Small molecule inhibitors of mammalian SLC6A19 function

Abstract

Disclosed are compounds, compositions and methods useful for treating or preventing diseases or conditions associated with abnormal levels of amino acids by modulating SLC6A19 transport.

Description

[0001] Related Applications

[0002] This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 389,244, filed Jul. 14, 2022. Background of the Invention

[0003] Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in the enzyme phenylalanine hydroxylase (PAH), which is responsible for metabolizing phenylalanine. PKU is an autosomal recessive metabolic disorder in which phenylalanine metabolism is inappropriate and results in abnormally high plasma phenylalanine levels. Individuals with PKU have abnormally high blood levels of phenylalanine, which, if untreated, can lead to irreversible nerve damage, resulting in a range of complications such as intellectual disability, seizures, and neurodevelopmental and behavioral disorders. Since the blood level of phenylalanine is directly related to diet, PKU is difficult to treat. Patients must adhere to a strict diet for life, which affects all aspects of the patient's life. The current standard of care is enzyme cofactor and enzyme replacement therapies, but these therapies are not effective for all patients and have the potential risk of adverse events.

[0004] The enzyme responsible for metabolizing phenylalanine and thus maintaining phenylalanine homeostasis is phenylalanine hydroxylase (PAH). Loss-of-function (LOF) mutations in the PAH gene at chromosome 12q23.2 are known to cause most forms of PKU. These LOF mutations leading to PKU can be diagnosed as classical PKU (the most severe form) and "mild PKU" or "hyperphenylalaninemia (hyperphe)" (less severe forms). In addition to PAH, mutations in other enzymes that affect phenylalanine metabolism, such as dihydropteridine reductase (DHPR), which is responsible for synthesizing the cofactor required for PAH activity, can also lead to elevated phenylalanine levels. In addition to diet, blood amino acid levels, including phenylalanine levels, are regulated by SLC6A19. SCL6A19 is located in the proximal tubules of the kidney and is responsible for reabsorbing amino acids back into the blood. Summary of the Invention

[0005] One aspect of the invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal levels of amino acids by modulating SLC6A19 transport.

[0006] Another aspect of the invention relates to compounds of formula (Ia) or (Ib):

[0007]

[0008] Wherein:

[0009] L 1Absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -;

[0010] L 2 Absent or -CH 2 -;

[0011] L 3 Absent or -C(O)-;

[0012] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, heterocyclic group, aryl and arylalkyl; provided that X 1 and X 2 are not both -H;

[0013] Y 1 is selected from aryl and heteroaryl;

[0014] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ”) 2 ;

[0015] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl; and

[0016] each Y 2 ” is independently alkyl, or two entities together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0017] Y 3 and Y 4 are independently selected from -H, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl and alkyl-CO 2 H;

[0018] or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder associated with a genetic defect of phenylalanine hydroxylase in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0020] Another aspect of the present invention relates to a method for treating or preventing phenylketonuria, hyperphenylalaninemia, tyrosinemia, non-ketotic hyperglycinemia, isovaleric academia, methylmalonic academia, propionic academia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder or hyperammonemia in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0021] Another aspect of the present invention relates to a method for modulating SLC6A19 transport in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0022] 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. The entire contents of all publications, patent applications, patents and other references mentioned herein are incorporated by reference. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0023] Other features, objects, and advantages of the present invention will be apparent from the detailed description and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a table summarizing the isoleucine transport data of exemplary compounds of the present invention. A = IC 50 <100 nM; and B = IC 50 100 nM - 500 nM. DETAILED DESCRIPTION

[0025] DEFINITIONS

[0026] For convenience, certain terms employed in the specification, examples, and appended claims are collected here before further description of the invention. These definitions should be read in light of the remainder of the disclosure and 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.

[0027] To more readily understand the present invention, certain terms and phrases are defined below and throughout the specification.

[0028] The articles "a" and "an" are used herein to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0029] As used herein in the specification and claims, the phrase "and / or" shall be understood to mean "any one or both" of the elements so combined, i.e., elements that exist in some cases in a combined manner and in other cases in a separated manner. Multiple elements listed with "and / or" shall be construed in the same manner, i.e., "one or more" of the elements so combined. Other elements may optionally exist in addition to those specifically identified by the "and / or" clause, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising", may, in one embodiment, refer to only A (optionally including elements other than B); in another embodiment, may refer to only B (optionally including elements other than A); in another embodiment, may refer to both A and B (optionally including other elements); and so on.

[0030] As used herein in the specification and in the claims, "or" shall 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" shall be construed as inclusive, i.e., including at least one (but also including more than one) of the multiple elements or list of elements and optionally including additional unlisted items. Terms that explicitly indicate the contrary, such as "only one of... " or "exactly one of... " or "consisting of... " when used in the claims, will refer to including exactly one element of the multiple elements or list of elements. In general, the term "or" as used herein shall be construed to indicate exclusive alternatives (i.e., "one or the other but not both") only when preceded by an exclusive term such as "either", "one of... ", "only one of... " or "exactly one of... ". When used in the claims, "consisting essentially of... " shall have its ordinary meaning as used in the field of patent law.

[0031] As used herein in the specification and in the claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, in one embodiment, "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") can mean at least one (optionally including more than one) A, with no B present (and optionally including elements other than B); in another embodiment, it can mean at least one (optionally including more than one) B, with no A present (and optionally including elements other than A); in another embodiment, it can mean at least one (optionally including more than one) A and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0032] It should also be understood that, unless explicitly indicated to the contrary, in any method claimed herein that includes more than one step or act, the order of the steps or acts of the method need not be limited to the order in which the steps or acts of the method are recited.

[0033] In the claims and in the specification above, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "consisting of", etc. should be understood to be open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" should be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0034] Certain compounds included in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Additionally, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures, and other mixtures thereof, all of which fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are intended to be included in the present invention.

[0035] "Geometric isomers" means isomers with different orientations of substituent atoms related to a carbon-carbon double bond, a cycloalkyl ring or a bridged bicyclic system. The atoms (except H) on each side of a carbon-carbon double bond can be in the E configuration (substituents on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents oriented on the same side). "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" indicate the configuration relative to the core molecule. Certain disclosed compounds can exist in "atropisomeric" form or as "atropisomers". Atropisomers are stereoisomers generated by hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow the isolation of conformational isomers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or by resolution of a mixture of isomers. Conventional resolution techniques include forming salts of the free bases of each isomer of an isomer pair with an optically active acid (followed by fractional crystallization and regeneration of the free base), forming salts of the acid form of each isomer of an isomer pair with an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each isomer of an isomer pair with an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving a mixture of isomers of the starting material or the final product using various well-known chromatographic methods.

[0036] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in cases where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, and then the diastereomers thus formed are resolved by fractional crystallization or chromatographic means well known in the art, and subsequently the pure enantiomer is recovered.

[0037] As used herein, the term "tautomer" means structurally isomeric forms that exist in equilibrium as a result of the migration of a hydrogen atom. For example, the two tautomers of 2-pyrimidinone are described below. A single tautomer can be provided in the structural representation of a given compound. However, the present invention encompasses all such tautomers of a given compound.

[0038]

[0039] The percentage purity by mole fraction is the ratio of the number of moles of the enantiomer (or diastereomer) or the ratio relative to the number of moles of the enantiomer (or diastereomer) plus the number of moles of its optical isomers. When the stereochemistry of the disclosed compound is named or depicted by a structure, the named or depicted stereoisomer has a purity by mole fraction 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 a structure, the depicted or named enantiomer has a purity by mole fraction 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 a structure, the depicted or named diastereomer has a purity by mole fraction of at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9%.

[0040] When the disclosed compound is named or depicted by a structure without indicating stereochemistry and the compound has at least one chiral center, it is understood that the name or structure encompasses any enantiomer of the compound without the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When the disclosed compound is named or depicted by a structure without indicating stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses diastereomers without other diastereomers, many diastereomers without other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is enriched relative to other diastereomers, or a mixture of diastereomers in which one or more diastereomers are enriched relative to other diastereomers. The present invention encompasses all such forms.

[0041] The structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by replacing hydrogen with deuterium or tritium or replacing carbon with carbon enriched in 13 C- or 14 C- are within the scope of the present invention.

[0042] As used herein, the term "prodrug" encompasses compounds that are converted to a therapeutically active agent under physiological conditions. Common methods for preparing prodrugs include those that will hydrolyze under physiological conditions to expose a selected moiety of the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

[0043] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject chemical from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, non-harmful to the patient, and substantially pyrogen-free. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the invention are pyrogen-free, i.e., do not induce a significant temperature increase when administered to a patient.

[0044] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, among others. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0045] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and may thus be capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic base addition salts of the compounds. Similarly, these salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its 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 organic primary, secondary or tertiary amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., supra).

[0046] The term "pharmaceutically acceptable co-crystal" refers to a solid co-former that does not form formal ionic interactions with small molecules.

[0047] For therapeutic use, a "therapeutically effective amount" (or "effective amount") of a compound is the amount of the compound in a formulation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human), alleviates symptoms, ameliorates a condition or retards the onset of a disease condition, according to clinically acceptable criteria for the condition or disorder to be treated or for cosmetic purposes, e.g., with a reasonable benefit / risk ratio applicable to any medical treatment.

[0048] The term "prophylactic or therapeutic" treatment is well recognized in the art and includes administering to a host one or more of the subject compositions. If it is administered prior to the clinical manifestation of an undesired condition (e.g., a disease or other undesired state of the host animal), the treatment is prophylactic (i.e., it protects the host from developing the undesired condition), while if it is administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate or stabilize the existing undesired condition or its side effects).

[0049] The term "patient" or "subject" refers to a mammal in need of specific treatment. In certain embodiments, the patient is a primate, dog, cat or horse. In certain embodiments, the patient is a human.

[0050] Aliphatic chains include the classes of alkyl, alkenyl and alkynyl as defined below. Straight-chain aliphatic chains are limited to non-branched carbon chain moieties. As used herein, the term "aliphatic group" refers to straight-chain, branched-chain or cyclic aliphatic hydrocarbon groups and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl.

[0051] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms or, if not specified, up to 30 carbon atoms. For example, an alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those that are positional isomers of these moieties. Alkyls having 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, henicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight-chain or branched alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for a straight chain and C 3 -C 30 for a branched chain), and more preferably has 20 or fewer carbon atoms. An alkyl may be substituted or unsubstituted.

[0052] 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 carbon atoms.

