Treatment of PKU using spirosubstituted and other piperidine inhibitors of 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 / 406,536, filed Sep. 14, 2022. Background of the Invention

[0003] Phenylketonuria (PKU) is a congenital metabolic error caused by mutations in phenylalanine hydroxylase (PAH), the enzyme responsible for metabolizing phenylalanine. PKU is an autosomal recessive metabolic disorder in which phenylalanine cannot be properly metabolized and results in abnormally high plasma phenylalanine levels. Individuals with PKU have abnormally high levels of phenylalanine in their blood, which, if left untreated, can lead to irreversible nerve damage and a range of complications such as intellectual disability, epilepsy, and neurodevelopmental and behavioral disorders. PKU is difficult to treat because the level of phenylalanine in the blood is directly related to diet. Patients must adhere to a lifelong and strict diet, which can affect 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 risk of potential adverse events.

[0004] The enzyme responsible for metabolizing phenylalanine and thus maintaining phenylalanine homeostasis is phenylalanine hydroxylase (PAH). Loss-of-function (LOF) mutations at the PAH gene, known to be located on chromosome 12q23.2, cause most forms of PKU. These LOF mutations that cause PKU can be diagnosed as classical PKU (the most severe form), while "mild PKU" or "hyperphe" is a less severe form. In addition to PAH, mutations in other enzymes that affect phenylalanine metabolism, such as dihydropteridine reductase (DHPR), the enzyme 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 also 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 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.

[0006] Accordingly, compounds having the structure of formula (I) are provided herein:

[0007]

[0008] Wherein:

[0009] n is 0, 1, or 2;

[0010] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -;

[0011] L 2 is absent or is -CH 2 -;

[0012] L 3 is absent or is -C(O)-;

[0013] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0014] Y 1 is selected from aryl and heteroaryl;

[0015] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, -O-hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ;

[0016] Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl;

[0017] each Y 2 ″ is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocyclic group; and

[0018] Y 3 and Y 4 together with the carbon to which they are attached form a 4-, 5- or 6-membered cycloalkyl, cycloheteroalkyl or heterocyclic group, or Y 3 and Y 4 are each independently selected from -OH, -CN, -CO 2 H, -CO 2 (alkyl), alkyl, hydroxyalkyl, cyanoalkyl and halogen;

[0019] or a pharmaceutically acceptable salt thereof.

[0020] This article also provides a compound having the structure of formula (II):

[0021]

[0022] Wherein:

[0023] m is 0, 1 or 2;

[0024] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -;

[0025] L 2 is absent or is -CH 2 -;

[0026] L 3 is absent or is -C(O)-;

[0027] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0028] Y 1 is selected from aryl and heteroaryl;

[0029] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, -O-hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ;

[0030] Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl;

[0031] Each Y 2 ″ is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocyclic group;

[0032] Y 5 is selected from cycloalkyl, heteroaryl, heterocyclic group, C 0 -C 6 alkyl-Y 5 ′ and C 2 -C 6 alkenyl-Y 5 ′;

[0033] Y 5 ′ is selected from -CN, -OH, -NH 2 -, -OSO 2 -alkyl, -NH(Y5 ″), -C(O)N(Y 5 ″′) 2 , -SO 2 N(Y 5 ″′) 2 , -O(CO)-Y 5 ″′, -(CO)O-Y 5 ″′, alkoxy, benzyloxy, -C=N-O(alkyl), and formamide moieties;

[0034] Y 5 ″ is selected from alkyl, -C(O)-alkyl, and -SO 2 -alkyl; and

[0035] Y 5 ″′ is independently selected from -H, alkylaminoalkyl, and aryl each time it appears;

[0036] or a pharmaceutically acceptable salt thereof.

[0037] The present invention further provides a compound having the structure of formula (III):

[0038]

[0039] Wherein:

[0040] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH 2 -;

[0041] L 3 is absent or is -C(O)-;

[0042] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0043] Y 1 is selected from aryl and heteroaryl;

[0044] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ;

[0045] Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl;

[0046] Each Y 2 ″is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; and

[0047] Y 6 and Y 7 together with the carbon to which they are attached form a 4-, 5- or 6-membered cycloalkyl or heterocyclic group;

[0048] or a pharmaceutically acceptable salt thereof.

[0049] The present invention further provides a compound having the structure of formula (IV):

[0050]

[0051] wherein:

[0052] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -;

[0053] L 2 is absent or is -CH 2 -;

[0054] L 3 is absent or is -C(O)-;

[0055] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0056] Y 1 is selected from aryl and heteroaryl;

[0057] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ") 2 ;

[0058] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl;

[0059] Each Y 2 " is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0060] Y 8 is selected from cyano, cycloalkyl, heteroaryl, heterocyclic group, alkyl-Y 8 ', and a formamide moiety;

[0061] Y 8 ' is selected from -CN, -OH, -NH 2 , -NH(Y 8 "), -C(O)N(Y 8 ″′) 2 , -SO 2 N(Y 8 ″′) 2 , and a formamide moiety;

[0062] Y 8 ″ is selected from alkyl, -C(O)-alkyl, and -SO 2 -alkyl; and

[0063] Y 8 ″′ is independently selected from -H and alkyl each time it appears;

[0064] or a pharmaceutically acceptable salt thereof.

[0065] 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 (I), (II), (III), or (IV).

[0066] 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 (I), (II), (III), or (IV).

[0067] 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 (I), (II), (III), or (IV).

[0068] 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, the following describes suitable methods and materials. The entire text of all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. In case of conflict, the present specification (including definitions) shall prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0069] Other features, objects, and advantages of the present invention will be apparent from the detailed description and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 is a table summarizing the isoleucine transport data of exemplary compounds of the present invention. A = IC 50 < 500 nM; B = IC 50 500 nM - 1500 nM; C = IC 50 > 1500 nM - 5000 nM; D = IC 50 > 5000 nM - 10000 nM; and E = IC 50 > 10000 nM.

[0071] Figure 2 is a table summarizing the isoleucine transport data of additional exemplary compounds of the present invention. A = IC 50 < 500 nM; B = IC 50 500 nM - 1500 nM; C = IC 50 > 1500 nM - 5000 nM; D = IC 50 > 5000 nM - 10000 nM; and E = IC 50 > 10000 nM. DETAILED DESCRIPTION

[0072] Definitions

[0073] For convenience, certain terms employed in this specification, the examples, and the appended claims are collected here prior to further description of the invention. These definitions should be read in light of the remainder of the disclosure and should be as understood by one of ordinary skill in the art. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0074] To more readily understand the present invention, certain terms and phrases are defined below and throughout the specification.

[0075] As used herein, the articles “a” or “an” refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, “an element” means one element or more than one element.

[0076] As used herein in the specification and claims, the phrase “and / or” shall be understood to mean “either or both” of the elements so joined (i.e., elements that coexist in some cases and separate in other cases). Multiple elements listed in “and / or” should be understood in the same way, i.e., “one or more” of the elements so joined. Optionally, there may be other elements in addition to those explicitly identified by the “and / or” clause, whether or not they are related to those explicitly identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising,” a reference to “A and / or B” may in one embodiment refer to only A (optionally including elements other than B); in another embodiment refer to only B (optionally including elements other than A); in yet another embodiment refer to both A and B (optionally including other elements); and so on.

[0077] As used herein in the specification and 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 interpreted inclusively, i.e., including at least one of the many elements or items in the list, but also including more than one element, and optionally other unlisted items. Only terms that explicitly indicate the contrary meaning, such as “only one” or “exactly one,” or when used in the claims, “consisting of,” will refer to including exactly one of the many elements or items in the list. In general, the term “or” as used herein shall be interpreted to mean exclusive alternatives (i.e., “one or the other but not both”) only when followed by exclusive terms such as “either,” “one of which,” “only one of which,” or “exactly one of which.” “Consisting essentially of,” when used in the claims, shall have the ordinary meaning as used in the field of patent law.

[0078] As used herein in the specification and claims, the phrase "at least one" when referring 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 element specifically listed in the list of elements, and also 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 in the list of elements referred to by the phrase "at least one", whether related or unrelated to the 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 refer to at least one (optionally including more than one) A without B (and optionally including elements other than B); in another embodiment, it can refer to at least one (optionally including more than one) B without A (and optionally including elements other than A); in yet another embodiment, it can refer to 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.

[0079] It should also be understood that, unless the context otherwise requires, in any method claimed herein that includes more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0080] In the claims and in the foregoing specification, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "consisting of", and the like are to be understood to be open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are to be respectively closed or semi-closed transitional phrases, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0081] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds that fall within the scope of the present invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are intended to be included within the present invention.

[0082] "Geometric isomers" means isomers that differ in the orientation of the substituted atoms relative to a carbon-carbon double bond, relative to a cycloalkyl ring, or relative to a bridged bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond can be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" denote configurations relative to the core molecule. Some of the compounds disclosed herein may exist in "atropisomeric" form or as "atropisomers". Atropisomers are stereoisomers resulting from restricted rotation about a single bond, where the rotational steric strain barrier 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 can be resolved from 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 the isomer mixture of the starting material or the final product using various well-known chromatographic methods.

[0083] 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 diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case 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 can be formed with an appropriate optically active acid or base, and the diastereomers so formed can then be resolved by fractional crystallization or chromatographic means well known in the art, and the pure enantiomer is then recovered.

[0084] As used herein, the term "tautomer" means structural isomers that exist in equilibrium due to the migration of a hydrogen atom. For example, two tautomers of 2-pyrimidinone are listed below. A single tautomer can be provided in the form represented by the structure of a given compound.

[0085] However, the present invention encompasses all such tautomers of a given compound.

[0086]

[0087] The purity percentage by mole fraction is the ratio of the number of moles of the enantiomer (or diastereomer) 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 structure, the purity of the named or depicted stereoisomer relative to other stereoisomers is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction. When an individual enantiomer is named or depicted by structure, the purity of the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction. When an individual diastereomer is named or depicted by structure, the purity of the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction.

[0088] When the disclosed compound is named or depicted by a structure that does not indicate stereochemistry and the compound has at least one chiral center, it should be understood that the name or structure encompasses the enantiomers of the compound that do not contain the corresponding optical isomers, the racemic mixture of the compound, or a mixture in which one enantiomer is enriched relative to its corresponding optical isomer. When the disclosed compound is named or depicted by a structure that does not indicate stereochemistry and has two or more chiral centers, it should be understood that the name or structure encompasses diastereomers that do not contain other diastereoisomers, many diastereomers that do not contain other diastereoisomer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, diastereomer mixtures in which one diastereomer is enriched relative to one or more other diastereoisomers, or diastereomer mixtures in which one or more diastereoisomers are enriched relative to other diastereoisomers. The present invention encompasses all these forms.

[0089] 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 carbon with 13 C- or 14 C-enriched carbon are within the scope of the present invention.

[0090] 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 hydrolysis 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.

[0091] 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 in the formulation, not injurious 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) gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (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., they do not cause a significant elevation in body temperature when administered to a patient.

[0092] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of one or more of the said compounds. These salts can be prepared in situ during the final isolation and purification of one or more of the said compounds, or by separately reacting one or more of the purified compounds in their free base form with a suitable organic or inorganic acid and isolating the salt so 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.)

[0093] In other instances, 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 such cases, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic base addition salts of one or more compounds. These salts may also be prepared in situ during the final isolation and purification of one or more of the said compounds, or may be prepared by separately reacting one or more purified compounds in their free acid form with a suitable base such as the 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, among others. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, e.g., Berge et al., supra).

[0094] The term "pharmaceutically acceptable cocrystal" refers to a solid coform that does not form formal ionic interactions with small molecules.

[0095] A "therapeutically effective amount" (or "effective amount") of a compound for use in therapy is an amount of the compound in a formulation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), alleviates symptoms, ameliorates a disorder or retards the onset of a disease disorder according to clinically acceptable criteria for the disorder or condition to be treated or for cosmetic purposes, e.g., with a reasonable benefit / risk ratio applicable to any pharmaceutical treatment.

[0096] 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 the treatment is administered prior to the clinical manifestation of an unwanted disorder (e.g., a disease or other unwanted condition in a host animal), the treatment is prophylactic (i.e., it protects the host from developing the unwanted disorder), while if the treatment is administered after the manifestation of the unwanted disorder, the treatment is therapeutic (i.e., it is intended to alleviate, ameliorate or stabilize an existing unwanted disorder or its side effects).

