Y ２ The compound according to claim 33 or 48, wherein Y is selected from unsubstituted pyridonyl, unsubstituted pyrimidinoyl, unsubstituted pyrazinonyl, unsubstituted triazinonyl, and unsubstituted quinazolinonyl.

64. Y ２ has a structure: 【Chemical 37】 The compound according to claim 63, selected from

65. Y ２ The compound according to claim 33 or 48, wherein Y is selected from substituted pyridonyl, substituted pyrimidinoyl, substituted pyrazinonyl, substituted triazinonyl, and substituted quinazolinonyl.

66. Y ２ has the structure: 【Chemical 38】 and; 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 an unsubstituted or substituted fused C ５ -C ７ -cycloalkyl; or Y ２ has a structure: 【Chemical 39】 and; 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 fused C ５ -C ７ -cycloalkyl; or Y ２ has a structure: 【Chemical 40】 and; 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 the structure: 【Chemical 41】 and; R １０ is selected from halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ , alkyl, alkoxy, alkylamino, and cycloalkyl; or Y ２ has the structure: 【Chemical 42】 and; R １１ is selected from halogen, -CN, -OH, -OCF ３ , -OCHF ２ , -NH ２ , alkyl, alkoxy, alkylamino, and cycloalkyl The compound according to claim 65.

67. Y ２ has a structure: 【Chemical Formula 43】 The compound according to claim 65 or 66, selected from

68. Y ２ The compound according to claim 33 or 48, wherein Y is N-substituted pyridonyl, N-substituted pyrimidinoyl, N-substituted pyrazinonyl, N-substituted triazinonyl, or N-substituted quinazolinonyl.

69. Y ２ The compound according to claim 68, wherein Y is N-alkyl-substituted pyridonyl, N-alkyl-substituted pyrimidinoyl, N-alkyl-substituted pyrazinonyl, N-alkyl-substituted triazinonyl, or N-alkyl-substituted quinazolinonyl.

70. Y ２ has the structure: 【Chemical 44】 The compound according to claim 69, selected from

71. Y ２ is -NH(Y ２ '), or Y ２ is -N(Y ２ '' ２ ), the compound according to claim 48.

72. Y ２ The compound according to claim 71, wherein Y' is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

73. Y ２ ’ is -H, -OCH ３ , -CH ３ , and -CH ２ CH ２ OH, and the compound according to claim 71, wherein the compound is selected from the group consisting of -H, -OCH

74. Y ２ The compound according to claim 71, wherein Y' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

75. Y ２ ’ is -H, -OH, -OCH ３ , -CH ３ , -CH ２ CH ２ OCH ３ and structure: 【Chemical 45】 The compound according to claim 74, selected from

76. Y ２ ‘‘ is each —CH ３ The compound according to claim 71, wherein is

77. Both Ys ２ The compound according to claim 71, wherein the '' together with the nitrogen atom to which they are attached forms morpholinyl.

78. Structure: 【Chemical 46】 The compound according to claim 1, having a structure selected from

79. Structure: 【Chemical 47】 The compound according to claim 1, having a structure selected from [[ID= L １ is selected from -alkyl-, -cycloalkyl-, and -heteroaryl-CH ２ -; L ２ is absent; 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 '); Y ２ The compound according to any one of claims 1 to 4 or 78 to 79, wherein Y' is selected from -H, alkyl, alkoxyalkyl, and hydroxyalkyl. ​ X ２ has the structure: 【Chemical 48】 ​ ​ L １ is -CH ２ -, the compound according to claim 80 or 81. ​ L １ has the structure: 【Chemical 49】 ​ ​ L １ has a structure: 【Chemical Formula 50】 ​ ​ Y １ has a structure: 【Chemical Formula 51】 ​ 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 、and -OCHF ２ ; 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 80 to 84. ​ R １ 、 R ２ 、 R ３ 、 R ４ 、 and R ５ wherein two of them are not -H, the compound according to claim 85. ​ Y １ has a structure: 【Chemical 52】 ​ ​ L ３ A compound according to any one of claims 80 to 87, wherein L is absent. ​ L ３ The compound according to any one of claims 80 to 87, wherein L is -C(O)-. ​ Y ２ has the structure: 【Chemical 53】 ​ ​ Y ２ The compound according to claim 89, wherein Y is alkyl or hydroxyalkyl. ​ Y ２ is -CH ３ and -CH ２ OH, the compound according to claim 91, selected from ​ Y ２ is -NH(Y ２ '), where Y ２ ' is -H or -CH ３ and the compound according to claim 89 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The method according to any one of claims 96 to 98, wherein the compound reduces the systemic phenylalanine level in a subject.

100. A method of treating or preventing tyrosinemia (type I, II, or III), 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 94.

101. The method according to claim 100, wherein the compound reduces the systemic tyrosine level in the subject.

102. A method of treating or preventing non-ketotic hyperglycinemia, 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 94.

103. The method according to claim 102, wherein the compound reduces the systemic glycine level in the subject.

104. A method of 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 a compound according to any one of claims 1 to 94.

105. A method of 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 a compound according to any one of claims 1 to 94.

106. The method according to any one of claims 96 to 105, wherein the compound inhibits SLC6A19 in the subject.

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