[0053] As used herein, the term "haloalkyl" refers to an alkyl as defined above that is substituted with at least one halogen.

[0054] As used herein, the term "hydroxyalkyl" refers to an alkyl as defined above that is substituted with at least one hydroxy group.

[0055] As used herein, the term "alkylene" refers to an alkyl having a specified number of carbons (e.g., 2 to 12 carbon atoms) that contains two points of attachment to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene include methylene -(CH 2 )-, ethylene -(CH 2 CH 2 ), n-propylene -(CH 2 CH 2 CH 2 ), isopropylidene -(CH 2 CH(CH 3 ))-, etc. An alkylene may be a cyclic or acyclic, branched or unbranched carbon chain moiety and may optionally be substituted with one or more substituents.

[0056] "Cycloalkyl" means a monocyclic or bicyclic or bridged or spiro or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Preferred cycloalkyls have 3 - 10 carbon atoms in their ring structure, and more preferably 3 - 6 carbons in the ring structure. A cycloalkyl may be substituted or unsubstituted.

[0057] As used herein, the term "halocycloalkyl" means a cycloalkyl as defined above which is substituted with at least one halogen.

[0058] "Heterocycloalkyl" means a cycloalkyl moiety as defined above which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms in place of carbon atoms. Preferred heterocycloalkyls have 4 - 8 carbon and heteroatoms in their ring structure, and more preferably 4 - 6 carbon and heteroatoms in the ring structure. Heterocycloalkyls may be substituted or unsubstituted.

[0059] Unless the number of carbons is otherwise indicated, "lower alkyl" as used herein means an alkyl as defined above but having 1 to 10 carbons, more preferably 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 a similar chain length. Throughout the application, preferred alkyls are lower alkyls. In certain embodiments, substituents named as alkyls herein are lower alkyls.

[0060] "Alkenyl" means any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the specified number of carbon atoms, or, if no limitation on the number of carbon atoms is specified, having up to 26 carbon atoms; and having one or more double bonds in the moiety. Alkenyls of 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl and tetracosenyl, in their various isomeric forms, where the unsaturated bond can be located at any position in the moiety and can have a (Z) or (E) configuration around the double bond.

[0061] "Alkynyl" means a hydrocarbon moiety in the alkenyl range but having one or more triple bonds in the moiety.

[0062] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups having 3 to 12 ring atoms, where each atom of the ring is carbon (i.e., carbocyclic aryl), or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl includes 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more rings, where two or more carbons are common to two adjacent rings, where at least one ring is aromatic, e.g., the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl includes substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include 1 to 4 heteroatoms. Heteroaryl includes, 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.

[0063] As used herein, the term "halo", "halide ion", or "halogen" means halogen and includes, for example, but not limited to, fluorine, chlorine, bromine, iodine, etc., in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluorine, chlorine, and bromine.

[0064] The term "heterocyclic group" or "heterocyclic moiety" refers to a 3- to 12-membered ring structure, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, 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 pyrrolidone), sultam, sultone, etc. The heterocycle can be substituted at one or more positions with such substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, mercapto, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF 3 , -CN, etc.

[0065] The term "substituted" refers to a moiety having substituents that replace hydrogen on one or more carbons of the backbone. It is understood that "substitution" or "substituted with" includes the implicit proviso that such substitution be consistent with the permitted valences of the atoms being substituted and the substituents, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformation (such as by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is contemplated to include all permitted substituents of organic compounds. Broadly, permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the permitted substituents can be one or more and can be the same or different. For the purposes of this invention, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any permitted substituents of the organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any of the substituents described herein, such as halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thiocarboxylate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, aralkyl or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituents on the substituted alkyl are selected from C 1-6 alkyl, C 3-6 cycloalkyl, halogen, carbonyl, cyano or hydroxy. In a more preferred embodiment, the substituents on the substituted alkyl are selected from fluorine, carbonyl, cyano or hydroxy. Those skilled in the art will understand that, if appropriate, substituents can themselves be substituted. Unless specifically stated as "unsubstituted", chemical moieties mentioned herein are understood to include substituted variants. For example, the mention of "aryl" or moiety implicitly includes both substituted and unsubstituted variants.

[0066] As used herein, each expression (e.g., alkyl, m, n, etc.) when it occurs more than once in any structure, is defined to be independent of its definition elsewhere in the same structure.

[0067] As used herein, "small molecule" refers to a small organic or inorganic molecule having a molecular weight of less than about 3,000 Daltons. Generally, small molecules useful in the present invention have a molecular weight of less than 3,000 Daltons (Da). Small molecules can be, for example, at least about 100 Da to about 3,000 Da (e.g., between about 100 and about 3,000 Da, about 100 and about 2500 Da, about 100 and about 2,000 Da, about 100 and about 1,750 Da, about 100 and about 1,500 Da, about 100 and about 1,250 Da, about 100 and about 1,000 Da, about 100 and about 750 Da, about 100 and about 500 Da, about 200 and about 1500, about 500 and about 1000, about 300 and about 1000 Da, or about 100 and about 250 Da).

[0068] In some embodiments, "small molecule" refers to an organic, inorganic, or organometallic compound having a molecular weight generally less than about 1000. In some embodiments, small molecules are organic compounds on the order of 1 nm in size. In some embodiments, the small molecule drugs of the present invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0069] "Effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is an amount necessary to prevent the onset of a disease or disease symptom. An effective amount can be administered, applied, or dosed one or more times. The therapeutically effective amount of a composition depends on the composition selected. The composition can be administered once or more times per day to once or more times per week; including administration every other day. Those skilled in the art will understand that certain factors can affect the dosage and time required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatment, the general health and / or age of the subject, and the presence of other diseases. In addition, treating a subject with a therapeutically effective amount of a composition described herein can include a single treatment or a series of treatments.

[0070] The terms "reduce", "reduced", "reduction", "decrease", and "inhibit" are generally used herein to mean a statistically significant decrease relative to a reference value. However, for the sake of clarity, "decrease" or "reduce" or "inhibit" generally means a decrease of at least 10% compared to a reference level, and may include, for example, a decrease of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, complete absence of a given entity or parameter compared to a reference level, or any decrease between 10 - 99% compared to the absence of a given treatment.

[0071] The terms "increased", "increase", or "enhanced" or "activated" are used herein to generally mean an increase by a statistically significant amount; for the sake of any doubt, the terms "increased" or "enhanced" or "activated" mean an increase of at least 10% compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including an increase of 100% compared to a reference level, or any increase between 10 - 100% compared to a 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 compared to a reference level, or any increase between 2-fold and 10-fold or higher.

[0072] As used herein, the term "modulate" includes upregulation and downregulation, such as enhancing or inhibiting a response.

[0073] A "radiopharmaceutical" as defined herein refers to a pharmaceutical agent containing at least one radiation-emitting radioisotope. Radiopharmaceuticals are commonly used in nuclear medicine for the diagnosis and / or treatment of various diseases. A radiolabeled pharmaceutical (e.g., a radiolabeled antibody) contains a radioisotope (RI) that serves as a radiation source. As contemplated herein, the term "radioisotope" includes metal and non-metal radioisotopes. The radioisotope is selected based on the medical application of the radiolabeled pharmaceutical. When the radioisotope is a metal radioisotope, a chelating agent is typically used to bind the metal radioisotope to the rest of the molecule. When the radioisotope is a non-metal radioisotope, the non-metal radioisotope is typically directly or through a linker attached to the rest of the molecule.

[0074] For the purposes of the present invention, chemical elements are identified according to the Periodic Table, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986 - 87, inside front cover.

[0075] Compounds of the invention

[0076] One aspect of the present invention relates to compounds of formula (Ia) or (Ib):

[0077]

[0078] wherein:

[0079] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -;

[0080] L 2 is absent or is -CH 2 -;

[0081] L 3 is absent or is -C(O)-;

[0082] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, heterocyclic, aryl and arylalkyl; provided that X 1 and X 2 are not both -H;

[0083] Y 1 is selected from aryl and heteroaryl;

[0084] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ”) 2 ;

[0085] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl; and

[0086] each Y 2 ” is independently alkyl, or two entities together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclic group;

[0087] Y 3 and Y 4 are independently selected from -H, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl and alkyl-CO2 H;

[0088] or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, the compound has the structure In other embodiments, the compound has the structure In other embodiments, the compound has the structure In other embodiments, the compound has the structure

[0090] In certain embodiments, Y 3 and Y 4 are independently selected from -H, F, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CO 2 H, -CH 2 NH and -CH 2 CH 2 NH 2 .

[0091] In certain embodiments, each of Y 3 and Y 4 is -H. In other embodiments, each of Y 3 and Y 4 is alkyl. In other embodiments, each of Y 3 and Y 4 is halo.

[0092] In certain embodiments, one of Y 3 and Y 4 is -H; and the other of Y 3 and Y 4 is not -H.

[0093] In certain embodiments, one of X 1 and X 2 is -H; and the other of X 1 and X 2 is selected from C 1 -C 4 alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, and heterocycloalkyl.

[0094] In certain embodiments, one of X 1 and X 2 is -H; and the other of X 1 and X 2 is selected from -CH 3 and -CH 2CH 3 ,-CH 2 CF 3 ,-CH 2 CH 2 CH 3 ,

[0095] In certain embodiments, X 1 is -H and X 2 is -CH 3 ; or X 2 is -H and X 1 is -CH 3 .

[0096] In certain embodiments, X 1 is -H and X 2 is or X 2 is -H and X 1 is

[0097] In certain embodiments, L 1 is absent.

[0098] In certain embodiments, L 1 is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH 2 .

[0099] In certain embodiments, L 1 is selected from -CH 2 -, -C(H)(CH 3 ), -, -CH 2 CH 2 -, and -C(H)(OH)CH 2 .

[0100] In certain embodiments, L 1 is

[0101] In certain embodiments, L 1 is selected from

[0102] In certain embodiments, L 1 is selected from

[0103] In certain embodiments, the compound has a structure selected from the following:

[0104]

[0105]

[0106] In certain embodiments, Y 1 is an unsubstituted aryl.

[0107] In certain embodiments, Y 1 is selected from unsubstituted phenyl and unsubstituted naphthyl.

[0108] In certain embodiments, Y 1 is a substituted aryl.

[0109] In certain embodiments, Y 1 is and

[0110] R 1 、R 2 、R 3 、R 4 and R 5 are independently selected from -H, halogen, -CN, -CF 3 、-CHF 2 、-CF 2 CH 3 、-OCF 3 、-OCHF 2 、alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl; provided that at least one of R 1 、R 2 、R 3 、R 4 and R 5 is not -H.