[0097] The term "patient" or "subject" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, canine, feline or equine. In certain embodiments, the patient is a human.

[0098] Aliphatic chains include the alkyl, alkenyl and alkynyl classes defined below. Straight-chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched-chain or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl or alkynyl.

[0099] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms or up to 30 carbon atoms if not specified. For example, 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. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, the straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its main chain (e.g., C 1刷 , for branched-chain C 3 -C 30 ), and more preferably 20 or fewer carbon atoms. The alkyl may be substituted or unsubstituted.

[0100] 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.

[0101] As used herein, the term "haloalkyl" refers to an alkyl as defined above that is substituted with at least one halogen.

[0102] As used herein, the term "hydroxyalkyl" refers to an alkyl as defined above that is substituted with at least one hydroxy group.

[0103] As used herein, the term "alkylene" refers to an alkyl having a specified number of carbon atoms, e.g., 2 to 12 carbon atoms, that contains two attachment points to the remainder of the compound on the 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. The alkylene may be a cyclic or acyclic, branched or unbranched carbon chain moiety and may optionally be substituted with one or more substituents.

[0104] "Cycloalkyl" means a monocyclic or bicyclic or bridged or spiro or polycyclic saturated carbon ring each having 3 to 12 carbon atoms. Preferred cycloalkyl has 3 to 10 carbon atoms in its ring structure, and more preferably 3 to 6 carbon atoms in the ring structure. The cycloalkyl may be substituted or unsubstituted.

[0105] As used herein, the term "halocycloalkyl" refers to a cycloalkyl as defined above that is substituted with at least one halogen atom.

[0106] "Heterocycloalkyl" refers to a cycloalkyl moiety as defined above that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred heterocycloalkyls have 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably 4-6 carbon atoms and heteroatoms in the ring structure. Heterocycloalkyls can be substituted or unsubstituted.

[0107] Unless otherwise specified as to carbon number, "lower alkyl" as used herein means an alkyl as defined above, but having from one to ten carbon atoms, more preferably from one to six carbon atoms, in the main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have a similar chain length. Throughout the application, preferred alkyls are lower alkyls. In certain embodiments, substituents designated as alkyl herein are lower alkyls.

[0108] "Alkenyl" refers to 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 located within the moiety. Examples of alkenyls having 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl in various isomeric forms, where one or more of the unsaturated bonds can be located at any position within the moiety and can have the (Z) or (E) configuration around one or more of the double bonds.

[0109] "Alkynyl" refers to a hydrocarbon moiety within the scope of alkenyls, but having one or more triple bonds located within the moiety.

[0110] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon (i.e., carbocyclic aryl) or 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, wherein two or more carbons are common to two adjacent rings, and wherein at least one of the rings is aromatic. For example, 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, the ring structures of which include one to four 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.

[0111] As used herein, the terms "halo", "halogen group", or "halogen" mean halogen and include, for example but not limited to, fluorine, chlorine, bromine, iodine, etc. in radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluorine, chlorine, and bromine.

[0112] 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, the ring structures of which contain 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, phenoxazine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinazoline, 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, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, mercapto, imino, amido, phosphate / ester group, phosphonate / ester group, phosphinate / ester group, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF 3 , -CN, etc.

[0113] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of the backbone. It is understood that "substitution" or "substituted by" includes the implicit condition that such substitution is in accordance with the allowed valences of the substituting atoms and substituents, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" contemplates all allowed substituents of organic compounds. In a broad aspect, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Allowed substituents may be one or more substituents and may be the same or different for a suitable organic compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any allowed substituents of the organic compounds described herein that satisfy the valence of the heteroatom. Substituents may 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 / ester, phosphonate / ester, phosphinate / ester, amino, amido, amidine, imine, cyano, nitro, azide, mercapto, alkylthio, sulfate / ester, sulfonate / ester, 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 the substituents themselves may be substituted where appropriate. Unless specifically stated as "unsubstituted", references to chemical moieties herein should be understood to include substituted variants. For example, references to "aryl" or moieties implicitly include substituted and unsubstituted variants.

[0114] As used herein, the definition of each expression (e.g., alkyl, m, n, etc.), when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0115] 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, the small molecules useful in the present invention have a molecular weight of less than 3,000 Daltons (Da). The small molecule can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 Da to about 3,000 Da, about 100 Da to about 2500 Da, about 100 Da to about 2,000 Da, about 100 Da to about 1,750 Da, about 100 Da to about 1,500 Da, about 100 Da to about 1,250 Da, about 100 Da to about 1,000 Da, about 100 Da to about 750 Da, about 100 Da to about 500 Da, about 200 Da to about 1500 Da, about 500 Da to about 1000 Da, about 300 Da to about 1000 Da, or about 100 Da to about 250 Da).

[0116] In some embodiments, "small molecule" refers to an organic, inorganic, or organometallic compound that generally has a molecular weight of less than about 1000. In some embodiments, the small molecule is an organic compound of a size of about 1 nm. 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.

[0117] "Effective amount" is an amount sufficient to produce a beneficial or desired result. For example, a therapeutic amount is an amount that achieves the 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. The effective amount may be administered in one or more administrations, applications, or dosages. The therapeutically effective amount of a composition depends on the composition selected. The composition may be administered once or more times per day to once or more times per week; including once every other day. Those skilled in the art will understand that certain factors may affect the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or condition, previous treatments, the overall health and / or age of the subject, and the presence of other diseases. In addition, treatment of a subject with a therapeutically effective amount of the compositions described herein may include a single treatment or a series of treatments.

[0118] The terms “decrease,” “reduce,” “reduced,” “reduction,” “decrease,” and “inhibit” are all generally used herein to mean a statistically significant decrease in amount relative to a reference. However, for the avoidance of doubt, “reduce,” “reduction,” or “decrease” 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 (e.g.) complete absence of a given entity or parameter, or a decrease between 10-99% compared to the situation where a given treatment is absent.

[0119] The terms “increased,” “increase,” or “enhance” or “activate” are all generally used herein to mean an increase in a statistically significant amount; for the avoidance of any doubt, the terms “increased,” “increase,” or “enhance” or “activate” 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 a 100% increase, or any increase between 10%-100%, or an increase of 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 compared to a reference level, or any increase between 2-fold and 10-fold or more.

[0120] As used herein, the term “modulate” includes upregulation and downregulation, e.g., enhancing or inhibiting a response.

[0121] As defined herein, a "radiopharmaceutical" refers to a pharmaceutical agent containing at least one radioactive isotope that emits radiation. Radiopharmaceuticals are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. A radiolabeled pharmaceutical agent, such as a radiolabeled antibody, contains a radioactive isotope (RI) that serves as a radiation source. As contemplated herein, the term "radioactive isotope" includes metallic and non-metallic radioactive isotopes. The radioactive isotope is selected based on the medical application of the radiolabeled pharmaceutical agent. When the radioactive isotope is a metallic radioactive isotope, a chelating agent is typically used to bind the metallic radioactive isotope to the rest of the molecule. When the radioactive isotope is a non-metallic radioactive isotope, the non-metallic radioactive isotope is typically directly or via a linker connected to the rest of the molecule.

[0122] For the purposes of this invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 67th Edition, 1986 - 87, inside front cover.

[0123] Compounds of the invention

[0124] Formulas (I) and (II):

[0125] This disclosure provides compounds having the structure of formula (I):

[0126]

[0127] wherein:

[0128] n is 0, 1, or 2;

[0129] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH 2 -;

[0130] L 2 is absent or is -CH 2 -;

[0131] L 3 is absent or is -C(O)-;

[0132] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0133] Y 1 is selected from aryl and heteroaryl;

[0134] Y 2Selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, -O-hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ;

[0135] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl;

[0136] Each Y 2 " is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocyclic group; and

[0137] Y 3 and Y 4 together with the carbon to which they are attached form a 4-, 5- or 6-membered cycloalkyl, cycloheteroalkyl or heterocyclic group, or Y 3 and Y 4 are each independently selected from -OH, -CN, -CO 2 H, -CO 2 (alkyl), alkyl, hydroxyalkyl, cyanoalkyl and halogen;

[0138] or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments,

[0140] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ) 2 ;

[0141] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl;

[0142] Each Y 2 " is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; and

[0143] Y 3 and Y 4 together with the carbon to which they are attached form a 4-, 5- or 6-membered cycloalkyl, cycloheteroalkyl or heterocyclic group. In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted 4-, 5- or 6-membered heterocyclic group.

[0144] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are bonded form an unsubstituted 4-, 5- or 6-membered cyclic urea, cyclic carbamate, cyclic sulfone, cyclic sulfonamide, lactam, azalactam or lactone.

[0145] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are bonded form any of the following structures:

[0146] wherein Z 1 is selected from O, NH and CH 2 ; Z 2 is selected from O, NH and CH 2 ; Z 3 is selected from O and NH; Z 4 is selected from NH and CH 2 ; and Z 5 is selected from NH and CH 2 ; provided that one of Z 1 and Z 2 is not CH 2 .

[0147] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are bonded form the following structure:

[0148] wherein Z 1 is selected from O, NH and CH 2 ; and Z 2 is selected from O, NH and CH 2 ; provided that one of Z 1 and Z 2 is not CH 2 .

[0149] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are bonded form any of the following structures:

[0150] wherein Z 3 is selected from O and NH; and Z 5 is selected from NH and CH 2 .

[0151] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are bonded form an unsubstituted 4-, 5- or 6-membered cycloheteroalkyl.

[0152] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted piperidinyl, tetrahydrofuranyl, azetidinyl, or morpholinyl group.

[0153] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures:

[0154] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form the following structure:

[0155] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5-, or 6-membered heterocyclic group.

[0156] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5-, or 6-membered cyclic urea, cyclic carbamate, cyclic sulfone, cyclic sulfonamide, lactam, azalactam, or lactone.

[0157] In certain embodiments, the cyclic urea, cyclic carbamate, cyclic sulfonamide, lactam, or azalactam is N-substituted.

[0158] In certain embodiments, the cyclic urea, cyclic carbamate, cyclic sulfonamide, lactam, or azalactam is N-alkyl-substituted.

[0159] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form the following structure: wherein Z 6 is selected from -H and alkyl; Z 7 is selected from -H and alkyl;

[0160] provided that Z 6 and Z 7 are not both -H.

[0161] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures:

[0162] wherein each Z 8is independently an alkyl group; and Z 9 is selected from -H and alkyl groups; and Z 10 is selected from -H and alkyl groups; provided that Z 9 and Z 10 are not both -H.

[0163] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form the following structure:

[0164] Z 9 is selected from -H and alkyl groups; and each Z 10 ’ is an alkyl group or together with the carbon to which they are attached forms an unsubstituted or substituted cycloalkyl group, such as cyclopropyl.

[0165] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form the following structure:

[0166] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form any one of the following structures: wherein Z 11 is an alkyl group; Z 12 is selected from -H and alkyl groups; and Z 13 is selected from -H and alkyl groups; provided that Z 12 and Z 13 are not both -H.

[0167] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form the following structure: wherein Z 14 is an alkyl group.

[0168] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5- or 6-membered cycloheteroalkyl group.

[0169] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted piperidinyl, tetrahydrofuranyl, azetidinyl or morpholinyl group.

[0170] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form an N-alkyl or N-acetyl-substituted piperidinyl, azetidinyl or morpholinyl group.

[0171] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5- or 6-membered cycloalkyl. In certain embodiments, the substituted 4-, 5- or 6-membered cycloalkyl is substituted with -CN, alkyl or hydroxyalkyl.

[0172] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted cyclopropyl. In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted cyclobutyl.

[0173] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures:

[0174]

[0175] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form the following structure:

[0176] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted 4-, 5- or 6-membered cycloheteroalkyl.

[0177] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form a substituted tetrahydrofuranyl or tetrahydropyranyl.

[0178] In certain embodiments, Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures:

[0179] In certain embodiments, Y 3 and Y 4 are each independently selected from -OH, -CN, -CO 2 H, -CO 2 (alkyl), alkyl, hydroxyalkyl, cyanoalkyl and halogen;

[0180] In certain embodiments, Y 3 and Y 4 are each independently selected from -F, -OH, -CN, -CO 2 H, -CO2 Et, -CH 3 , -CH 2 CH 3 , -CH 2 CN, -CH 2 OH and -CH 2 OSO 2 Me.

[0181] In certain embodiments, Y 3 is selected from -F, CH 3 and -CH 2 CH 3 ; and Y 4 is selected from -OH, -CN, -CO 2 H, -CO 2 Et, -CH 2 CN, -CH 2 OH and -CH 2 OSO 2 Me.

[0182] In certain embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In certain embodiments, the compound has a structure selected from the following:

[0183]

[0184] The present invention also provides a compound having the structure of formula (II):

[0185]

[0186] Wherein:

[0187] m is 0, 1 or 2;

[0188] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -;

[0189] L 2 is absent or is -CH 2 -;

[0190] L 3 is absent or is -C(O)-;

[0191] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0192] Y 1 is selected from aryl and heteroaryl;

[0193] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, -O-hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ;

[0194] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl;

[0195] Each Y 2 " independently is alkyl, or two instances together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocyclic group;

[0196] Y 5 is selected from cycloalkyl, heteroaryl, heterocyclic group, C 0 -C 6 alkyl-Y 5 ' and C 2 -C 6 alkenyl-Y 5 ';

[0197] Y 5 ' is selected from -CN, -OH, -NH 2 , -OSO 2- alkyl, -NH(Y 5 "), -C(O)N(Y 5 ″′) 2 , -SO 2 N(Y 5 ″′) 2 , -O(CO)-Y 5 ″′, -(CO)O-Y 5 ″′, alkoxy, benzyloxy, -C=N-O(alkyl) and formamide moiety;

[0198] Y 5 " is selected from alkyl, -C(O)-alkyl and -SO 2 -alkyl; and

[0199] Y 5 ″′ each occurrence is independently selected from -H, alkyl, aminoalkyl and aryl;

[0200] or a pharmaceutically acceptable salt thereof.

[0201] In certain embodiments,

[0202] Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ) 2 ;

[0203] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl;

[0204] Each Y 2 " is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0205] Y 5 is selected from cyano, cycloalkyl, heteroaryl, heterocyclic, alkyl-Y 5 ' and formamide moiety;

[0206] Y 5 ' is selected from -CN, -OH, -NH 2 , -NH(Y 5 "), -C(O)N(Y 5 ) 2 , -SO 2 N(Y 5 ) 2 , - and formamide moiety;

[0207] Y 5 " is selected from alkyl, -C(O)-alkyl and -SO 2 -alkyl; and

[0208] Y 5 "' is independently selected from -H and alkyl each time it appears.

[0209] In certain embodiments, the compound has the following structure:

[0210]

[0211] In certain embodiments, Y 5 is an unsubstituted 5-membered heteroaryl.

[0212] In certain embodiments, Y 5 is selected from unsubstituted pyrazolyl, unsubstituted oxadiazolyl, unsubstituted oxazolyl and unsubstituted isoxazolyl.

[0213] In certain embodiments, Y 5 is selected from:

[0214] In certain embodiments, Y 5 is a substituted 6-membered heteroaryl.

[0215] In certain embodiments, Y 5 is selected from substituted pyridyl and substituted pyrimidinyl.

[0216] In certain embodiments, Y 5 is selected from:

[0217] In certain embodiments, Y 5 is alkyl-Y 5 '.

[0218] In certain embodiments, Y 5 is C 1 -C 4 alkyl-Y 5 '; and the alkyl is unbranched.

[0219] In certain embodiments, Y 5 is C 1 -C 4 alkyl-Y 5 ′; and the alkyl is branched.

[0220] In certain embodiments, Y 5 is C 1 -C 4 alkyl-Y 5 ′; and the alkyl is substituted by cycloalkyl.

[0221] In certain embodiments, Y 5 ' is selected from -NH(Y 5 )、-C(O)N(Y 5 ″′) 2 and -SO 2 N(Y 5 ″′) 2 ; Y 5 " is selected from -C(O)-CH 3 and -SO 2 -CH 3 ; and Y 5 ″′ is independently selected from -H and -CH 3 each time it appears.

[0222] In certain embodiments, Y 5 ' is -OH, -CN or alkoxy.

[0223] In certain embodiments, Y 5 ' is O(CO)-Y 5″′ or -(CO)O-Y 5 ″′.

[0224] In certain embodiments, Y 5 ″′ is alkyl, aminoalkyl or aryl. In certain embodiments, Y 5 ' is a squaramide moiety.

[0225] In certain embodiments, Y 5 ' is where Z 15 is independently selected from -H and alkyl each time it appears.

[0226] In certain embodiments, each Z 15 is -H, each Z 15 is -CH 3 , or one Z 15 is -H and the other is -CH 3 .

[0227] In certain embodiments, Y 5 is a squaramide moiety.

[0228] In certain embodiments, Y 5 is where Z 15 is independently selected from -H and alkyl each time it appears.

[0229] In certain embodiments, each Z 15 is -H, each Z 15 is -CH 3 , or one Z 15 is -H and the other is -CH 3 .

[0230] In certain embodiments, Y 5 is selected from

[0231] In certain embodiments, Y 5 is selected from: -OH, -OAc,

[0232]

[0233] In certain embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2.

[0234] In certain embodiments, the compound has the following structure:

[0235]

[0236] Further embodiments of formulas (I) and (II) are:

[0237] 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 、-CH 2 CH 3 、-CH 2 CF 3 、-CH 2 CH 2 CH 3 、

[0238] In certain embodiments, X 1 is -H; and X 2 is

[0239] In certain embodiments, X 1 is -H; and X 2 is -CH 3 。In other embodiments, X 1 is -H; and X 2 is -CH 2 CH 3 。In other embodiments, X 1 is -H; and X 2 is -CH 2 CH 2 CH 3 。

[0240] In certain embodiments, X 2 is -H; and X 1 is

[0241] In certain embodiments, X 2 is -H; and X 1 is -CH 3 。In other embodiments, X 2 is -H; and X 1 is -CH 2 CH 3 。In other embodiments, X 2 is -H; and X 1 is -CH 2 CH 2 CH 3 。

[0242] In certain embodiments, L 1 is absent.

[0243] In certain embodiments, L 1 is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl-, and -heteroaryl-CH 2 -.

[0244] In certain embodiments, L 1 is selected from -CH 2 -, -C(H)(CH 3 )-, -CH 2 CH 2 -, and -C(H)(OH)CH 2 -.

[0245] In certain embodiments, L 1 is

[0246] In certain embodiments, L 1 is selected from

[0247] In certain embodiments, L 1 is selected from

[0248] In certain embodiments, Y 1 is an unsubstituted aryl. In other embodiments, Y 1 is selected from an unsubstituted phenyl and an unsubstituted naphthyl.

[0249] In certain embodiments, Y 1 is a substituted aryl.

[0250] In certain embodiments, Y 1 is and

[0251] 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, heterocycloalkyl, aryl, and heteroaryl; provided that R 1 , R2 , R 3 , R 4 and R 5 is not -H.

[0252] 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 ,

[0253] 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 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCF 3 and

[0254] In certain embodiments, R 1 , R 2 , R 3 , R 4 and R 5 two of which are not -H, or 1 , R 2 , R 3 , R 4 and R 5 three of which are not -H.

[0255] In certain embodiments, Y 1 is selected from

[0256]

[0257] In certain embodiments, Y 1 is

[0258] In certain embodiments, Y 1 is an unsubstituted heteroaryl.

[0259] In certain embodiments, Y 1 is selected from:[[]]

[0260] In certain embodiments, Y 1 is a substituted heteroaryl.

[0261] In certain embodiments, Y 1 is selected from

[0262] and

[0263] R 6 、R 7 、R 8 and R 9 each occurrence of which is independently selected from -H, halogen, -CN, -OCF 3 、-OCHF 2 、alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, and heteroaryl; provided that at least one of R 6 、R 7 、R 8 and R 9 is not -H.

[0264] In certain embodiments, L 2 is absent.

[0265] In certain embodiments, L 2 is -CH 2 -.

[0266] In certain embodiments, L 3 is absent.

[0267] In certain embodiments, Y 2 is an unsubstituted heteroaryl.

[0268] In certain embodiments, Y 2 is selected from

[0269]

[0270] In certain embodiments, Y 2 is

[0271] In certain embodiments, Y 2 is a substituted heteroaryl.

[0272] In certain embodiments, Y 2 is

[0273] 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, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 、-CO 2 R 15 and -C(O)NHSO 2 R 15 ; provided that at least one of R 10 、R 11 and R 12 is not -H; and

[0274] each occurrence of R 13 、R 14 and R 15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[0275] 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 、-C(O)NHSO2 CH 2 CH 3 、 -CH 2 OH, -CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

[0276] 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 、

[0277] 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 、

[0278] 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 、

[0279] In certain embodiments, Y 2 is selected from or Y 2 is selected from

[0280] In certain embodiments, R 16 is independently selected, each occurrence, from halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , -CO 2 R 15 ; and each occurrence of R 13 , R 14 and R 15 is independently selected from -H, alkyl, aryl, and heteroaryl. In certain embodiments, R 16 is independently selected, each occurrence, from hydroxyalkyl and alkoxyalkyl.

[0281] In certain embodiments, R 16 is selected from -CN, -CH 3 , -CF 3 , -C(O)NH 2 , -CO 2 CH 2 CH 3 and In certain embodiments, R 16 is selected from i-Pr, -CH 2 OH, and - CH2 OCH 3 .

[0282] In certain embodiments, Y 2 is selected from

[0283] R 17 、R 18 、R 19 、R 20 and R 21 is independently selected, each occurrence, from -H, halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR13 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

[0284] R 13 、R 14 and R 15 each occurrence is independently selected from -H, alkyl, aryl, and heteroaryl.

[0285] 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 .

[0286] In certain embodiments, Y 2 is selected from In other embodiments, Y 2 is selected from In other embodiments, Y 2 is selected from

[0287] In certain embodiments, Y 2 is selected from

[0288] In certain embodiments, Y 2 is

[0289] and

[0290] R 26 and R 27 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0291] Y 2 is and

[0292] R 27 and R 28 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0293] Y 2 is and

[0294] R 26 and R 29 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

[0295] Y 2 is and

[0296] R 30 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl; or

[0297] Y 2 is and

[0298] R 31 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl.

[0299] In certain embodiments, Y 2 is selected from

[0300]

[0301] In certain embodiments, L 3 is -C(O)-.

[0302] In certain embodiments, Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and haloalkyl.

[0303] In certain embodiments, Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cyanoalkyl.

[0304] where Y 2 is selected from -CH 3 , -CH 2 CH 3 , -CF 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 , -OCH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH 2 F, -CH 2 CH 2 CN and -CH 2 OCH 3 .

[0305] In certain embodiments, Y 2 is selected from -CH 3 , -CF 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 C≡CH, -CH 2 CH 2 OCH 3 , -C(H)(CH3 )CH 2 OCH 3 、-OCH 3 、-CH 2 OH, -CH 2 CH 2 OH, -C(CH 3 ) 2 OH and -CH 2 OCH 3 .

[0306] In certain embodiments, Y 2 Selected from -CH 2 OH and -CH 2 CH 2 OH.

[0307] In certain embodiments, Y 2 is an unsubstituted heteroaryl group.

[0308] In certain embodiments, Y 2 Selected from

[0309] In certain embodiments, Y 2 for

[0310] In certain embodiments, Y 2 is a substituted heteroaryl.

[0311] In certain embodiments, Y 2 Selected from

[0312] In certain embodiments, Y 2 for

[0313]

[0314] R 10 , R 11 and R 12 independently selected from -H, halogen, -CN, -OH, -NH 2 、-OCF 3 、-OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; The premise is R 10 , R 11 and R 12At least one of them is not -H; and R 13 、R 14 and R 15 Each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

[0315] 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 、-C(O)NHSO 2 CH 2 CH 3 、-CH 2 OH、-CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl, and tetrazolyl.

[0316] In certain embodiments, Y 2 is

[0317] In certain embodiments, Y 2 is

[0318] And

[0319] R 26 and R 27 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 6and R 7 Together with the carbon atom to which they are bonded, form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0320] Y 2 is and

[0321] R 27 and R 28 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 atom to which they are bonded, form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0322] Y 2 is and

[0323] R 26 and R 29 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

[0324] Y 2 is and

[0325] R 30 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl; or

[0326] Y 2 is and

[0327] R 31 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2, alkyl, alkoxy, alkylamino, and cycloalkyl.