[0111] In certain embodiments, R 1 、R 2 、R 3 、R 4 and R 5 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 、

[0112]

[0113] In certain embodiments, R 1, R 2 , R 3 , R 4 and R 5 are independently selected from -H, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -OCF 3 and

[0114] In certain embodiments, two of R 1 , R 2 , R 3 , R 4 , and R 5 are not -H.

[0115] In certain embodiments, three of R 1 , R 2 , R 3 , R 4 , and R 5 are not -H.

[0116] In certain embodiments, Y 1 is selected from

[0117] In certain embodiments, Y 1 is an unsubstituted heteroaryl.

[0118] In certain embodiments, Y 1 is selected from

[0119] In certain embodiments, Y 1 is a substituted heteroaryl.

[0120] In certain embodiments, Y 1 is selected from:

[0121] and

[0122] R 6 , R 7 , R 8 , and R 9 are independently selected from -H, halogen, -CN, -OCF 3 , -OCHF 2 , alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, and heteroaryl; provided that R 6 , R 7 , R 8 , and R 9At least one of them is not -H.

[0123] In certain embodiments, L 2 is absent.

[0124] In certain embodiments, L 2 is -CH 2 -.

[0125] In certain embodiments, L 3 is absent.

[0126] In certain embodiments, L 3 is -C(O)-.

[0127] In certain embodiments, the compound has a structure selected from the following:

[0128]

[0129]

[0130] In certain embodiments, Y 2 is an unsubstituted heteroaryl.

[0131] In certain embodiments, Y 2 is selected from:

[0132]

[0133] In certain embodiments, Y 2 is

[0134] In certain embodiments, Y 2 is a substituted heteroaryl.

[0135] In certain embodiments, Y 2 is

[0136] R 10 , R 11 and R 12 are independently selected from -H, halogen, -CN, -OH, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , -CO 2 R 15 and -C(O)NHSO 2 R 15 ; provided that R10 、R 11 and R 12 in at least one is not -H; and

[0137] R 13 、R 14 and R 15 are independently selected from -H, alkyl, aryl and heteroaryl each time they appear.

[0138] In certain embodiments, 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 、

[0139] -C(O)NHSO 2 CH 2 CH 3 、-CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

[0140] In certain embodiments, R 10 and R 12 are each -H; and R 11 is selected from -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 、

[0141] In certain embodiments, R 11 and R 12 are each -H; and R 10 is selected from -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 ,

[0142] In certain embodiments, R 10 and R 11 are each -H; and R 12 is selected from -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 ,

[0143] In certain embodiments, Y 2 is selected from

[0144] R 16 is independently selected from halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , -CO 2 R 15 ; and

[0145] R 13 、R 14 and R 15Independently selected from -H, alkyl, aryl, and heteroaryl each time it appears.

[0146] In certain embodiments, R 16 is selected from -CN, -CH 3 , -CF 3 , -C(O)NH 2 , -CO 2 CH 2 CH 3 and

[0147] In certain embodiments, Y 2 is selected from

[0148] R 17 、R 18 、R 19 、R 20 and R 21 Independently selected from -H, halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; provided that at least one of R 17 , R 18 , R 19 , R 20 and R 21 is not -H; and

[0149] R 13 , R 14 and R 15 Independently selected from -H, alkyl, aryl, and heteroaryl each time it appears.

[0150] In certain embodiments, R 17 , R 18 , R 19 , R 20 and R 21 are independently selected from -H, -CN, -CH 3 and -OCH 3 .

[0151] In certain embodiments, Y 2 is selected from

[0152] In certain embodiments, the compound has a structure selected from the following:

[0153]

[0154]

[0155] In certain embodiments, Y 2 is an unsubstituted cycloalkyl or heterocyclic group.

[0156] In certain embodiments, Y 2 is selected from

[0157] In certain embodiments, Y 2 is selected from

[0158] In certain embodiments, Y 2 is a substituted cycloalkyl or heterocyclic group.

[0159] In certain embodiments, Y 2 is selected from

[0160]

[0161] In certain embodiments, Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, and hydroxyalkyl.

[0162] In certain embodiments, Y 2 is selected from -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 .

[0163] In certain embodiments, Y2 is an unsubstituted heteroaryl or an alkyl-substituted heteroaryl.

[0164] In certain embodiments, Y 2 is selected from:

[0165]

[0166] In certain embodiments, Y 2 is a substituted heteroaryl.

[0167] In certain embodiments, Y 2 is

[0168] R 10 、R 11 and R 12 are independently selected from -H, halogen, -CN, -OH, -NH 2 、-OCF 3 、-OCHF 2 、-OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; and

[0169] R 13 、R 14 and R 15 are independently selected from -H, alkyl, aryl, and heteroaryl each time they appear, provided that at least one of R 10 、R 11 and R 12 is not -H.

[0170] In certain embodiments, Y 2 is selected from

[0171]

[0172] R 17 、R 18 、R 19 、R 20 and R 21 are independently selected from -H, halogen, -CN, -NH 2 、-OCF 3 、-OCHF 2 、-OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R14 and -CO 2 R 15 ; and

[0173] R 13 、R 14 and R 15 are each independently selected from -H, alkyl, aryl, and heteroaryl each time they appear, provided that at least one of R 17 、R 18 、R 19 、R 20 and R 21 is not -H.

[0174] In certain embodiments, Y 2 is selected from

[0175] R 22 、R 23 、R 24 and R 25 which are each independently selected from -H, halogen, -CN, -NH 2 、-OCF 3 、-OCHF 2 、-OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; and

[0176] R 13 、R 14 and R 15 are each independently selected from -H, alkyl, aryl, and heteroaryl each time they appear, provided that at least one of R 22 、R 23 、R 24 and R 25 is not -H.

[0177] In certain embodiments, R 22 、R 23 、R 24 and R 25 are each independently selected from -H and -CH 3 .

[0178] In certain embodiments, Y 2 is selected from unsubstituted pyridonyl, unsubstituted pyrimidinonyl, unsubstituted pyrazinonyl, unsubstituted triazinonyl, and unsubstituted quinazolinonyl.

[0179] In certain embodiments, Y 2 is selected from

[0180]

[0181] In certain embodiments, Y 2 is selected from a substituted pyridone group, a substituted pyrimidinone group, a substituted pyrazinone group, a substituted triazinone group, and a substituted quinazolinone group.

[0182] In certain embodiments, Y 2 is and

[0183] R 6 and R 7 are 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 to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0184] Y 2 is and

[0185] R 7 and R 8 are 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 to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0186] Y 2 is and

[0187] R 6 and R 9 are 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

[0188] Y 2 is and

[0189] R 10 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino, and cycloalkyl; or

[0190] Y 2 is and

[0191] R 11 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino, and cycloalkyl.

[0192] In certain embodiments, Y 2 is selected from

[0193]

[0194] In certain embodiments, Y 2 is an N-substituted pyridone group, an N-substituted pyrimidinone group, an N-substituted pyrazinone group, an N-substituted triazinone group, or an N-substituted quinazolinone group.

[0195] In certain embodiments, Y 2 is an N-alkyl-substituted pyridone group, an N-alkyl-substituted pyrimidinone group, an N-alkyl-substituted pyrazinone group, an N-alkyl-substituted triazinone group, or an N-alkyl-substituted quinazolinone group.

[0196] In certain embodiments, Y 2 is selected from

[0197]

[0198] In certain embodiments, Y 2 is -NH(Y 2 ') or Y 2 is -N(Y 2 ) 2 .

[0199] In certain embodiments, Y 2 ' is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

[0200] In certain embodiments, Y 2 ' is selected from -H, -OCH 3 , -CH 3 and -CH 2 CH 2 OH.

[0201] In certain embodiments, Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

[0202] In certain embodiments, Y 2 ' is selected from -H, -OH, -OCH 3 , -CH 3 , -CH 2 CH 2 OCH 3 and

[0203] In certain embodiments, each Y 2 ” is -CH 3 .

[0204] In certain embodiments, Y 2 ” together with the nitrogen atom to which it is bonded forms a morpholinyl group.

[0205] In certain embodiments, the compound has a structure selected from the following:

[0206]

[0207] In certain embodiments, the compound has a structure selected from the following:

[0208]

[0209] In certain embodiments, 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 cycloalkyl; Y 1 is selected from aryl and heteroaryl; Y 2 is selected from alkyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, and -NH(Y 2 '); and Y 2 ' is selected from -H, alkyl, alkoxyalkyl, and hydroxyalkyl.

[0210] In certain embodiments, X 2 is

[0211] In certain embodiments, L 1 is -CH 2 -. In other embodiments, L 1 is selected from In other embodiments, L 1 is selected from

[0212] In certain embodiments, Y 1 is and

[0213] 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.

[0214] In certain embodiments, two of R 1 、R 2 、R 3 、R 4 and R 5 are not -H.

[0215] In certain embodiments, is selected from

[0216] In certain embodiments, L 3 is absent. In other embodiments, L 3 is -C(O)-.

[0217] In certain embodiments, Y 2 is

[0218] In certain embodiments, Y 2 is alkyl or hydroxyalkyl.

[0219] In certain embodiments, Y 2 is selected from -CH 3 and -CH 2 OH.

[0220] In certain embodiments, Y 2 is -NH(Y 2 '); and Y 2 ' is -H or -CH 3 .

[0221] In some embodiments, the compounds are selected from Table 1 below:

[0222] Table 1

[0223]

[0224]

[0225]

[0226] In some embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by substituting hydrogen with deuterium or tritium or substituting carbon with 13 C- or 14 C-enriched carbon are within the scope of the present invention. According to the present invention, such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents. For example, in the case of the variable R 1 , (C 1 -C 4 )alkyl or -O-(C 1 -C 4 )alkyl can be suitably deuterated (e.g., -CD 3 , -OCD 3 ).

[0227] Any compound of the present invention can also be radiolabeled for the preparation of radiopharmaceuticals.

[0228] Treatment methods

[0229] One aspect of the present invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal levels of amino acids by modulating SLC6A19 transport.

[0230] Another aspect of the present invention relates to a method of modulating SLC6A19 transport in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0231] 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, comprising administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0232] In some embodiments, the present invention relates to a method for treating or preventing phenylketonuria in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0233] In some embodiments, the present invention relates to a method for treating or preventing hyperphenylalaninemia in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0234] In some embodiments, the compound reduces the systemic phenylalanine level in the subject.

[0235] 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 thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0236] In some embodiments, the compound reduces the systemic glycine level in the subject.

[0237] 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 deficiency, urea cycle disorder or hyperammonemia in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (Ia) or (Ib).

[0238] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 in the subject.

[0239] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 in the subject.

[0240] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 transport in the subject.

[0241] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 transport in the subject.

[0242] In some embodiments, the compound reduces the systemic amino acid level in the subject.

[0243] In some embodiments of any of the disclosed methods, the subject is a mammal. In some embodiments of any of the disclosed methods, the mammal is a human.

[0244] In some embodiments of any of the disclosed methods, the compound of formula (Ia) or (Ib) is defined as:

[0245]

[0246] Wherein:

[0247] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -;

[0248] L 2 is absent or is -CH 2 ;

[0249] L 3 is absent or is -C(O)-;

[0250] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, heterocyclic group, aryl and arylalkyl; provided that X 1 and X 2 are not both -H;

[0251] Y 1 is selected from aryl and heteroaryl;

[0252] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ”) 2 ;

[0253] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl; and

[0254] each Y 2 ” is independently alkyl, or two entities together with the nitrogen atom to which they are bonded form a 5- or 6-membered heterocyclic group;

[0255] Y 3 and Y 4 are independently selected from -H, halogen, alkyl, hydroxyalkyl, aminoalkyl, hydroxy and alkyl-CO 2 H;

[0256] or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 1.

[0258] Pharmaceutical compositions, routes of administration and dosing

[0259] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0260] In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent other than the compound of the present invention. The at least one additional pharmaceutically active agent can be an agent useful for treating ischemic reperfusion injury.

[0261] The pharmaceutical composition of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutically active agents.

[0262] As described above, an "effective amount" means 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 designed by selecting among the various active compounds and trade-off factors such as potency, relative bioavailability, patient body weight, severity of adverse side effects, and mode of administration, which does not cause significant undesired toxicity but is still effective in treating a particular subject. The effective amount for any particular application 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. A person of ordinary skill in the art can determine the effective amount of a particular compound of the present invention and / or other therapeutic agents empirically, without undue experimentation. The maximum dose, i.e., the highest safe dose according to some medical judgment, can be used. Multiple doses per day can be considered 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 levels of the drug in the patient. "Dose" and "dosage" are used interchangeably herein.

[0263] In certain embodiments, the intravenous administration of the compound can generally be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, the intravenous administration of the compound can generally be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, the intravenous administration of the compound can generally be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, the intravenous administration of the compound can generally be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, the intravenous administration of the compound can generally be from 1 mg / kg / day to 10 mg / kg / day.

[0264] Typically, for human subjects, the daily oral dose of the compound will be from about 0.01 mg / kg / day to 1000 mg / kg / day. An oral dose in the range of 0.5 to 50 mg / kg administered once or multiple times per day is expected to produce a therapeutic result. The dose may be adjusted as appropriate depending on the mode of administration to achieve the desired drug level locally or systemically. For example, intravenous administration is expected to be at a dose that is lower by one to several orders of magnitude per day. If the response in the subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent tolerated by the subject. Multiple doses per day may be considered to achieve an appropriate systemic level of the compound.

[0265] For any of the compounds described herein, a therapeutically effective amount can initially be determined in an animal model. For compounds that have been tested in humans and compounds known to exhibit similar pharmacological activity (such as other related active agents), the therapeutically effective dose can also be determined from human data. Parenteral administration may require higher doses. The administered dose can be adjusted based on the relative bioavailability and potency of the compound being administered. Adjusting the dose to achieve maximum efficacy based on the above methods and other methods well known in the art is entirely within the capabilities of a person of ordinary skill in the art.

[0266] The formulations of the present invention can be administered in a pharmaceutically acceptable solution, which generally may contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0267] For use in therapy, an effective amount of the compound can be administered to a subject by any means of delivering the compound to the desired surface. Administration of the pharmaceutical composition can be accomplished by any means 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., injection into a tumor or abscess), mucosal (e.g., topical administration to the eye), inhalation, and topical administration.

[0268] For intravenous and other parenteral routes of administration, the compounds of the present invention can be formulated as lyophilized preparations, lyophilized preparations of liposome-embedded or encapsulated active compounds, lipid complexes, or salt complexes in aqueous suspensions. Lyophilized preparations are generally reconstituted in a suitable aqueous solution (such as sterile water or saline) shortly before administration.

[0269] For oral administration, the compounds can be readily formulated by combining one or more active compounds 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, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained in solid excipient form by optionally grinding the resulting mixture and processing the granule mixture, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Specifically, suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof (such as sodium alginate) can be added. Optionally, the oral preparation can also be formulated in saline or buffer (e.g., EDTA) for neutralizing internal acidic conditions, or can be administered without any carrier.

[0270] Oral dosage forms of one or more of the above components are also specifically contemplated. The one or more components can be chemically modified such that oral delivery of the derivative is effective. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, wherein the moiety permits (a) inhibition of acid hydrolysis; and (b) uptake from the stomach or intestine into the bloodstream. It is also desirable to increase the overall stability of one or more components and increase the circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, in: Enzymes as Drugs, Hocenberg and Roberts editors, Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-trioxocane. As indicated above, polyethylene glycol moieties are suitable for pharmaceutical use.

[0271] For the component (or derivative), the site of release can be the stomach, small intestine (duodenum, jejunum or ileum) or large intestine. Those skilled in the art have available formulations that will not dissolve in the stomach but will release the substance in the duodenum or elsewhere in the intestine. Preferably, by protecting the compound (or derivative) of the present invention or by releasing the bioactive substance outside the gastric environment (such as in the intestine), this release will avoid the harmful effects of the gastric environment.

[0272] To ensure complete gastric resistance, a coating that is impermeable to at least pH 5.0 is necessary. Examples of more common inert ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S and shellac. These coatings can be used as mixed films.

[0273] The coating or mixture of coatings can also be used on tablets that are not intended for gastric protection. This can include sugar coatings or coatings that make the tablets easier to swallow. Capsules can consist of a hard shell (such as gelatin) for delivering dry therapeutic agents (e.g., powders); for liquid forms, soft gelatin shells can be used. The shell material of cachets can be thick starch or other edible paper. For pills, lozenges, molded tablets or triturated tablets, wet granulation techniques can be used.

[0274] The therapeutic agent can be included in the formulation as fine multi-particles in the form of granules or pellets with a particle size of about 1 mm. The formulation of the material for capsule administration can also be a powder, a lightly compressed plug or even a tablet. The therapeutic agent can be prepared by compression.

[0275] Both colorants and flavorants can be included. For example, the compound (or derivative) of the present invention can be formulated (such as by encapsulation in liposomes or microspheres) and then further included in an edible product, such as a refrigerated beverage containing colorants and flavorants.

[0276] The volume of the therapeutic agent can be diluted or increased with inert materials. These diluents can include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextran and starch. Certain inorganic salts can also be used as fillers, including calcium phosphate tribasic, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx1500, Emcompress and Avicell.

[0277] Disintegrants can be included in the formulation of a therapeutic agent into a solid dosage form. Materials used as disintegrants include, but are not limited to, starches, including the starch-based commercial disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, hyperbranched starch, sodium alginate, gelatin, orange peel, acidic carboxymethylcellulose, natural sponge, and bentonite can all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, and these can include powdered gums such as agar, gum acacia, or tragacanth. Algic acid and its sodium salt can also be used as disintegrants.

[0278] Binders can be used to hold the therapeutic agent together to form a hard tablet, and include materials from natural products such as gum arabic, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic agent.

[0279] Antifriction agents can be included in the formulation of the therapeutic agent to prevent adhesion during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the die wall, and these can include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oil, and wax. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000, and 6000 can also be used.

[0280] Glidants can be added, which can improve the flow properties of the drug during formulation and assist in rearrangement during compression. Glidants can include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0281] To assist the therapeutic agent in dissolving into an aqueous environment, surfactants can be added as wetting agents. Surfactants can include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents that can be used can include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that can be included in the formulation as surfactants include polidocanol 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 can be present alone or in mixtures at different ratios in the formulation of the compounds or derivatives of the present invention.

[0282] Oral administrable pharmaceutical preparations include push-fit capsules made of gelatin and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain a mixture of an active ingredient with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All oral administration preparations should be in a dosage suitable for such administration.

[0283] For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0284] For local administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection), and those designed for transdermal, transmucosal oral or pulmonary administration.

[0285] For administration by inhalation, the compounds used according to the present invention may be conveniently delivered in the form of an aerosol spray by using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases from a pressurized package or nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. Capsules and cartridges made of, for example, gelatin for use in an inhaler or insufflator may be formulated to contain a powder mixture of the compound with a suitable powder matrix such as lactose or starch.

[0286] The present invention also contemplates pulmonary delivery of the compounds (or salts thereof) disclosed herein. The compounds are delivered to the lungs of a mammal upon inhalation and cross the inner lining of the lung epithelium into the bloodstream. Other reports of inhaled molecules include 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) (endothelin-1); 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-γ and tumor necrosis factor α) and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). Methods and compositions for pulmonary delivery of drugs for systemic effects are set forth in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al. (incorporated by reference).

[0287] Consideration is given to the use in the practice of the present invention of various mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0288] 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 Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0289] All such devices require the use of a formulation suitable for dispensing the compounds of the present invention. Generally, each formulation is specific to the type of device employed and may involve the use of suitable propellant materials in addition to the usual diluents, adjuvants, and / or carriers available in therapy. In addition, the use of liposomes, microcapsules or microspheres, inclusion compounds, or other types of carriers is contemplated. Depending on the type of chemical modification or the type of device employed, the chemically modified compounds of the present invention may also be formulated in different formulations.

[0290] Formulations suitable for use with nebulizers (jet or ultrasonic) will generally contain the compound (or derivative) of the present invention dissolved in water at a concentration of about 0.1 to 25 mg of the bioactive compound of the present invention per milliliter of solution. The formulation may also include a buffer and a monosaccharide (e.g., for inhibitor stabilization and osmotic pressure regulation). Nebulizer formulations may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the present invention caused by atomization of the solution during aerosol formation.

[0291] Formulations for use with metered-dose inhaler devices will generally contain a fine powder containing the compound (or derivative) of the present invention, the powder being suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane or combinations thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid may also be used as a surfactant.