[0328] In certain embodiments, Y 2 is selected from

[0329]

[0330] In certain embodiments, Y 2 is an unsubstituted cycloalkyl or heterocyclic group.

[0331] In certain embodiments, Y 2 is selected from:

[0332] In certain embodiments, Y 2 is selected from

[0333] In certain embodiments, Y 2 is a substituted cycloalkyl or heterocyclic group.

[0334] In certain embodiments, Y 2 is selected from

[0335] In certain embodiments, Y 2 is selected from

[0336] Each occurrence of R 17 , R 18 , R 19 , R 20 , and R 21 is independently selected from -H, halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , and -CO 2 R 15 ; and

[0337] Each occurrence of R 13 , R 14 , and R 15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[0338] In certain embodiments, R 17 , R 18 , R19 , R 20 and R 21 in at least one is not -H.

[0339] In certain embodiments, Y 2 is selected from

[0340] R 22 , R 23 , R 24 , and R 25 each occurrence of which is independently selected from -H, halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; and

[0341] R 13 , R 14 and R 15 each occurrence of which is independently selected from -H, alkyl, aryl, and heteroaryl.

[0342] In certain embodiments, R 22 , R 23 , R 24 and R 25 each occurrence of which is independently selected from -H and -CH 3 .

[0343] In certain embodiments, Y 2 is -NH(Y 2 ’).

[0344] In certain embodiments, Y 2 ’ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

[0345] In certain embodiments, Y 2 ’ is selected from -H, -OH, -OCH 3 , -CH 3 , -CH 2 CH 2 OCH 3 and

[0346] In certain embodiments, Y 2 ’ is selected from -H, alkyl, alkoxy, haloalkyl, and hydroxyalkyl.

[0347] In certain embodiments, Y 2 ′ is selected from -H, alkyl, alkoxy, and hydroxyalkyl.

[0348] In certain embodiments, Y 2 ′ is selected from -H, -OCH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 F, and -CH 2 CH 2 CH 2 F.

[0349] In certain embodiments, Y 2 ′ is selected from -H, -OCH 3 , -CH 3 , -CH 2 OH, and -CH 2 CH 2 OH.

[0350] In certain embodiments, Y 2 is -N(Y 2 ″) 2 .

[0351] In certain embodiments, each Y 2 ″ is -CH 3 .

[0352] In certain embodiments, two instances of Y 2 ″ together with the nitrogen atom to which they are attached form a morpholinyl group.

[0353] In certain embodiments, two instances of Y 2 ″ together with the nitrogen atom to which they are attached form an azetidinyl group.

[0354] In certain embodiments, Y 2 ′ is selected from cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, and -O-hydroxyalkyl,

[0355] In certain embodiments, Y 2 ′ is selected from -CH 2 CH 2 CN and -OCH 2CH 2 CH 2 CN, -OCH 2 CHF 2 , -OCH 2 CH 2 CHF 2 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 and -OCH 2 CH 2 CH 2 OH.

[0356] Formulas (III) and (IV):

[0357] The present invention also provides compounds having the structure of formula (III):

[0358]

[0359] Wherein:

[0360] L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -;

[0361] L 3 is absent or is -C(O)-;

[0362] X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H;

[0363] Y 1 is selected from aryl and heteroaryl;

[0364] Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ) 2 ;

[0365] Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl;

[0366] Each Y 2″independently an alkyl group, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; and

[0367] Y 6 and Y 7 together with the carbon atom to which they are attached form a 4-, 5- or 6-membered cycloalkyl or heterocyclic group;

[0368] or a pharmaceutically acceptable salt thereof.

[0369] In certain embodiments, Y 6 and Y 7 together with the carbon atom to which they are attached form an unsubstituted 4-, 5- or 6-membered heterocyclic group.

[0370] In certain embodiments, Y 6 and Y 7 together with the carbon atom to which they are attached form an unsubstituted 4-, 5- or 6-membered cyclic urea, cyclic carbamate, cyclic sulfone, cyclic sulfonamide, lactam, azalactam or lactone.

[0371] In certain embodiments, Y 6 and Y 7 together with the carbon atom to which they are attached form any one of the following structures:

[0372] wherein

[0373] Z 1 is selected from O, NH and CH 2 ;

[0374] Z 2 is selected from O, NH and CH 2 ;

[0375] Z 3 is selected from O and NH;

[0376] Z 4 is selected from NH and CH 2 ; and

[0377] Z 5 is selected from NH and CH 2 ;

[0378] provided that one of Z 1 and Z 2 is not CH 2 .

[0379] In certain embodiments, Y 6 and Y 7 together with the carbon atom to which they are attached form the following structure: wherein Z 1 is selected from O, NH and CH 2; and Z 2 is selected from O, NH, and CH 2 ; provided that Z 1 and Z 2 one of which is not CH 2 .

[0380] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form any of the following structures: wherein Z 3 is selected from O and NH; and Z 5 is selected from NH and CH 2 .

[0381] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl.

[0382] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form an unsubstituted piperidinyl, tetrahydrofuranyl, azetidinyl, or morpholinyl.

[0383] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form any of the following structures:

[0384] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form a substituted 4-, 5-, or 6-membered heterocyclic group.

[0385] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form a substituted 4-, 5-, or 6-membered cyclic urea, cyclic carbamate, cyclic sulfone, cyclic sulfonamide, lactam, azalactam, or lactone.

[0386] In certain embodiments, the cyclic urea, cyclic carbamate, cyclic sulfonamide, lactam, or azalactam is N-substituted.

[0387] In certain embodiments, the cyclic urea, cyclic carbamate, cyclic sulfonamide, lactam, or azalactam is N-alkyl substituted.

[0388] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form the following structure: wherein Z 6 is selected from -H and alkyl; and Z 7 is selected from -H and alkyl;

[0389] provided that Z 6 and Z 7 are not both -H.

[0390] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form any of the following structures: wherein each Z 8 is independently alkyl; Z 9 is selected from -H and alkyl; and Z 10 is selected from -H and alkyl; provided that Z 9 and Z 10 are not both -H.

[0391] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form any of the following structures: wherein Z 11 is alkyl; Z 12 is selected from -H and alkyl; and Z 13 is selected from -H and alkyl; provided that Z 12 and Z 13 are not both -H.

[0392] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form the following structure: wherein Z 14 is alkyl.

[0393] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form a substituted 4-, 5-, or 6-membered cycloalkyl.

[0394] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form a substituted piperidinyl, tetrahydrofuranyl, azetidinyl, or morpholinyl.

[0395] In certain embodiments, Y 6 and Y 7 together with the carbon to which they are attached form an N-alkyl- or N-acetyl-substituted piperidinyl, azetidinyl, or morpholinyl.

[0396] In certain embodiments, Y 6 and Y7 Form a substituted 4-, 5- or 6-membered cycloalkyl together with the carbon to which they are bonded.

[0397] In certain embodiments, Y 6 and Y 7 Form a substituted cyclobutyl together with the carbon to which they are bonded.

[0398] In certain embodiments, Y 6 and Y 7 Form any one of the following structures together with the carbon to which they are bonded:

[0399]

[0400] In certain embodiments, the compound has a structure selected from the following:

[0401]

[0402] The present invention also provides a compound having the structure of formula (IV):

[0403]

[0404] Wherein:

[0405] L 1 Is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -;

[0406] L 2 Is absent or is -CH 2 -;

[0407] L 3 Is absent or is -C(O)-;

[0408] X 1 and X 2 Are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 Are not both -H;

[0409] Y 1 Is selected from aryl and heteroaryl;

[0410] Y 2 Is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ') and -N(Y 2 ) 2 ;

[0411] Y2 'selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and cycloalkyl;

[0412] Each Y 2 "is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0413] Y 8 selected from cyano, cycloalkyl, heteroaryl, heterocyclic group, alkyl-Y 8 'and formamidine moiety;

[0414] Y 8 ′ is selected from -CN, -OH, -NH 2 , -NH(Y 8 "), -C(O)N(Y 8 ″′) 2 , -SO 2 N(Y 8 ″′) 2 and formamidine moiety;

[0415] Y 8 "is selected from alkyl, -C(O)-alkyl, and -SO 2 -alkyl; and

[0416] Y 8 ″′ is independently selected from -H and alkyl each time it appears;

[0417] or a pharmaceutically acceptable salt thereof.

[0418] In certain embodiments, the compound has the following structure:

[0419]

[0420] In certain embodiments, Y 8 is an unsubstituted 5-membered heteroaryl.

[0421] In certain embodiments, Y 8 is selected from unsubstituted pyrazolyl, unsubstituted oxadiazolyl, unsubstituted oxazolyl, and unsubstituted isoxazolyl.

[0422] In certain embodiments, Y 8 is selected from

[0423] In certain embodiments, Y 8 is a substituted 6-membered heteroaryl.

[0424] In certain embodiments, Y 8 is selected from substituted pyridyl and substituted pyrimidinyl.

[0425] In certain embodiments, Y 8 is selected from

[0426] In certain embodiments, Y 8 is alkyl-Y 8 ′.

[0427] In certain embodiments, Y 8 is C 1 -C 4 alkyl-Y 8 ′; and the alkyl is unbranched.

[0428] In certain embodiments, Y 8 is C 1 -C 4 alkyl-Y 8 ′; and the alkyl is branched.

[0429] In certain embodiments, Y 8 is C 1 -C 4 alkyl-Y 8 ′; and the alkyl is substituted with cycloalkyl.

[0430] In certain embodiments, Y 8 ′ is selected from -NH(Y 8 "), -C(O)N(Y 5 ″′) 2 and -SO 2 N(Y 5 ″′) 2 ; Y 5 " is selected from -C(O)-CH 3 and -SO 2 -CH 3 ; and Y 5 ″′ is independently selected from -H and -CH 3 each time it appears.

[0431] In certain embodiments, Y 8 ′ is a squaramide moiety.

[0432] In certain embodiments, Y 8 ′ is and Z 15 is independently selected from -H and alkyl each time it appears.

[0433] In certain embodiments, each Z 15 is -H, each Z 15 is -CH 3 or one Z 15 is -H and the other is -CH3 .

[0434] In certain embodiments, Y 5 is a squaramide moiety.

[0435] In certain embodiments, Y 8 is and Z 15 is independently selected from -H and alkyl each time it appears.

[0436] In certain embodiments, each Z 15 is -H, each Z 15 is -CH 3 , or one Z 15 is -H and the other is -CH 3 .

[0437] In certain embodiments, Y 8 is selected from

[0438] In certain embodiments, the compound has a structure selected from the following:

[0439]

[0440] Further embodiments of formulas (III) and (IV) are:

[0441] 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 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 CH 3 ,

[0442] In certain embodiments, X 1 is -H; and X 2 is

[0443] In certain embodiments, X 1 is -H; and X 2 is -CH 3 . In other embodiments, X 1 is -H; and X 2 is -CH 2CH 3 。In other embodiments, X 1 is -H; and X 2 is -CH 2 CH 2 CH 3 。

[0444] In certain embodiments, X 2 is -H; and X 1 is

[0445] In certain embodiments, X 2 is -H; and X 1 is -CH 3 。In other embodiments, X 2 is -H; and X 1 is -CH 2 CH 3 。In other embodiments, X 2 is -H; and X 1 is -CH 2 CH 2 CH 3 。

[0446] In certain embodiments, L 1 is absent.

[0447] In certain embodiments, L 1 is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl-, and -heteroaryl-CH 2 -.

[0448] In certain embodiments, L 1 is selected from -CH 2 -, -C(H)(CH 3 )-, -CH 2 CH 2 -, and -C(H)(OH)CH 2 -.

[0449] In certain embodiments, L 1 is

[0450] In certain embodiments, L 1 is selected from

[0451] In certain embodiments, L 1 is selected from

[0452] In certain embodiments, Y 1is an unsubstituted aryl. In other embodiments, Y 1 is selected from unsubstituted phenyl and unsubstituted naphthyl.

[0453] In certain embodiments, Y 1 is a substituted aryl.