[0292] Formulations for dispensing from powder inhaler devices will contain a fine dry powder containing the compound (or derivative) of the present invention and may also include bulking agents such as lactose, sorbitol, sucrose, or mannitol in an amount that facilitates dispersion of the powder from the device, e.g., 50% to 90% by weight of the formulation. The compound (or derivative) of the present invention should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for most effective delivery deep into the lungs.

[0293] Transnasal delivery of the pharmaceutical compositions of the present invention is also contemplated. Transnasal delivery allows the pharmaceutical compositions of the present invention to enter the bloodstream directly after administration of the therapeutic product to the nose without the need for deposition of the product in the lungs. Formulations for transnasal delivery include those having dextran or cyclodextran.

[0294] For nasal administration, an available device is a small, rigid bottle attached to a metered-dose nebulizer. In one embodiment, a metered dose is delivered by inhaling the pharmaceutical composition solution of the present invention into a chamber of defined volume, the chamber having apertures sized to aerosolize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0295] Alternatively, a plastic squeeze bottle with apertures or openings sized to aerosolize the aerosol formulation by forming a spray when squeezed is used. The opening is typically present at the top of the bottle, and the top is typically tapered to fit partially into the nasal passage for effective administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation for administering the measured dose of the drug.

[0296] When systemic delivery of the compound is desired, the compound can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage forms, for example, in ampoules or in multi-dose containers, with an added preservative. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents.

[0297] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound can be prepared as appropriate oily injection suspensions. 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 injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0298] Alternatively, the active compound can be in powder form for constitution with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0299] The compound can also be formulated in rectal or vaginal compositions, such as suppositories or retention enemas containing, for example, conventional suppository bases (such as cocoa butter or other glycerides).

[0300] In addition to the above formulations, the compound can also be formulated as a depot preparation. Such long-acting formulations can be formulated using suitable polymeric or hydrophobic materials (such as an emulsion in an acceptable oil) or ion exchange resins, or as a slightly soluble derivative (such as a slightly soluble salt).

[0301] The pharmaceutical composition may also comprise a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0302] Suitable liquid or solid pharmaceutical dosage forms are, for example, aqueous or saline solutions for inhalation, microencapsulation, embedding, coating on microscopic gold particles, inclusion in liposomes, atomization, aerosols, pellets for implantation into the skin, or drying on sharp objects for scratching into the skin. The pharmaceutical composition also includes granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or formulations for extended release of the active compound, in which excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweetening agents, or solubilizing agents are generally used as described above. The pharmaceutical composition is suitable for a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249:1527-33 (1990).

[0303] The compounds of the invention and optionally other therapeutic agents can 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 non-pharmaceutically acceptable salts or co-crystals can be conveniently used to prepare their pharmaceutically acceptable salts or 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. In addition, such salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts of carboxylic acid groups.

[0304] Suitable buffering agents include: acetic acid and salts (1-2% weight / volume (w / v)); citric acid and salts (1-3% weight / volume); boric acid and salts (0.5-2.5% weight / volume); and phosphoric acid and salts (0.8-2% weight / volume). Suitable preservatives include benzalkonium chloride (0.003-0.03% weight / volume); chlorobutanol (0.3-0.9% weight / volume); parabens (0.01-0.25% weight / volume); and thimerosal (0.004-0.02% weight / volume).

[0305] The pharmaceutical composition of the present invention comprises an effective amount of a compound as described herein and an optional therapeutic agent, including in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" denotes a natural or synthetic organic or inorganic ingredient which is combined with the active ingredient to facilitate its application. The components of the pharmaceutical composition are also capable of being commingled with the compounds of the present invention and with each other in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0306] One or more therapeutic agents (specifically including but not limited to the compounds of the present invention) may be provided in particulate form. As used herein, particulate means nanoparticles or microparticles (or in some cases larger particles) which may be composed in whole or in part of the compounds of the present invention or one or more other therapeutic agents as described herein. The particulate may contain one or more therapeutic agents in a core surrounded by a coating, the coating including but not limited to an enteric coating. One or more therapeutic agents may also be dispersed throughout the particulate. One or more therapeutic agents may also be adsorbed into the particulate. The particulate may have any level of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. In addition to one or more therapeutic agents, the particulate may include any of those materials commonly used in the pharmaceutical and medical arts, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof. The particulate may be a microcapsule which contains the compounds of the present invention in solution or semi-solid state. The particulate may be virtually any shape.

[0307] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particulates for delivering one or more therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the desired period of release. Particularly interesting bioadhesive polymers include 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, gelatin protein, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate).

[0308] One or more therapeutic agents may be included in a controlled release system. The term "controlled release" is intended to refer to any pharmaceutical formulation containing a drug, wherein the manner and profile of release of the drug from the formulation are controlled. This refers to both immediate release and non-immediate release formulations, where 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 pharmaceutical formulation that releases a drug gradually over an extended period of time and preferably, although not necessarily, produces a substantially constant blood level of the drug over an extended period of time. The term "delayed release" is used in its conventional meaning and refers to a pharmaceutical formulation in which there is a time delay between administration of the formulation and release of the drug from it. "Delayed release" may or may not involve gradual release of the drug over an extended period of time and thus may or may not be "sustained release".

[0309] The use of long-term sustained release implants may be particularly suitable for the treatment of chronic conditions. As used herein, "long-term" release means that the implant is constructed and arranged to deliver a therapeutic level of the active ingredient for at least 7 days and preferably 30 - 60 days. Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the above-described release systems.

[0310] Those of ordinary skill in the relevant art will understand that, given the information known to ordinary skill in the art, other suitable modifications and adaptations of the compositions and methods described herein will be readily apparent from the description of the invention contained herein and may be made without departing from the scope of the invention or any of its embodiments. The invention has now been described in detail, and the invention will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0311] Examples

[0312] The invention is further described in the following examples, which do not limit the scope of the invention as described in the claims.

[0313] Example 1: SLC6A19 Isoleucine Transport Assay

[0314] Cell line generation and maintenance

[0315] Flp-In TM T-REx TMThe 293 cell line was purchased from Thermo Fisher Scientific. This cell line was used to generate a stable cell line that could inducibly express human SLC6A19 with a C-terminal V5 tag and stably express human TMEM27 (also known as Collectrin) with a C-terminal myc-DDK tag. This stable cell line was generated by transfecting SLC6A19- and TMEM27-encoding plasmids using standard protocols followed by antibiotic selection. The stable cells were maintained in DMEM / F12 (Thermo Fisher) 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.

[0316] Assays : Isoleucine transport assay in 96-well format

[0317] On day 0, the stable cell line was seeded at a density of 35,000 cells per well in a poly-D-lysine-coated 96-well cell culture treatment plate. On day 1, the expression of SLC6A19 was induced by dispensing tetracycline at a final concentration of 1 μg / mL using a Tecan D300e digital dispenser. On day 2, the transport assay was run. The medium was removed from the plate using the GentleSpin setting of a Centrifugal BlueWasher (Blue Cat Bio), and the cells were washed with 175 μL of live cell imaging solution (Thermo Fisher) using the Blue Washer. After washing, the cells were treated with: 70 μL of DMSO, positive control, or compound, diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl 2 , 1.2 mM MgCl 2 , 11 mM HEPES, 10 mM glucose, pH 7.4) at room temperature. After 20 - 60 minutes, 30 μL of 3.3 mM 13 C 6 , 15 N-L-isoleucine solution (Cambridge Isotope Laboratories) was added. After incubating with the isoleucine substrate for 20 min at room temperature, the cells were washed with 175 μL of live cell imaging solution using the Blue Washer. The cells were then lysed in 15 μM D-leucine-d10 (CDN Isotopes) in 150 μL of ultrapure water. The plate was placed on an oscillator at 700 rpm for at least 40 minutes to facilitate lysis. After lysis, the 13 C 6 ,15 The standard dilution curve of N-L-isoleucine was added to the wells containing the lysates of untreated cells. The plate was placed back on the shaker for at least 2 minutes to ensure proper mixing of the standard curve. Then the plate was centrifuged at 4,000 rpm for 5 min to pellet cell debris and precipitates. The supernatant was diluted 1:10 in acetonitrile + 0.1% formic acid in a polypropylene plate.

[0318] Assays : Isoleucine transport assay in 384-well format

[0319] On day 0, the stable cell line was seeded at a density of 20,000 cells per well in medium containing 1 μg / mL tetracycline in poly-D-lysine-coated 384-well cell culture-treated plates using a Viaflo 384-well pipettor. The transport assay was run the next day (day 1). The medium was removed from the plate using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio), and the cells were washed with 80 μL of live cell imaging solution (Thermo Fisher) using the Blue Washer. After washing, the cells were treated with 20 μL of DMSO, positive control, or compound diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl 2 , 1.2 mM MgCl 2 , 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 3.3 mM 13 C 6 , 15 N-L-isoleucine solution (Cambridge Isotope Laboratories) was added. After incubation with the isoleucine substrate at room temperature for 20 min, the cells were washed with 80 μL of live cell imaging solution using the Blue Washer. Then the cells were lysed in 15 μM D-leucine-d10 (CDN Isotopes) in 80 μL of ultrapure water. The plate was placed on a shaker at 700 rpm for at least 2 hours to facilitate lysis. After lysis, the 13 C 6 , 15 The standard dilution curve of N-L-isoleucine was added to the wells containing the lysates of untreated cells. The plate was placed back on the shaker for at least 5 minutes to ensure proper mixing of the standard curve. Then the plate was centrifuged at 4,000 rpm for 10 min to pellet cell debris and precipitates. The supernatant was diluted 1:10 in acetonitrile + 0.1% formic acid in a polypropylene plate.

[0320] Performed using RapidFire365-QTOF 6545 (Agilent) 13 C 6 , 15 N-L-isoleucine analysis. Quantitative sample analysis was performed using automated solid-phase extraction (HILIC H6 column), followed by injection into the mass spectrometer. Samples were loaded using 95% acetonitrile, 0.1% formic acid, and eluted directly from the column with 5% acetonitrile, 0.1% formic acid for ESI-MS (electrospray ionization) analysis. Analyte quantification was performed using Agilent Masshunter Quant software from high-resolution full-scan data.