[0454] In certain embodiments, Y 1 is and

[0455] 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 one of R 1 、R 2 、R 3 、R 4 and R 5 is not -H.

[0456] 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 、

[0457] 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, -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCF 3 and

[0458] In certain embodiments, two of R 1 , R 2 , R 3 , R 4 and R 5 are not -H, or three of R 1 , R 2 , R 3 , R 4 and R 5 are not -H.

[0459] In certain embodiments, Y 1 is selected from

[0460]

[0461] In certain embodiments, Y 1 is

[0462] In certain embodiments, Y 1 is an unsubstituted heteroaryl.

[0463] In certain embodiments, Y 1 is selected from:

[0464] In certain embodiments, Y 1 is a substituted heteroaryl.

[0465] In certain embodiments, Y 1 is selected from

[0466] and

[0467] Each occurrence of R 6 , R 7 , R 8 and R 9 is 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 R9 At least one of them is not -H.

[0468] In certain embodiments, L 3 is absent.

[0469] In certain embodiments, Y 2 is an unsubstituted heteroaryl.

[0470] In certain embodiments, Y 2 is selected from

[0471]

[0472] In certain embodiments, Y 2 is

[0473] In certain embodiments, Y 2 is a substituted heteroaryl.

[0474] In certain embodiments, Y 2 is

[0475] 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, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , -CO 2 R 15 and -C(O)NHSO 2 R 15 ; provided that at least one of R 10 , R 11 and R 12 is not -H; and

[0476] R 13 , R 14 and R 15 each occurrence of which is independently selected from -H, alkyl, aryl, and heteroaryl.

[0477] In certain embodiments, R 10 , R 11 and R 12 are independently selected from -H, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH3 、 -CF 3 、 -CHF 2 、 -CF 2 CH 3 、 -OCH 3 、 -OCF 3 、 -OCHF 2 、 -OAc, -NH 2 、 -NHCH 3 、 -NHAc, -C(O)NH 2 、 -C(O)NHCH 3 、 -C(O)NHCH 2 CH 3 、 -C(O)NHSO 2 CH 3 、 -C(O)NHSO 2 CH 2 CH 3 、 -CH 2 OH, -CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

[0478] 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)NH 3 、 -C(O)NHCH 2 CH 3 、

[0479] 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 、

[0480] 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 ,

[0481] In certain embodiments, Y 2 is selected from:

[0482] In certain embodiments, Y 2 is

[0483] and

[0484] R 26 and R 27 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0485] Y 2 is and

[0486] R 27 and R 28 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; or7 and R 8 together with the carbon atom to which they are bonded form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0487] Y 2 is and

[0488] R 26 and R 29 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

[0489] Y 2 is and

[0490] R 30 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl; or

[0491] Y 2 is and

[0492] R 31 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl.

[0493] In certain embodiments, Y 2 is selected from

[0494]

[0495] In certain embodiments, Y 2 is selected from

[0496] R 16 is independently selected from halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; and

[0497] R 13 、R 14 and R 15 each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

[0498] In certain embodiments, R 16 is selected from -CN, -CH 3 , -CF 3 , -C(O)NH 2 , -CO 2 CH 2 CH 3 and

[0499] In certain embodiments, Y 2 is selected from

[0500] R 17 、R 18 、R 19 、R 20 and R 21 each occurrence of is independently selected from -H, halogen, -CN, -NH 2 , -OCF 3 , -OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; provided that at least one of R 17 、R 18 、R 19 、R 20 and R 21 is not -H; and

[0501] R 13 、R 14 and R 15 each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

[0502] 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 .

[0503] In certain embodiments, Y 2 is selected from

[0504] In certain embodiments, L 3 is -C(O)-.

[0505] In certain embodiments, Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, and haloalkyl.

[0506] In certain embodiments, Y 2 is selected from -CH 3 , -CF 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 .

[0507] In certain embodiments, Y 2 is selected from -CH 2 OH and -CH 2 CH 2 OH.

[0508] In certain embodiments, Y 2 is unsubstituted heteroaryl.

[0509] In certain embodiments, Y 2 is

[0510] In certain embodiments, Y 2 is substituted heteroaryl.

[0511] In certain embodiments, Y 2 is selected from

[0512] In certain embodiments, Y 2 is

[0513]

[0514] 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, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; provided that at least one of R 10 , R 11 and R 12 is not -H; and

[0515] each occurrence of R 13 , R 14 and R 15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[0516] 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 , -C(O)NHSO 2CH 2 CH 3 、 -CH 2 OH、 -CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

[0517] In certain embodiments, Y 2 is

[0518] In certain embodiments, Y 2 is

[0519] and

[0520] R 26 and R 27 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0521] Y 2 is and

[0522] R 27 and R 28 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or

[0523] Y 2 is and

[0524] R 26 and R 29 are independently selected from -H, halogen, -CN, -OH, -OCF3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino, and cycloalkyl; provided that at least one of R 6 and R 9 is not -H; or

[0525] Y 2 is and

[0526] R 30 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino, and cycloalkyl; or

[0527] Y 2 is and

[0528] R 31 is selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino, and cycloalkyl.

[0529] In certain embodiments, Y 2 is selected from

[0530]

[0531]

[0532] In certain embodiments, Y 2 is unsubstituted cycloalkyl or heterocyclic group.

[0533] In certain embodiments. Y 2 is selected from:

[0534] In certain embodiments, Y 2 is selected from

[0535] In certain embodiments, Y 2 is substituted cycloalkyl or heterocyclic group.

[0536] In certain embodiments, Y 2 is selected from

[0537] In certain embodiments, Y 2Selected from

[0538] R 17 , R 18 , R 19 , R 20 and R 21 Each occurrence of is independently selected from -H, halogen, -CN, -NH 2 、-OCF 3 、-OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ;and

[0539] R 13 , R 14 and R 15 Each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

[0540] In certain embodiments, R 17 , R 18 , R 19 , R 20 and R 21 At least one of them is not -H.

[0541] In certain embodiments, Y 2 Selected from

[0542] R 22 , R 23 , R 24 , and R 25 Each occurrence of is independently selected from -H, halogen, -CN, -NH 2 、-OCF 3 、-OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and-Co 2 R 15 ;and

[0543] R 13 , R 14 and R 15 Each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

[0544] In certain embodiments, R 22 , R 23 , R 24 and R 25 Each occurrence of is independently selected from -H and -CH 3 .

[0545] In certain embodiments, Y 2 -NH(Y 2 ').

[0546] In certain embodiments, Y 2 ' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl and cycloalkyl.

[0547] In certain embodiments, Y 2 'Selected from -H, -OH, -OCH 3 、-CH 3 、-CH 2 CH 2 OCH 3 and

[0548] In certain embodiments, Y 2 ' is selected from -H, alkyl, alkoxy and hydroxyalkyl.

[0549] In certain embodiments, Y 2 'Selected from -H, -OCH 3 、-CH 3 、-CH 2 OH and -CH 2 CH 2 OH.

[0550] In certain embodiments, Y 2 -N(Y 2 ″) 2 .

[0551] In certain embodiments, each Y 2 ″ is -CH 3 .

[0552] In certain embodiments, two Y 2 "Together with the nitrogen atom to which they are bound, they form a morpholinyl group.

[0553] Exemplary compounds of formula (I):

[0554] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any of the following compounds:

[0555]

[0556]

[0557]

[0558]

[0559]

[0560] (Prepared from the racemic mixture of trans-cyclopropyl stereoisomers).

[0561] Other exemplary compounds of formula (I):

[0562] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any of the following compounds:

[0563]

[0564]

[0565]

[0566]

[0567] Exemplary compounds of formula (II):

[0568] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any of the following compounds:

[0569]

[0570]

[0571]

[0572]

[0573] Other exemplary compounds of formula (II):

[0574] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any of the following compounds:

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the following structure:

[0592]

[0593] Exemplary compounds of formula (III):

[0594] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any one of the following compounds:

[0595]

[0596]

[0597] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0598] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0599] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0600] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0601]

[0602] Exemplary compounds of formula (IV):

[0603] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of any one of the following compounds:

[0604]

[0605] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0606]

[0607] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0608]

[0609] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers),

[0610] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers) and

[0611] (prepared from a racemic mixture of the trans-cyclopropyl stereoisomers).

[0612] In certain embodiments, the compound is selected from the structures of any one of the compounds listed in Table 1, 2 or 3 (listed in Example 2).

[0613] In some embodiments, the compound is an atropisomer. Additionally, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, compounds produced by replacing hydrogen with deuterium or tritium, or carbon with 13 C- or 14 C-enriched carbon are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. For example, with respect to 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 ).

[0614] Any compound of the present invention can also be radiolabeled for the preparation of radiopharmaceuticals.

[0615] Methods of treatment

[0616] One aspect of the present invention provides compounds, compositions, and methods that can be used to treat or prevent diseases or disorders associated with abnormal levels of amino acids by modulating SLC6A19 transport.

[0617] Another aspect of the present invention relates to methods of modulating SLC6A19 transport in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I), (II), (III), or (IV).

[0618] Another aspect of the present invention relates to methods of treating or preventing diseases or disorders associated with a genetic defect in phenylalanine hydroxylase in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I), (II), (III), or (IV).

[0619] In some embodiments, the present invention relates to methods of treating or preventing phenylketonuria in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I), (II), (III), or (IV).

[0620] In some embodiments, the present invention relates to methods of treating or preventing hyperphenylalaninemia in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I), (II), (III), or (IV).

[0621] In some embodiments, the compound reduces the systemic phenylalanine level in the subject.

[0622] In some embodiments, the present invention relates to methods of treating or preventing tyrosinemia (type I, II, or III) in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I), (II), (III), or (IV).

[0623] In some embodiments, the compound reduces the systemic glycine level in the subject.

[0624] In some embodiments, the present invention relates to methods of treating or preventing isovaleric academia, methylmalonic academia, propionic academia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, or hyperammonemia in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I), (II), (III), or (IV).

[0625] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 in the subject.

[0626] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 in a subject.

[0627] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 transport in a subject.

[0628] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 transport in a subject.

[0629] In some embodiments, the compound reduces systemic amino acid levels in a subject.

[0630] 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.

[0631] In some embodiments of any of the disclosed methods, a compound of formula (I).

[0632] In some embodiments of any of the disclosed methods, a compound of formula (II).

[0633] In some embodiments of any of the disclosed methods, a compound of formula (III).

[0634] In some embodiments of any of the disclosed methods, a compound of formula (IV).

[0635] 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.

[0636] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 2.

[0637] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 3.

[0638] Pharmaceutical compositions, routes of administration and dosing

[0639] 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.

[0640] 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.

[0641] 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.

[0642] As stated above, an "effective amount" means any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, a prophylactic or therapeutic treatment regimen that does not cause substantial unwanted toxicity but is effective in treating a particular subject can be planned by making choices 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. The effective amount for any particular administration can vary depending on factors such as the disease or disorder being treated, the particular compound of the present invention being administered, the size of the subject, or the severity of the disease or disorder. 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 can be used, i.e., the highest safe dose according to some medical diagnoses. Multiple daily doses 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 / dosage" is used interchangeably herein.

[0643] 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.

[0644] Generally, for human subjects, the daily oral dose of the compound will be from about 0.01 mg / kg / day to 1000 mg / kg / day. Oral doses in the range of 0.5 to 50 mg / kg administered once or more times per day are expected to produce a therapeutic result. The dose can be adjusted appropriately to achieve the desired local or systemic drug level, depending on the mode of administration. For example, it is expected that the daily dose for intravenous administration will be reduced by one to several orders of magnitude. If the subject's response at such a dose is insufficient, higher doses (or effectively higher doses via a different, more localized delivery route) can be used within the limits of patient tolerance. Multiple daily doses are considered to achieve an appropriate systemic level of the compound.

[0645] For any compound described herein, a therapeutically effective amount can be initially determined in an animal model. The therapeutically effective dose can also be determined based on human data for compounds that have been tested in humans and for compounds known to exhibit similar pharmacological activity (such as other related active agents). Parenteral administration may require higher doses. The dose administered can be adjusted based on the relative bioavailability and potency of the compound administered. Adjusting the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art is entirely within the capabilities of a person of ordinary skill in the art.

[0646] The formulations of the present invention can be administered in the form of a pharmaceutically acceptable solution which can routinely contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants and optionally other therapeutic ingredients.