[0321] Example 2: Preparation of Exemplary Compounds

[0322] General Procedure A

[0323]

[0324] Step 1

[0325] At -78 °C, NaBH 4 (7.2 g, 189.39 mmol) was added to a mixture of A1 (12.0 g, 126.26 mmol) and NaHCO 3 (9.54 g, 113.64 mmol) in MeOH (100 mL), and the resulting mixture was stirred at -78 °C for 20 minutes. Then, at -78 °C under an N 2 atmosphere, CbzCl (35.5 mL, 252.52 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. Then the mixture was quenched with water (150 mL) and extracted twice with DCM (100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 dried, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 60% EtOAc in PE) to give pure A2 (8.7 g, 35% yield) as a yellow oil. LC / MS (ESI) m / z: 234 (M + H) + .

[0326] Step 2

[0327] At 0 °C under an N 2 atmosphere, Et 2 Zn (56 mL, 55.98 mmol) was added to a solution of A2 (8.7 g, 37.32 mmol) in anhydrous DCE (100 mL), and the resulting mixture was stirred at 0 °C for 15 minutes. Then, at 0 °C under an N 2 atmosphere, CH 2 I2 (4.51 mL, 55.98 mmol) and the resulting mixture was stirred overnight at room temperature. Then the mixture was quenched with water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 50% EtOAc in PE) to afford A3 (7.1 g, yield 77%) as a yellow oil. LC / MS (ESI) m / z: 248 (M+H) + .

[0328] Step 3

[0329] Under N 2 to a solution of A3 (7.1 g, 28.74 mmol) in EtOAc (100 mL) was added 10% Pd / C (1.4 g) and (Boc) 2 O (7.53 g, 34.49 mmol), and the resulting suspension was degassed under vacuum and purged with H 2 several times. Then the mixture was stirred under H 2 atmosphere at room temperature for 4 h. Then the mixture was filtered through a pad, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 50% EtOAc in PE) to give A4 (5.5 g, yield 90%) as a yellow oil. LC / MS (ESI) m / z: 214 (M+H) + .

[0330] Step 4

[0331] To a solution of A4 (3.1 g, 14.55 mmol) in toluene (60 mL) was added TEA (3.0 g, 29.1 mmol) and DPPA (4.8 g, 17.46 mmol), and the resulting mixture was stirred at 120 °C for 18 h. Then the mixture was diluted with water (120 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude A5 (3.5 g, yield 99%), which was used in the next step without any further purification. LC / MS (ESI) m / z: 239 (M+H) + .

[0332] Step 5

[0333] PPh 3(7.71 g, 29.42 mmol) was added to a solution of A5 (3.5 g, 14.71 mmol) in THF (40 mL) and H 2 O (10 mL), and the resulting mixture was stirred at 45 °C for 18 h. The mixture was then concentrated under reduced pressure to give crude A6 (3.1 g, 99% yield), which was used in the next step without any further purification. LC / MS (ESI) m / z: 213 (M+H) + .

[0334] Step 6

[0335] At 0 °C, 2,4-dimethoxybenzaldehyde (2.67 g, 16.08 mmol) and NaBH(OAc) 3 (7.75 g, 36.55 mmol) were added to a solution of A6 (3.1 g, 14.62 mmol) and AcOH (8 drops) in MeOH (60 mL), and the resulting mixture was stirred at room temperature for 18 h under a N 2 atmosphere. The mixture was then quenched with water (80 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH in DCM) to give A7 (3.2 g, 60% yield) as a yellow oil. LC / MS (ESI) m / z: 363 (M+H) + .

[0336] Step 7

[0337] At 0 °C, (1-ethoxycyclopropoxy)trimethylsilane (2.31 g, 13.26 mmol) and NaBH 3 CN (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), and the resulting mixture was stirred at 80 °C under a N 2 atmosphere for 18 h. The mixture was then quenched with water (80 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH in DCM) to give A8 (2.9 g, 82% yield) as a yellow oil. LC / MS (ESI) m / z: 403 (M+H) + .

[0338] Step 8

[0339] To a solution of A8 (1.2 g, 2.99 mmol) in DCM (16 mL) was added TFA (4 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 afford crude A9 (820 mg, 91% yield), which was used in the next step without any further purification. LC / MS (ESI) m / z: 303 (M+H) + .

[0340] General procedure B

[0341]

[0342] Step 1

[0343] To a solution of diethylzinc (6.02 mL, 6.02 mmol) in anhydrous DCE (10 mL) was added CH 3 I 2 (3.23 g, 12.05 mmol) dropwise over 3 min at 0 °C, giving a clear solution of Zn(CH 2 I) 2 Then Zn(CH 2 I) 2 was added dropwise to a solution of B1 (800 mg, 4.02 mmol) in DCE (10 mL) at -10 °C, and the resulting reaction mixture was stirred at -10 °C for 2 h. The reaction was then quenched with saturated aqueous NH 4 Cl (20 mL) and extracted with EtOAc (50 mL x2). The combined organic layers were washed with water and brine (25 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM:MeOH = 100:1 to 15:1) to afford B2 (530.0 mg, 62% yield) as an oil. LC / MS (ESI) m / z: 214 (M+H) + .

[0344] Step 2

[0345] To a solution of B2 (530.0 mg, 2.49 mmol) and TEA (301.8 mg, 2.98 mmol) in THF (15 mL) was added DPPA (750.3 mg, 2.73 mmol) dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 17 h. The mixture was then diluted with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2 SO 4 Dry, filter and concentrate to obtain B3, a colorless oil, which is used in the next step without any further purification. LC / MS (ESI) m / z: 183 (M - 56 + H) + 。

[0346] Step 3

[0347] Add PPh 3 (990.6 mg, 3.78 mmol) to a solution of B3 (450.0 mg, 1.89 mmol) in THF (20 mL) and H 2 O (10 mL), and stir the resulting mixture at room temperature for 17 h. Then concentrate the mixture to obtain B4, which is used in the next step without any further purification. LC / MS (ESI) m / z: 213 (M + H) + 。

[0348] Step 4

[0349] At room temperature, add AcOH (480.9 mg, 8.01 mmol) and 2,4 - dimethoxybenzaldehyde (279.4 mg, 1.68 mmol) to a solution of B4 (340.0 mg, 1.60 mmol) in DCM (10 mL), and stir the resulting mixture for 1.5 h. Then add NaBH(OAc) 3 (678.9 mg, 3.20 mmol) at 0 °C. Then stir the reaction overnight at room temperature, quench with saturated NaHCO 3 aqueous solution (100 mL, aq.) and extract with DCM (100 mL x 2). Wash the combined organic layers with brine (150 mL), dry over anhydrous Na 2 SO 4 dry, and concentrate under reduced pressure. Purify the residue by flash column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain B5 (320.0 mg, yield 55%), an oil. LC / MS (ESI) m / z: 363 (M + H) + 。

[0350] Step 5

[0351] At room temperature, add (1 - ethoxycyclopropoxy)trimethylsilane (384.7 mg, 2.21 mmol), NaBH 3CN (138.7 mg, 2.21 mmol) and AcOH (530.2 mg, 8.83 mmol), and the resulting mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO 3 aqueous solution (30 mL, aq.), and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 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 oil. LC / MS (ESI) m / z: 403 (M+H) + .

[0352] Step 6

[0353] At 0 °C under N 2 atmosphere, TFA (5 mL) was added to a solution of B6 (350.0 mg, 0.87 mmol) in DCM (20 mL), and 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 oil, which was used in the next step without any further purification. LC / MS (ESI) m / z: 303 (M+H) + .

[0354] General procedure C

[0355]

[0356] At 0 °C, Ac 2 O (167 mg, 1.63 mmol) and DIEA (0.47 mL, 2.72 mmol) were added to a solution of A9 (410 mg, 1.36 mmol) in DCM (15 mL), and the resulting mixture was stirred at 0 °C for 1 h. Then the mixture was diluted with water (50 mL) and extracted twice with DCM (30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH in DCM) to give C2 (390 mg, 84% yield) as a yellow oil. LC / MS (ESI) m / z: 345 (M+H) + .

[0357] General procedure D

[0358]

[0359] Step 1 - Method A

[0360] At 0 °C under N 2 atmosphere, D1 (2 eq.) and DIEA (3 eq.) were added to a solution of A9 (1 eq.) in DCM, and the resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography to give D3.

[0361] Step 1 - Method B

[0362] HATU (1.3 eq.) was added to a mixture of D2 (1.2 eq.) and DIEA (3 eq.) in DMF, and the resulting mixture was stirred at room temperature for 5 - 10 min before adding A9. The reaction was stirred for 15 min, then the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography to give D3.

[0363] Synthesis of 2-(4-(cyclopropyl(3,4 - dimethoxybenzyl)amino)-2 - azabicyclo[4.1.0]hept - 2 - yl)-2 - oxoethyl acetate

[0364]

[0365] At 0 °C under N 2 atmosphere, 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), and the resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (50 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 5% MeOH in DCM) to give D3 (650 mg, yield 87%) as a yellow oil. LC / MS (ESI) m / z: 403 (M + H) + .

[0366] General procedure E

[0367]

[0368] At 0 °C, DIEA (0.4 mL, 3.48 mmol) and E1 (259 mg, 1.39 mmol) were added to a solution of A9 (350 mg, 1.16 mmol) in DMF (10 mL), and the resulting mixture was stirred at 100 °C for 18 h. Then the mixture was diluted with water (60 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 8% MeOH in DCM) to give E2 (265 mg, 51% yield) as a yellow oil. LC / MS (ESI) m / z: 453 (M+H) + 。

[0369] General procedure F

[0370]

[0371] Step 1

[0372] At 0 °C under a N 2 atmosphere, CDI (1.2 eq.) was added dropwise to a solution of F1 (1 eq.) in anhydrous THF, and the resulting mixture was stirred at room temperature for 30 min until complete conversion. Then the mixture was concentrated under reduced pressure to give crude F2, which was used in the next step without any further purification.

[0373] Step 2

[0374] To a solution of A9 (1.0 eq.) in MeCN were added TEA (3.0 eq.) and F2 (1.2 eq.), 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 Na 2 SO 4 dried, filtered and concentrated to dryness. The residue was purified by flash column chromatography to give F3.

[0375] Synthesis of 4-(cyclopropyl(3,4 - dimethoxybenzyl)amino)-N - methyl - 2 - azabicyclo[4.1.0]heptane - 2 - carboxamide

[0376]

[0377] Step 1

[0378] At 0 °C under a N 2Under an atmosphere, 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), and the resulting mixture was stirred at room temperature for 30 minutes until complete conversion. The mixture was then concentrated under reduced pressure to obtain crude F2, which was used in the next step without any further purification.

[0379] Step 2

[0380] At 0 °C, TEA (0.42 mL, 3 mmol) and F2 (150 mg, 1.2 mmol) were added to a solution of A9 (302 mg, 1 mmol) in MeCN (10 mL), and the resulting mixture was stirred at 50 °C for 18 hours. The mixture was then 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 Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH in DCM) to give F3 (350 mg, 97% yield) as a yellow oil. LC / MS (ESI) m / z: 360 (M+H) + 。

[0381] General procedure G

[0382]

[0383] At 0 °C, 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), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then 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 Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 10% MeOH in DCM) to give G1 (470 mg, 63% yield) as a yellow oil. LC / MS (ESI) m / z: 346 (M+H) + 。

[0384] General procedure H

[0385]

[0386] Step 1

[0387] At 0 °C, K was added to a solution of A9 (510 mg, 1.69 mmol) in DMF (15 mL). 2 CO 3 (700 mg, 5.07 mmol) and H1 (300 mg, 2.03 mmol) were added, and the resulting mixture was stirred at 90 °C for 18 h. The mixture was then diluted with water (100 mL) and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 6% MeOH in DCM) to give H2 (284 mg, 41% yield) as a yellow oil. LC / MS (ESI) m / z: 415 (M + H) + .

[0388] Step 2

[0389] Under N 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). The resulting suspension was degassed under vacuum and purged with H 2 several times. Then it was stirred at room temperature for 1 h under a H 2 atmosphere. The mixture was then filtered through a pad, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 - 6% MeOH in DCM) to give H3 (70 mg, 27% yield) as a yellow oil. LC / MS (ESI) m / z: 381 (M + H) + .

[0390] General procedure I

[0391]

[0392] A solution of I1 (1 eq.) in TFA was stirred at 80 °C for 3 h. The mixture was then concentrated under reduced pressure to give crude I2, which was used in the next step without any further purification.

[0393] Synthesis of 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2-carboxamide

[0394]

[0395] A solution of I1 (470 mg, 1.36 mmol) in TFA (10 mL) was stirred at 80 °C for 3 h. The mixture was then concentrated under reduced pressure to give crude I2 (270 mg), which was used in the next step without any further purification. LC / MS (ESI) m / z: 196 (M+H) + .

[0396] General procedure J

[0397]

[0398] To a solution of I2 (1 eq.) in MeCN at 0 °C was added F2 (1.1 eq.) and TEA (5 eq.), and the resulting mixture was stirred at 50 °C for 3 h. The mixture was then quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give J1, as a mixture of stereoisomers, which was further purified by chiral chromatography.

[0399] Synthesis of Compound 3

[0400]

[0401] To a solution of J1 (50 mg, 0.203 mmol) in MeCN (8 mL) at 0 °C was added TEA (0.14 mL, 1.02 mmol) and J2 (80 mg, 0.223 mmol), and the resulting mixture was stirred at 50 °C for 3 h. The mixture was then diluted with water (80 mL) and extracted twice with DCM (30 mL). The combined organic layers were washed with brine (90 mL), dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give a mixture of enantiomers (55 mg, yield 51%), which was then further separated by SFC (Waters Thar 80 preparative SFC; CHIRALPAK C-IG 100*4.6 mm 5 μm; C-IG-M-D-40) to give 3 (21 mg, yield 38%, d.e. >99%), as a white solid. LC / MS (ESI) m / z: 531 (M+H) + . 11H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 5.9 Hz, 1H), 6.72 (s, 1H), 5.77 (d, J = 6.8 Hz, 1H), 4.54 (d, J = 4.3 Hz, 2H), 4.42 - 4.30 (m, 1H), 3.49 - 3.37 (m, 1H), 3.35 - 3.25 (m, 1H), 2.85 - 2.75 (m, 1H), 2.62 - 2.51 (m, 2H), 2.20 - 2.10 (m, 1H), 1.64 - 1.54 (m, 1H), 1.14 - 1.05 (m, 1H), 1.00 - 0.90 (m, 2H), 0.87 - 0.73 (m, 2H), 0.48 - 0.40 (m, 1H); 19 19F NMR (377 MHz, MeOD) δ -59.47 (s).

[0402] General procedure K

[0403]

[0404] At 0 °C under N 2 atmosphere, F2 (1.0 eq.) and DIPEA (3 eq.) were added to a mixture of K1 (1 eq.) in DMF, and the resulting mixture was stirred at 50 °C for 30 minutes. Then the mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 2SO 4 4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to give K2 as a mixture of 4 stereoisomers, which was further purified by chiral chromatography.

[0405] Synthesis of Compound 24

[0406]

[0407] At 0 °C under N 2 atmosphere, K4 (201.9 mg, 0.67 mmol) and DIPEA (258.1 mg, 2.00 mmol) were added to a mixture of K3 (130.0 mg, 0.67 mmol) in DMF (5 mL), and the resulting mixture was stirred at 50 °C for 30 minutes. Then the mixture was diluted with water and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na 2 2SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by flash column chromatography (eluting with 1 - 5% MeOH in DCM) to afford the racemic mixture (210.0 mg, 73% yield) as a white solid. LC / MS: m / z: 431 (M + H) + The mixture was then further purified by SFC (Shimadzu E - UC; CHIRALPAK C - IG 100*4.6 mm 5 μm; C - IG - M - D - 10 - 40) to give 24 (8 mg, 4% yield, d.e. >99%) 1 H NMR (400 MHz, MeOD) δ 7.47 - 7.43 (m, 1H), 7.13 - 7.04 (m, 2H), 4.77 - 4.69 (m, 1H), 4.50 - 4.41 (m, 2H), 3.76 - 3.66 (m, 1H), 3.52 - 3.44 (m, 2H), 3.06 (t, J = 12.1 Hz, 1H), 2.55 - 2.45 (m, 1H), 1.36 - 1.22 (m, 2H), 1.00 - 0.92 (m, 2H), 0.90 - 0.82 (m, 2H), 0.80 - 0.74 (m, 2H); 19 F NMR (377 MHz, MeOD) δ - 59.78 (s), - 116.97 (s).

[0408] General procedure L

[0409]

[0410] Step 1

[0411] To a solution of L1 (1 eq.) in toluene was added TEA (2 eq.) and DPPA (1.5 eq.), and the resulting mixture was stirred at 80 °C for 2 h under N 2 atmosphere. The mixture was then concentrated under reduced pressure to give crude L2, which was used in the next step without any further purification.

[0412] Step 2

[0413] At 0 °C, TEA (5 eq.) and L2 (1.2 eq.) were added to a solution of I2 (1 eq.) in DCM, and the resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give L3.

[0414] Synthesis of compound 21

[0415]

[0416] Step 1

[0417] To a solution of L4 (60 mg, 0.24 mmol) in toluene (8 mL) was added TEA (0.07 mL, 0.48 mmol) and DPPA (0.08 mL, 0.36 mmol), and the resulting mixture was stirred under N 2 atmosphere at 80 °C for 2 h. The mixture was then concentrated under reduced pressure to give crude L5 (60 mg), which was used in the next step without any further purification.

[0418] Step 3: Synthesis of 4-P1

[0419] At 0 °C, TEA (0.2 mL, 1.45 mmol) and L5 (60 mg, 0.35 mmol) were added to a solution of L6 (60 mg, 0.29 mmol) in DCM (10 mL), and the resulting mixture was stirred at room temperature for 1 h. The mixture was then 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 Na 2 SO 4 2, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give a racemic mixture (66 mg, 50% yield) as a white solid. LC / MS (ESI) m / z: 453 (M+H) + . The mixture was further purified by SFC (Shimadzu E-UC; CHIRALCEL OZ 100*4.6 mm 5 μm; OZ-M-D-10-40) to give 21 (18 mg, 27% yield, d.e. >98%) 1 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 19F NMR (377 MHz, MeOD) δ -59.63 (s).

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] Incorporated by reference

[0430] All U.S. patents and U.S. and PCT patent application publications cited herein are incorporated by reference into this application.

[0431] Equivalents

[0432] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A compound of formula (Ia) or (Ib): in: L1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH2-; L2 does not exist or is -CH2-; L3 does not exist or is -C(O)-; X1 and X2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, heterocyclyl, aryl and arylalkyl; provided that X1 and X2 are not both -H; Y1 is selected from aryl and heteroaryl; Y2 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH(Y2') and -N(Y2")2; Y2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl; and Each Y2" is independently alkyl, or the two entities together with the nitrogen atom to which they are bound form a 5- or 6-membered heterocyclic group; Y3 and Y4 are independently selected from -H, halo, hydroxy, alkyl, hydroxyalkyl, aminoalkyl and alkyl-CO2H; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, having the structure:

3. The compound according to claim 1, having the structure:

4. The compound according to claim 2 or 3, wherein each of Y3 and Y4 is H.

5. The compound according to any one of claims 1 to 4, wherein one of X1 and X2 is -H; and the other of X1 and X2 is selected from C1-C4 alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclyl.

6. The compound according to claim 5, wherein one of X1 and X2 is -H; and the other of X1 and X2 is selected from -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, 7. The compound according to claim 6, wherein X1 is -H and X2 is -CH3; or X2 is -H and X1 is -CH3.

8. The compound according to claim 6, wherein X1 is -H and X2 is or X2 is -H and X1 is 9. The compound according to any one of claims 1 to 8, wherein L1 is absent.

10. The compound according to any one of claims 1-8, wherein L1 is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH2-.

11. The compound of claim 10, wherein L1 is selected from -CH2-, -C(H)(CH3)-, -CH2CH2- and -C(H)(OH)CH2-.

12. The compound according to claim 10, wherein L1 is 13. The compound according to claim 10, wherein L1 is selected from 14. The compound according to claim 10, wherein L1 is selected from 15. A compound according to any one of claims 9 to 14, having a structure selected from the following:

16. The compound according to any one of claims 1 to 15, wherein Y1 is unsubstituted aryl.

17. The compound according to claim 16, wherein Y1 is selected from unsubstituted phenyl and unsubstituted naphthyl.

18. The compound according to any one of claims 1 to 17, wherein Y1 is substituted aryl.

19. The compound according to claim 18, wherein Y1 is and R1, R2, R3, R4 and R5 are 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.

20. The compound of claim 19, wherein R1, R2, R3, R4 and R5 are independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -OCH3, -OCF3, -OCHF2, 21. The compound of claim 20, wherein R1, R2, R3, R4 and R5 are independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCF3 and 22. The compound of any one of claims 19-21, wherein two of R1, R2, R3, R4 and R5 are not -H.