[0647] For use in therapy, an effective amount of the compound can be administered to a subject by any mode of delivering the compound to the desired surface. Administration of the pharmaceutical composition can be accomplished by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (e.g., injection into a tumor or abscess), mucosal (e.g., topical to the eye), inhalation, and topical.

[0648] For intravenous and other parenteral routes of administration, the compounds of the present invention can be formulated as lyophilized preparations, lyophilized preparations of liposome-encapsulated or -embedded active compounds, lipid complexes in aqueous suspensions, or salt complexes. Lyophilized formulations are generally reconstituted in a suitable aqueous solution, such as sterile water or saline, shortly before administration.

[0649] 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. Oral pharmaceutical preparations can be obtained as solid excipients, optionally grinding the resulting mixture, and, if desired, processing the granular mixture after adding suitable auxiliaries to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose 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 formulations can also be formulated in saline or buffer (e.g., EDTA for neutralizing internal acidic conditions), or can be administered without any carrier.

[0650] Also particularly contemplated are oral dosage forms of one or more of the above components. The one or more components can be chemically modified to render the oral delivery of the derivatives effective. Generally, the chemical modifications contemplated are the attachment of at least one moiety to the component molecule itself, wherein the moiety permits (a) inhibition of acid hydrolysis; (b) absorption 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 in vivo circulation time. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, in Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, 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. For the pharmaceutical uses indicated above, polyethylene glycol moieties are suitable.

[0651] For a component (or derivative), the release site can be the stomach, small intestine (duodenum, jejunum or ileum), or large intestine. Those skilled in the art can obtain formulations that will not dissolve in the stomach but will release the substance elsewhere in the duodenum or 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, the release will avoid the harmful effects of the gastric environment.

[0652] To ensure complete gastric juice tolerance, a coating that is at least impermeable at pH 5.0 is essential. 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 a mixed film.

[0653] The coating or coating mixture can also be used on tablets, not for the purpose of protecting the stomach. The coating can include a sugar coating or a coating that makes the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivering dry therapeutic agents (such as 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, compression tablets or stamped tablets, the moist massing technique can be used.

[0654] The therapeutic agent can be included in the formulation as fine multi-microparticles 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 slightly compressed plug or even a tablet. The therapeutic agent can be prepared by pressing.

[0655] 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.

[0656] The therapeutic agent can be diluted with an inert material or the volume of the therapeutic agent can be increased. These diluents may 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-Rx 1500, Emcompress, and Avicell.

[0657] Disintegrants can be included in the formulation of therapeutic agents to form solid dosage forms. Materials used as disintegrants include, but are not limited to, starches, including the starch-based commercial disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethyl cellulose, hyperbranched starch, sodium alginate, gelatin, orange peel, acidic carboxymethyl cellulose, natural sponge, and bentonite can all be used. Another form of disintegrant is insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, and these disintegrants and binders can include powdered gums such as agar, karaya gum, or tragacanth gum. Alginic acid and its sodium salt can also be used as disintegrants.

[0658] Binders can be used to hold the therapeutic agent together to form hard tablets and include materials from natural products such as gum arabic, tragacanth gum, 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.

[0659] Antifriction agents can be included in the formulation of therapeutic agents to prevent adhesion during the formulation process. Lubricants can be used as a layer between the therapeutic agent wall and the die wall, and these lubricants 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.

[0660] Glidants may be added, which may modify the flow properties of the drug during the formulation process and assist in rearrangement during compression. Glidants can include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0661] 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 sodium dioctyl sulfonate. Available cationic detergents can include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that can be included as surfactants in the formulation include polidocanol 400, polyethylene glycol 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid ester, methylcellulose, and carboxymethylcellulose. These surfactants can be present in the formulation of the compounds or derivatives of the present invention alone or as mixtures in different proportions.

[0662] Oral 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 an active ingredient mixed 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. Additionally, a stabilizer may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in a dosage suitable for such administration.

[0663] For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.

[0664] For topical administration, the compound may be formulated as a solution, gel, ointment, cream, suspension, etc., as is well known in the art. Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), and those designed for transdermal, transmucosal oral, or pulmonary administration.

[0665] For administration by inhalation, the compounds used according to the present invention may be conveniently delivered in the form of an aerosol spray by a pressurized pack or nebulizer using a suitable propellant (such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases). In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. Capsules and cartridges, such as of gelatin, containing a powder mixture of the compound with a suitable powder matrix (such as lactose or starch) may be formulated for use in an inhaler or insufflator.

[0666] 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 pulmonary epithelial lining 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 to achieve a systemic effect are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al. (incorporated by reference).

[0667] Contemplated for use in practicing the present invention are a wide range of mechanical devices designed for the 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.

[0668] Some specific examples of commercially available devices suitable for practicing 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.

[0669] 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 used and may involve the use of a suitable propellant material in addition to the common diluents, adjuvants, and / or carriers that can be used in therapy. In addition, the use of liposomes, microcapsules or microspheres, inclusion complexes or other types of carriers is contemplated. The chemically modified compounds of the present invention can also be prepared in different formulation forms depending on the type of chemical modification or the type of device used.

[0670] Formulations suitable for use with jet or ultrasonic nebulizers generally contain the compound (or derivative) of the present invention dissolved in water at a concentration of about 0.1 mg to 25 mg of the bioactive compound of the present invention per milliliter of solution. The formulation may also include buffers and monosaccharides (e.g., for the stabilization of inhibitors and the regulation of osmotic pressure). Nebulizer formulations may also contain surfactants to reduce or prevent surface-induced aggregation of the compounds of the present invention caused by the atomization of the solution during aerosol formation.

[0671] Formulations for use with metered-dose inhaler devices generally contain a fine powder containing the compound (or derivative) of the present invention suspended in a propellant with the aid of a surfactant. The propellant can 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 can also be used as a surfactant.

[0672] Formulations for dispensing from powder inhaler devices will contain a fine dry powder containing the compound (or derivative) of the present invention, and the amount that can also facilitate the dispersion of the powder from the device (e.g., 50 wt% to 90 wt% of the formulation) includes bulking agents such as lactose, sorbitol, sucrose, or mannitol. The compound (or derivative) of the present invention should advantageously be prepared in the form of fine particles with an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for the most effective delivery to the deep lungs.

[0673] Nasal delivery of the pharmaceutical compositions of the present invention is also contemplated. Nasal delivery allows the pharmaceutical compositions of the present invention to enter the bloodstream directly after nasal administration of the therapeutic product, without the product being deposited in the lungs. Formulations for nasal delivery include those having dextran or cyclodextrin.

[0674] For nasal administration, a useful device is a small, rigid bottle to which a metered sprayer is attached. In one embodiment, a metered dose is delivered by inhaling the pharmaceutical composition solution of the present invention into a defined volume chamber having apertures sized to atomize and aerosolize the 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 particular embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0675] Alternatively, a plastic squeeze bottle having apertures or openings is used, the size of which is designed to atomize the aerosol formulation by forming a spray upon squeezing. The opening is typically located at the top of the bottle, and the top is typically tapered to fit partially into the nasal passage to effectively administer the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation for administering a measured dose of the drug.

[0676] 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. Injectable formulations can be presented in unit dosage forms, for example, in ampoules or multi-dose containers with added preservatives. The composition can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizers and / or dividing powders.

[0677] Pharmaceutical formulations 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 carboxymethyl cellulose, 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.

[0678] Alternatively, the active compound can be in the form of a powder to be reconstituted with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0679] The compound can also be formulated as a rectal or vaginal composition, such as (for example) a suppository or a retention enema containing a conventional suppository base (such as cocoa butter or other glycerides).

[0680] In addition to the formulations described above, the compound can also be formulated as a depot formulation. Such long-acting formulations can be formulated with suitable polymeric materials or hydrophobic materials (such as formulated as an emulsion in an acceptable oil) or ion exchange resins, or formulated as a slightly soluble derivative, such as a slightly soluble salt.

[0681] 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.

[0682] Suitable liquid or solid pharmaceutical dosage forms are, for example, aqueous or saline solutions for inhalation, which are microencapsulated, embedded, coated onto fine gold particles, contained in liposomes, atomized, aerosols for implantation into the skin, pellets, or dried onto 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 of sustained-release active compounds, and excipients, additives, and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorants, sweeteners, or solubilizers are generally used as described above in the preparation of the pharmaceutical composition. The pharmaceutical composition is suitable for a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527-33 (1990).

[0683] The compounds of the invention and optionally other therapeutic agents can be administered in themselves (pure) or in the form of pharmaceutically acceptable salts or co-crystals. 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, salts 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.

[0684] Suitable buffers include: acetic acid and salts (1-2% w / v); citric acid and salts (1-3% w / v); boric acid and salts (0.5-2.5% w / v); and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v); and thimerosal (0.004-0.02% w / v).

[0685] The pharmaceutical composition of the present invention contains an effective amount of a compound as described herein and optionally a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are 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 admixed with the compounds of the present invention and with each other in such a manner that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0686] 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 particles may contain one or more therapeutic agents located in a core surrounded by a coating (including but not limited to an enteric coating). The one or more therapeutic agents may also be dispersed throughout the particles. The one or more therapeutic agents may also be adsorbed into the particles. The particles 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 the one or more therapeutic agents, the particles may include any of those materials conventionally used in the pharmaceutical and medical arts (including but not limited to corrodible, non-corrodible, biodegradable or non-biodegradable materials or combinations thereof). The particles may be microcapsules containing the compounds of the present invention in solution or semi-solid state. The particles may actually be of any shape.

[0687] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture the particles for delivering the one or more therapeutic agents. Such polymers may be natural polymers or synthetic polymers. The polymers are selected based on the desired period of release. Particularly interesting bioadhesive polymers include the bioerodible hydrogels described by Sawhney H S et al. (1993) Macromolecules 26: 581-7, the teachings of which are incorporated herein. These polymers 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).

[0688] The one or more therapeutic agents may be included in a controlled release system. The term "controlled release" means any medicated formulation in which 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 sense to mean a pharmaceutical formulation that provides for the gradual release of a drug over an extended period of time and preferably, but not necessarily, results in substantially constant blood levels of the drug over the extended period. The term "delayed release" is used in its conventional sense to mean a pharmaceutical formulation in which there is a time delay between the administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not involve the gradual release of the drug over an extended period of time and thus may or may not be "sustained release".

[0689] 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 therapeutic levels 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 release systems described above.

[0690] Those of ordinary skill in the relevant art will appreciate that other suitable modifications and adaptations of the compositions and methods described herein will be apparent from the description of the invention contained herein in light of information known to those of ordinary skill in the art and can be made without departing from the scope of the invention or any of its embodiments. The invention has been described in detail and 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.

[0691] Examples

[0692] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0693] Example 1: SLC6A19 Isoleucine Transport Assay

[0694] Generation and maintenance of cell lines

[0695] 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 inducibly expresses human SLC6A19 with a C-terminal V5 tag and stably expresses human TMEM27 (also known as Collectrin) with a C-terminal myc-DDK tag. This stable cell line was generated by transfecting plasmids encoding SLC6A19 and TMEM27 using standard protocols followed by antibiotic selection. The stable cells were maintained in DMEM / F12 supplemented with Glutamax, 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, 200 μg / mL hygromycin, 10 μg / mL blasticidin, and 300 μg / mL neomycin (Thermo Fisher).

[0696] Assays: Isoleucine transport assay in 96-well plate format

[0697] 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-treated plate. On day 1, tetracycline was dispensed at a final concentration of 1 μg / mL using a Tecan D300e digital dispenser to induce the expression of SLC6A19. The transport assay was run on day 2. The medium was removed from the plate using the GentleSpin setting of a Centrifugal BlueWasher (Blue Cat Bio), and then the cells were washed with 175 μL of live cell imaging solution (Thermo Fisher) using the Blue Washer. After washing, the cells were incubated at room temperature with 70 μL of Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl 2 、 12 mMMgCl 2 、 11Cells were treated with DMSO, positive control or compound diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl 2 , 12 mM MgCl 2、11 mM HEPES, 10 mM glucose, pH 7.4), 10 mM glucose, pH 7.4). After 20 - 60 minutes, 30 μL of 3.3 mM 13C6,15N-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 175 μL of live cell imaging solution using a Blue Washer. The cells were then lysed in 150 μL of 15 μM D-leucine-d10 (CDN Isotopes) in ultrapure water. The plate was placed on an orbital shaker at 700 rpm for at least 40 minutes to facilitate lysis. After lysis, a standard dilution curve of 13C6,15N-L-isoleucine was added to the wells containing the lysates of untreated cells. The plate was returned to the shaker for at least 2 minutes to ensure proper mixing of the standard curve. The plate was then centrifuged at 4,000 rpm for 5 min to pellet the cell debris and precipitate. The supernatant was diluted 1:10 in acetonitrile + 0.1% formic acid in a polypropylene plate.