23. The compound of any one of claims 19-21, wherein three of R1, R2, R3, R4 and R5 are not -H.

24. The compound according to claim 21, wherein Y1 is selected from 25. The compound of any one of claims 1-15, wherein Y1 is unsubstituted heteroaryl.

26. The compound according to claim 25, wherein Y1 is selected from 27. A compound according to any one of claims 1-15, wherein Y1 is substituted heteroaryl.

28. The compound according to claim 27, wherein Y1 is selected from: and R6, R7, R8 and R9 are independently selected at each occurrence from -H, halogen, -CN, -OCF3, -OCHF2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl and heteroaryl; provided that at least one of R6, R7, R8 and R9 is not -H.

29. A compound according to any one of claims 1-28, wherein L2 is absent.

30. The compound of any one of claims 1-28, wherein L2 is -CH2-.

31. A compound according to any one of claims 1-28, wherein L3 is absent.

32. A compound according to any one of claims 1-28, wherein L3 is -C(O)-.

33. The compound according to claim 31, having a structure selected from the group consisting of:

34. The compound of claim 33, wherein Y2 is unsubstituted heteroaryl.

35. The compound according to claim 34, wherein Y2 is selected from:

36. The compound according to claim 35, wherein Y2 is 37. The compound of claim 33, wherein Y2 is substituted heteroaryl.

38. The compound according to claim 37, wherein Y2 is R 10 , R 11 and R 12 independently selected from -H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 、-CO2R 15 and -C(O)NHSO2R 15 ; The condition is R 10 , R 11 and R 12 At least one of is not -H; and R 13 , R 14 and R 15 and -4-( ...

39. The compound according to claim 38, wherein R 10 , R 11 and R 12 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.

40. The compound according to claim 39, wherein R 10 and R 12 Each is -H; and R 11 Selected from -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, 41. The compound according to claim 39, wherein R 11 and R 12 Each is -H; and R 10 Selected from -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, 42. The compound according to claim 39, wherein R 10 and R 11 Each is -H; and R 12 Selected from -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, 43. The compound according to claim 37, wherein Y2 is selected from R 16 is independently selected at each occurrence from halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 、-CO2R 15 ;and R 13 , R 14 and R 15 and -4-( ...

44. The compound according to claim 43, wherein R 16 Selected from -CN, -CH3, -CF3, -C(O)NH2, -CO2CH2CH3 and 45. The compound according to claim 37, wherein Y2 is selected from R 17 , R 18 , R 19 , R 20 and R 21 is independently selected at each occurrence from -H, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO2R 15 ; The condition is R 17 , R 18 , R 19 , R 20 and R 21 At least one of is not -H; and R 13 , R 14 and R 15 and -4-( ...

46. The compound according to claim 45, wherein R 17 , R 18 , R 19 , R 20 and R 21 Independently selected from -H, -CN, -CH3 and -OCH3.

47. The compound according to claim 37, wherein Y2 is selected from 48. The compound of claim 32 having a structure selected from the group consisting of:

49. The compound of claim 48, wherein Y2 is unsubstituted cycloalkyl or heterocyclyl.

50. The compound according to claim 49, wherein Y2 is selected from 51. The compound according to claim 48, wherein Y2 is selected from 52. The compound of claim 48, wherein Y2 is a substituted cycloalkyl or heterocyclyl.

53. The compound according to claim 52, wherein Y2 is selected from 54. The compound of claim 48, wherein Y2 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, and hydroxyalkyl.

55. The compound of claim 54, wherein Y2 is selected from -CH3, -CH2CH(CH3)2, -CH2CH2C≡CH, -CH2CH2OCH3, -C(H)(CH3)CH2OCH3, -OCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH and -CH2OCH3.

56. The compound of claim 48, wherein Y2 is unsubstituted heteroaryl or alkyl-substituted heteroaryl.

57. The compound according to claim 56, wherein Y2 is selected from:

58. The compound of claim 48, wherein Y2 is substituted heteroaryl.

59. The compound according to claim 58, wherein Y2 is R 10 , R 11 and R 12 independently selected from -H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO2R 15 ;and R 13 , R 14 and R 15 is independently selected at each occurrence from -H, alkyl, aryl, and heteroaryl, provided that R 10 , R 11 and R 12 At least one of them is not -H.

60. The compound according to claim 67, wherein Y2 is selected from R 17 , R 18 , R 19 , R 20 and R 21 is independently selected at each occurrence from -H, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO2R 15 ;and R 13 , R 14 and R 15 is independently selected at each occurrence from -H, alkyl, aryl, and heteroaryl, provided that R 17 , R 18 , R 19 , R 20 and R 21 At least one of them is not -H.

61. The compound according to claim 58, wherein Y2 is selected from R 22 , R 23 , R 24 and R 25 is independently selected at each occurrence from -H, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO2R 15 ;and R 13 , R 14 and R 15 is independently selected at each occurrence from -H, alkyl, aryl, and heteroaryl, provided that R 22 , R 23 , R 24 and R 25 At least one of them is not -H.

62. The compound according to claim 61, wherein R 22 , R 23 , R 24 and R 25 is independently selected at each occurrence from -H and -CH3.

63. A compound according to claim 33 or 48, wherein Y2 is selected from unsubstituted pyridone, unsubstituted pyrimidone, unsubstituted pyrazinone, unsubstituted triazinone and unsubstituted quinazolinone.

64. The compound according to claim 63, wherein Y2 is selected from 65. A compound according to claim 33 or 48, wherein Y2 is selected from substituted pyridonyl, substituted pyrimidonyl, substituted pyrazinonyl, substituted triazinonyl and substituted quinazolinonyl.

66. The compound according to claim 65, wherein Y2 is and R6 and R7 are independently selected from -H, halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino and cycloalkyl; provided that at least one of R6 and R7 is not -H; or R6 and R7 together with the carbon to which they are bound form an unsubstituted or substituted fused C5-C7 cycloalkyl; or Y2 is and R7 and R8 are independently selected from -H, halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino and cycloalkyl; provided that at least one of R7 and R8 is not -H; or R7 and R8 together with the carbon to which they are bound form an unsubstituted or substituted fused C5-C7 cycloalkyl; or Y2 is and R6 and R9 are independently selected from -H, halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino and cycloalkyl; provided that at least one of R6 and R9 is not -H; or Y2 is and R 10 is selected from halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino and cycloalkyl; or Y2 is and R 11 Selected from halogen, -CN, -OH, -OCF3, -OCHF2, -NH2, alkyl, alkoxy, alkylamino and cycloalkyl.

67. A compound according to claim 65 or 66, wherein Y2 is selected from 68. A compound according to claim 33 or 48, wherein Y2 is N-substituted pyridonyl, N-substituted pyrimidonyl, N-substituted pyrazinonyl, N-substituted triazinonyl or N-substituted quinazolinonyl.

69. A compound according to claim 68, wherein Y2 is an N-alkyl-substituted pyridonyl, an N-alkyl-substituted pyrimidonyl, an N-alkyl-substituted pyrazinonyl, an N-alkyl-substituted triazinonyl or an N-alkyl-substituted quinazolinonyl.

70. The compound according to claim 69, wherein Y2 is selected from 71. The compound of claim 48, wherein Y2 is -NH(Y2') or Y2 is -N(Y2")2.

72. The compound of claim 71, wherein Y2' is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

73. The compound of claim 71, wherein Y2' is selected from -H, -OCH3, -CH3 and -CH2CH2OH.

74. The compound of claim 71, wherein Y2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

75. The compound of claim 74, wherein Y2' is selected from -H, -OH, -OCH3, -CH3, -CH2CH2OCH3 and 76. The compound of claim 71, wherein each Y2" is -CH3.

77. according to the compound described in claim 71, wherein two Y2 " form morpholinyl together with the nitrogen atom to which they are bonded.

78. The compound of claim 1 having a structure selected from the group consisting of:

79. The compound of claim 1 having a structure selected from the group consisting of:

80. A compound according to any one of claims 1-4 or 78-79, wherein L1 is selected from -alkyl-, -cycloalkyl- and -heteroaryl-CH2-; L2 does not exist; L3 does not exist or is -C(O)-; X1 is -H; X2 is a cycloalkyl group; Y1 is selected from aryl and heteroaryl; Y2 is selected from alkyl, alkoxyalkyl, hydroxyalkyl, heteroaryl and -NH(Y2'); and Y2' is selected from -H, alkyl, alkoxyalkyl and hydroxyalkyl.

81. The compound according to claim 80, wherein X2 is 82. The compound of claim 80 or 81, wherein L1 is -CH2-.

83. The compound according to claim 80 or 81, wherein L1 is selected from 84. The compound according to claim 80 or 81, wherein L1 is selected from 85. according to the compound described in any one of claims 80-84, wherein Y1 is 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.

86. The compound of claim 85, wherein two of R1, R2, R3, R4 and R5 are not -H.

87. A compound according to claim 85 or 86, wherein Y1 is selected from 88. A compound according to any one of claims 80-87, wherein L3 is absent.

89. A compound according to any one of claims 80-87, wherein L3 is -C(O)-.

90. The compound according to claim 88, wherein Y2 is 91. The compound of claim 89, wherein Y2 is alkyl or hydroxyalkyl.

92. The compound of claim 91, wherein Y2 is selected from -CH3 and -CH2OH.

93. The compound of claim 89, wherein Y2 is -NH(Y2'); and Y2' is selected from -H or -CH3.

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

95. A pharmaceutical composition comprising a compound according to any one of claims 1-94, and a pharmaceutically acceptable excipient.

96. A method of treating or preventing a disease or condition associated with a genetic defect in phenylalanine hydroxylase, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

97. A method for treating or preventing phenylketonuria, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

98. A method for treating or preventing hyperphenylalaninemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

99. The method of any one of claims 96-98, wherein the compound reduces systemic phenylalanine levels in the subject.

100. A method for treating or preventing tyrosinemia (type I, II or III), comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

101. The method of claim 100, wherein the compound reduces systemic tyrosine levels in the subject.

102. A method for treating or preventing nonketotic hyperglycinemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

103. The method of claim 102, wherein the compound reduces systemic glycine levels in the subject.

104. A method for treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder or hyperammonemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

105. A method for treating or preventing diabetes, chronic kidney disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, metabolic syndrome, obesity-related disorders, or neurodevelopmental and autism spectrum disorders, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94.

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

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