[0698] Assays: Isoleucine transport assay in 384-well plate format

[0699] On day 0, a stable cell line was seeded at a density of 20,000 cells per well in a medium containing 1 μg / mL tetracycline in a poly-D-lysine-coated 384-well cell culture-treated plate using a Viaflo 384-well pipettor. The transport assay was run the following 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 then washed with 80 μL of live cell imaging solution (ThermoFisher) using a 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 、 12 mM MgCl 2、11 mM HEPES, 10 mM glucose, pH 7.4). After incubation at room temperature for 20 - 60 minutes, 8.6 μL of 3.3 mM 13C6,15N-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 a Blue Washer. The cells were then lysed in 80 μL of 15 μM D-leucine-d10 (CDN Isotopes) was lysed. The plate was placed on an oscillator at 700 rpm for at least 2 hours to facilitate lysis. After lysis, 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 returned to the oscillator for at least 5 minutes to ensure proper mixing of the standard curve. The plate was then centrifuged at 4,000 rpm for 10 min to pellet cell debris and precipitate. The supernatant was diluted 1:10 in acetonitrile + 0.1% formic acid in a polypropylene plate.

[0700] Analysis of 13 C 6 , 15 N-L-isoleucine was performed using RapidFire365-QTOF 6545 (Agilent). Quantitative sample analysis utilized automated solid-phase extraction (HILIC H6 cartridges) prior to mass spectrometry injection. Samples were loaded using 95% acetonitrile, 0.1% formic acid, and eluted directly from the cartridges using 5% acetonitrile, 0.1% formic acid for ESI-MS (electrospray ionization) analysis. Analytes were quantified using Agilent Masshunter Quant software based on high-resolution full-scan data.

[0701] Example 2: Synthesis of Exemplary Compounds

[0702] Procedure 1: Synthesis of 2-Fluoro-1-(isocyanatomethyl)-4-(trifluoromethoxy)benzene

[0703]

[0704] At 0 °C, a solution of triphosgene (53 mg, 0.18 mmol) in toluene (1 mL) was added to a solution of A1 (78 mg, 0.37 mmol) in toluene (3 mL). The resulting mixture was stirred at 120 °C under N 2 atmosphere for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give crude A2 (87 mg, 99.20% yield) as a yellow oil, which was used directly in the next step without further purification.

[0705] Procedure 2: Synthesis of N-(2-Fluoro-4-(trifluoromethoxy)benzyl)-1H-imidazole-1-carboxamide

[0706]

[0707] To a solution of CDI (426 mg, 2.63 mmol) and diisopropylethylamine (833 μL, 4.78 mmol) in DMF (3.95 mL) was added A1 (500 mg, 2.39 mmol) portionwise. The mixture was stirred at room temperature for 2 h, at which point LCMS indicated complete consumption of the starting material. The crude solution of B2 (0.5 M) was used directly in the next step. LC / MS (ESI) m / z: 304 (M+H) + .

[0708] Procedure 3: Synthesis of (5R,9R)-9-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-methyl-3-oxo-2,7-diazaspiro[4.5]decane-7-carboxamide (C14-1) and (5S,9R)-9-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-methyl-3-oxo-2,7-diazaspiro[4.5]decane-7-carboxamide (C14-2)

[0709]

[0710] Synthesis of C2: To a mixture of C1 (1.0 g, 4.62 mmol) and TEA (1.17 g, 11.56 mmol) in DCM (15 mL) at 0 °C was added Cbz-OSu (1.73 g, 6.94 mmol). The resulting mixture was stirred at room temperature for 20 h. Then the mixture was diluted with H 2 O (40 mL) and extracted twice with DCM (30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 100:3) to afford C2 as a white solid (1.59 g, 98.14% yield). LC / MS (ESI) m / z: 295 (M+H-56) + .

[0711] Synthesis of C3: To a solution of C2 (800 mg, 2.28 mmol) in DCM (10 mL) at 0 °C was added Dess-Martin periodinane (1.94 g, 4.57 mmol). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was quenched with saturated NaHCO 3 solution (30 mL) and extracted twice with DCM (20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4Dry and concentrate to dryness. Purify the residue by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 50:1) to give C3 as a pale yellow oil (789 mg, 99.20% yield). LC / MS (ESI) m / z: 249 (M+H-100) + 。

[0712] Synthesis of C4: At 0 °C, under N 2 atmosphere, add NaHH (109 mg, 2.72 mmol) to a mixture of trimethylphosphonoacetate (496 mg, 2.72 mmol) in THF (12 mL). Stir the mixture at 0 °C for 30 min. Then add a solution of C3 (789 mg, 2.27 mmol) in THF (6 mL) to the above mixture at 0 °C. Stir the resulting mixture at room temperature for another 16 h. Then quench the mixture with saturated NH 4 Cl solution (40 mL) and extract with EtOAc (25 mL×2). Wash the combined organic layers with brine (30 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness. Purify the residue by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 3:1) to give C4 as a colorless oil (733 mg, 80.03% yield). LC / MS (ESI) m / z: 305 (M+H-100) + 。

[0713] Synthesis of 5: Add nitromethane (1.08 g, 17.77 mmol) to a mixture of C4 (718 mg, 1.78 mmol) and K 2 CO 3 (246 mg, 1.78 mmol) in DMSO (16 mL). Stir the resulting mixture at 100 °C under N 2 atmosphere for 16 h. Then dilute the mixture with H 2 O (40 mL) and extract with EtOAc (25 mL×2). Wash the combined organic layers with brine (40 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness. Purify the residue by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 4:1) to give C5 as a colorless oil (384 mg, 46.47% yield). LC / MS (ESI) m / z: 366 (M+H-100) + 。

[0714] Synthesis of C6: Nickel(II) chloride hexahydrate (1.04 g, 8.01 mmol) and NaBH 4 (304 mg, 8.01 mmol) were added to a solution of C5 (384 mg, 0.80 mmol) in EtOH (15 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. Then the mixture was quenched with saturated NH 4 Cl solution (30 mL) and extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 25:1) to give C6 (221 mg, 68.40% yield) as a colorless oil. LC / MS (ESI) m / z: 304 (M+H−100) + .

[0715] Synthesis of C7: Pd / C (200 mg, 10% w / w) was added to a solution of C6 (221 mg, 0.55 mmol) in MeOH (10 mL), and the resulting mixture was degassed three times under N 2 atmosphere and stirred at room temperature under H 2 atmosphere for 2 h. Then the mixture was filtered, and the filtrate was concentrated to give crude C7 (147 mg, 99.64% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 270 (M+H) + .

[0716] Synthesis of C8: AcOH (65 mg, 1.09 mmol) was added to a mixture of C7 (147 mg, 0.55 mmol) and 2,4-dimethoxybenzaldehyde (91 mg, 0.55 mmol) in DCM (8 mL), and the mixture was stirred at room temperature for 1 h. Then NaBH(OAc) 3 (348 mg, 1.64 mmol) was added at 0 °C and the resulting mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 12:1) to give C8 (228 mg, 99.58% yield) as a colorless oil. LC / MS (ESI) m / z: 420 (M+H) + .

[0717] Synthesis of C10: To a mixture of C8 (228 mg, 0.54 mmol) and C9 (238 mg, 1.36 mmol) in EtOH (5 mL) and THF (10 mL) was added AcOH (327 mg, 5.44 mmol) and NaBH 3 CN (120 mg, 1.90 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 4 h. Then the mixture was concentrated to dryness, and the residue was dissolved in EtOAc (30 mL) and washed with saturated NaHCO 3 solution (30 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 20:1) to give C10 (210 mg, 84.08% yield) as a colorless oil. LC / MS (ESI) m / z: 460 (M+H) + .

[0718] Synthesis of C11: To a solution of C10 (210 mg, 0.46 mmol) in DCM (8 mL) at 0 °C was added dropwise TFA (2 mL), and the resulting mixture was stirred at room temperature for 1 h. LCMS indicated complete consumption of the starting material. Then the mixture was concentrated to give crude C11 (161 mg, 98.02% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 360 (M+H) + .

[0719] Synthesis of C12: To a mixture of C11 (161 mg, 0.45 mmol) and DIEA (271 mg, 2.08 mmol) in MeCN (10 mL) was added N-methyl-1H-imidazole-1-carboxamide (325 mg, 2.60 mmol), and the resulting mixture was stirred at 60 °C for 16 h. Then the mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 12:1) to give C12 (168 mg, 90.05% yield) as a colorless oil. LC / MS (ESI) m / z: 417 (M+H) + .

[0720] Synthesis of C13: C12 (168 mg, 0.40 mmol) and TFA (5 mL) were charged into a round-bottom flask, and the mixture was stirred at 80 °C for 4 h. LCMS indicated complete consumption of the starting material. The mixture was then concentrated to give crude C13 (98 mg, 91.23% yield) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 267 (M+H) + 。

[0721] Synthesis of C14-1 and C14-2: A solution of A2 (87 mg, 0.37 mmol) in DCM (2 mL) was added to a mixture of C13 (98 mg, 0.37 mmol) and TEA (0.2 mL, 1.07 mmol) in DCM (6 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 30 min. The mixture was then diluted with H 2 O (30 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 8:1) to give pure C14 (42 mg, 18.88% yield) as a white solid. LC / MS (ESI) m / z: 502 (M+H) + 。It was further separated and purified by SFC (SHIMADZU preparative solution SFC, ChiralCel OZ, 250×21.2 mm I.D., 5 μm) to give C14-1 (6.4 mg, 3.47% yield) as a white solid. 1 1H NMR (400 MHz, MeOD) δ 7.50 - 7.41 (m, 1H), 7.17 - 7.05 (m, 2H), 4.52 - 4.39 (m, 2H), 4.15 - 4.03 (m, 1H), 3.97 - 3.87 (m, 1H), 3.83 - 3.70 (m, 1H), 3.32 - 3.30 (m, 1H), 3.25 - 3.18 (m, 1H), 3.17 - 3.07 (m, 1H), 2.72 (s, 3H), 2.64 - 2.57 (m, 1H), 2.56 - 2.49 (m, 1H), 2.33 - 2.21 (m, 2H), 2.19 - 2.10 (m, 1H), 2.00 - 1.92 (m, 1H), 1.02 - 0.94 (m, 2H), 0.83 - 0.72 (m, 2H); 1919F NMR (377 MHz, MeOD) δ -59.76 (s), -116.95 (s); and C14-2 was obtained as a white solid (6.5 mg, 3.52% yield). 1 1H NMR (400 MHz, MeOD) δ 7.49 - 7.41 (m, 1H), 7.16 - 7.07 (m, 2H), 4.51 - 4.39 (m, 2H), 4.09 - 4.02 (m, 1H), 3.97 - 3.88 (m, 1H), 3.80 - 3.67 (m, 1H), 3.22 - 3.14 (m, 3H), 2.72 (s, 3H), 2.66 - 2.60 (m, 1H), 2.59 - 2.53 (m, 1H), 2.38 - 2.31 (m, 1H), 2.30 - 2.21 (m, 2H), 1.94 - 1.86 (m, 1H), 1.02 - 0.95 (m, 2H), 0.82 - 0.75 (m, 2H); 19 19F NMR (377 MHz, MeOD) δ -59.77 (s), -116.97 (s).

[0722] Procedure 4: Synthesis of (9R)-9-(1-cyclopropyl-3-((1S,2R)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)ureido)-N-methyl-3-oxo-2,7-diazaspiro[4.5]decane-7-carboxamide (D5)

[0723]

[0724] Synthesis of D1: To a mixture of 1-bromo-4-(trifluoromethoxy)benzene (5.00 g, 20.75 mmol) and tert-butyl acrylate (3.99 g, 31.12 mmol) in DMF (70 mL) was added TEA (20 mL), PPh 3 (544 mg, 2.07 mmol) and Pd(OAc) 2 (466 mg, 2.07 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 8 h. Then the mixture was diluted with EtOAc (100 mL), filtered, and the filtrate was washed twice with saturated NH 4 Cl solution (80 mL). The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 30:1) to give D1 as a colorless oil (3.80 g, 63.54% yield).

[0725] Synthesis of D2: At 0 °C, NaHH (791 mg, 19.77 mmol, 60% dispersed in paraffin liquid) was added portionwise to a solution of trimethylsulfoxonium iodide (4.35 g, 19.77 mmol) in anhydrous DMSO (50 mL). After stirring for 30 min at 0 °C, a solution of D1 (3.80 g, 13.18 mmol) in DMSO (30 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 4 hours and then the mixture was quenched with saturated NH 4 Cl solution (120 mL) and extracted twice with EtOAc (70 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over MgSO 4 , filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 30:1) to give D2 (2.10 g, 52.70% yield) as a colorless oil.

[0726] Synthesis of D3: At 0 °C, under N 2 atmosphere, TFA (10 mL) was added dropwise to a solution of D2 (2.10 g, 6.95 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure to give crude D3 (1.71 g, 99.97% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 245 (M-H)-.

[0727] Synthesis of D4: At 0 °C, DPPA (53 mg, 0.19 mmol) was added dropwise to a mixture of D3 (39 mg, 0.16 mmol) and TEA (32 mg, 0.32 mmol) in toluene (4 mL). The resulting mixture was stirred at 120 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give crude D4 (38 mg, 98.64% yield) as a colorless oil, which was used directly in the next step without further purification.

[0728] Synthesis of D5: At 0 °C, TEA (162 mg, 1.60 mmol) and a solution of D4 (38 mg, 0.16 mmol) in DCM (2 mL) were added to a solution of C13 (42 mg, 0.16 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 30 min. Then the mixture was diluted with H 2 O (20 mL) and extracted twice with DCM (20 mL). The separated combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by preparative HPLC to give D5 as a white solid (17.7 mg, 22.02% yield). LC / MS (ESI) m / z: 510 (M+H) + . 1 1H NMR (400 MHz, MeOD) δ 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 4.12 - 4.00 (m, 1H), 3.99 - 3.87 (m, 1H), 3.80 - 3.66 (m, 1H), 3.32 - 3.30 (m, 0.5H), 3.24 - 3.20 (m, 0.5H), 3.20 - 3.18 (m, 1H), 3.17 - 3.08 (m, 1H), 2.80 - 2.74 (m, 1H), 2.72 (s, 3H), 2.67 - 2.58 (m, 1H), 2.53 - 2.44 (m, 1H), 2.39 - 2.31 (m, 0.5H), 2.31 - 2.20 (m, 2H), 2.17 - 2.11 (m, 0.5H), 2.11 - 2.03 (m, 1H), 1.99 - 1.87 (m, 1H), 1.31 - 1.19 (m, 2H), 1.02 - 0.89 (m, 2H), 0.82 - 0.69 (m, 2H). 19 19F NMR (376 MHz, MeOD) δ -59.62 (d, J = 4.4 Hz).

[0729] Procedure 5: Synthesis of (5R,9R)-9-(1-cyclopropyl-3-((3-(3-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)ureido)-N-methyl-3-oxo-2,7-diazaspiro[4.5]decane-7-carboxamide (E5-1) and (5S,9R)-9-(1-cyclopropyl-3-((3-(3-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)ureido)-N-methyl-3-oxo-2,7-diazaspiro[4.5]decane-7-carboxamide (E5-2)

[0730]

[0731] Synthesis of E1: Add TEA (586 mg, 5.79 mmol) and hydroxylamine hydrochloride (402 mg, 5.79 mmol) to a solution of 3-(trifluoromethoxy)benzaldehyde (1.0 g, 5.26 mmol) in DCM (25 mL) at 0 °C. Stir the resulting mixture at room temperature for 4 h. Then dilute the mixture with water (50 mL) and extract twice with DCM (30 mL). Separate the combined organic layers, wash with brine (30 mL), and dry over anhydrous Na 2 2SO4 It was dried, filtered and concentrated under reduced pressure to dryness to obtain crude E1 (950 mg, 88.05% yield) as a pale yellow oil, which was directly used in the next step without further purification. LC / MS (ESI) m / z: 206 (M+H) + .

[0732] Synthesis of E2: At 0 °C, under a N 2 atmosphere, [bis(trifluoroacetoxy)iodo]benzene (2.59 g, 6.02 mmol) was added to a mixture of E1 (950 mg, 4.63 mmol) and tert-butyl prop-2-yn-1-ylcarbamate (719 mg, 4.63 mmol) in MeOH (40 mL) and H 2 O (10 mL). The resulting mixture was stirred at room temperature for 16 h. Then the mixture was diluted with water (60 mL) and extracted twice with EtOAc (40 mL). The combined organic layers were separated, washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluting with PE:EtOAc = 100:0 to 2:1) to obtain E2 (390 mg, 23.50% yield) as a white solid. LC / MS (ESI) m / z: 359 (M+H) + .

[0733] Synthesis of E3: At 0 °C, under a N 2 atmosphere, TFA (1 mL) was added dropwise to a mixture of E2 (390 mg, 1.09 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 1 h. Then the mixture was concentrated to dryness under reduced pressure to obtain crude E3 (281 mg, 99.98% yield) as a yellow oil, which was directly used in the next step without further purification. LC / MS (ESI) m / z: 259 (M+H) + .

[0734] Synthesis of E4: At 0 °C, CDI (36 mg, 0.22 mmol) was added to a mixture of E3 (53 mg, 0.21 mmol) and TEA (64 mg, 0.63 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 45 min. Then the mixture was concentrated under reduced pressure to obtain crude E4 (72 mg, 99.57% yield) as a yellow oil, which was directly used in the next step without further purification. LC / MS (ESI) m / z: 353 (M+H) + .

[0735] Synthesis of E5-1 and E5-2: At 0 °C, TEA (162 mg, 1.60 mmol) and E4 (72 mg, 0.20 mmol) were added to a solution of C13 (42 mg, 0.16 mmol) in THF (5 mL). The resulting mixture was stirred at 60 °C for 16 h. Then the mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were separated, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 10:1) to give E5 as a white solid (31.2 mg, 35.93% yield). LC / MS (ESI) m / z: 551 (M+H) + . 1 1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 4.61 - 4.52 (m, 2H), 4.12 - 4.01 (m, 1H), 4.00 - 3.90 (m, 1H), 3.83 - 3.71 (m, 1H), 3.32 - 3.31 (m, 0.5H), 3.25 - 3.19 (m, 1H), 3.19 - 3.16 (m, 1H), 3.16 - 3.10 (m, 0.5H), 2.72 (d, J = 1.1 Hz, 3H), 2.68 - 2.59 (m, 1H), 2.59 - 2.52 (m, 1H), 2.38 - 2.32 (m, 0.5H), 2.31 - 2.22 (m, 2H), 2.18 - 2.10 (m, 0.5H), 2.01 - 1.90 (m, 1H), 1.04 - 0.96 (m, 2H), 0.87 - 0.79 (m, 2H). 19 19F NMR (376 MHz, MeOD) δ -59.47 (s). This product was further separated by SFC (ChiralPak IB 250×30 mm I.D., 5 μm; mobile phase: A was CO 2 and B was MeOH + 0.1% NH 3 H 2 O; B%: 35% - 35%, 3.0 min; 120 min) to give E5-1 as a white solid (9.5 mg, 10.94% yield). 11H NMR (400 MHz, MeOD) δ 7.86 - 7.80 (m, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 4.59 - 4.50 (m, 2H), 4.12 - 4.02 (m, 1H), 3.96 - 3.88 (m, 1H), 3.81 - 3.69 (m, 1H), 3.29 - 3.27 (m, 1H), 3.23 - 3.16 (m, 1H), 3.15 - 3.08 (m, 1H), 2.69 (s, 3H), 2.63 - 2.56 (m, 1H), 2.56 - 2.49 (m, 1H), 2.29 - 2.21 (m, 2H), 2.15 - 2.08 (m, 1H), 2.01 - 1.92 (m, 1H), 1.02 - 0.94 (m, 2H), 0.85 - 0.77 (m, 2H). 1 9 19F NMR (376 MHz, MeOD) δ -59.48 (s); and E5-2 was obtained as a white solid (8.5 mg, 9.79% yield). 1 1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.72 (s, 1H), 4.58 - 4.48 (m, 2H), 4.05 - 3.98 (m, 1H), 3.97 - 3.89 (m, 1H), 3.80 - 3.68 (m, 1H), 3.21 - 3.16 (m, 1H), 3.16 - 3.12 (m, 2H), 2.69 (s, 3H), 2.65 - 2.59 (m, 1H), 2.59 - 2.52 (m, 1H), 2.36 - 2.30 (m, 1H), 2.28 - 2.19 (m, 2H), 1.94 - 1.86 (m, 1H), 1.01 - 0.95 (m, 2H), 0.84 - 0.77 (m, 2H). 19 19F NMR (376 MHz, MeOD) δ -59.48 (s).

[0736] Procedure 6: Synthesis of (9R)-9-(3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)-N-methyl-3-oxo-2,7-diazaspiro[4.5]decane-7-carboxamide (F5)

[0737]

[0738] Synthesis of F1: NIS (29.1 g, 129.3 mmol) was added portionwise to a solution of 2-chloro-4-fluoro-1-methylbenzene (17.0 g, 117.6 mmol) in TFA (170 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. Then the mixture was concentrated under reduced pressure, the residue was diluted with DCM (200 mL) and washed with aqueous NaHCO 3 solution (150 ml * 3), the organic layer was separated, washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude F1 (27.7 g, 87.1% yield) as a white solid, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, MeOD-d4) δ 7.71 (dd, J = 6.8, 0.5 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 2.30 (s, 3H).

[0739] Synthesis of F2: Zn(CN) 2 (12.9 g, 109.8 mmol) was added to a solution of F1 (27 g, 99.8 mmol) in DMF (270 mL), followed by Pd(PPh 3 ) 4 (5.7 g, 4.9 mmol). The resulting mixture was stirred at 100 °C under N 2 atmosphere for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (400 mL) and filtered. The filtrate was washed twice with saturated NH 4 Cl (200 mL) aqueous solution. The organic layer was separated, washed with brine (200 mL), dried over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with PE:EtOAc = 100:0 to 95:5) to give F2 (10.0 g, 59.1% yield) as a white solid.

[0740] Synthesis of compound F3: BH 3 -THF (295 mL, 1 M in THF) was added dropwise to a solution of F2 (10 g, 58.9 mmol) in anhydrous THF (100 mL) at 0 °C. The resulting mixture was stirred at room temperature under N 2Stir for 16 h under an atmosphere. LCMS showed complete consumption of the starting material. The mixture was then quenched dropwise with MeOH (80 mL), and then concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (150 mL) and washed with an aqueous solution of HCl (100 mL, 1 N). The aqueous phase was separated and basified to pH = 10 with 15% aqueous NaOH. The mixture was then extracted with EtOAc (100 mL * 3), the combined organic layers were separated, washed with brine (100 mL), and dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give crude 4 as a colorless oil (5.5 g, 53.4% yield), which was used directly in the next step without further purification. LCMS: ESI m / z: 174 (M + H) + 。

[0741] Synthesis of F4: CDI (36 mg, 0.22 mmol) was added to a solution of F3 (36 mg, 0.21 mmol) in THF (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 50 min. The mixture was then concentrated under reduced pressure to give crude F4 as a colorless oil (55 mg, 98.99% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 268 (M + H) + 。

[0742] Synthesis of F5: TEA (162 mg, 1.60 mmol) and F4 (55 mg, 0.21 mmol) were added to a solution of C13 (42 mg, 0.16 mmol) in THF (5 mL). The resulting mixture was stirred at 60 °C for 16 h. The mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were separated, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give F5 as a white solid (20.7 mg, 28.19% yield). LC / MS (ESI) m / z: 466 (M + H) + 。 11H NMR (400 MHz, MeOD) δ 7.26 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 9.8 Hz, 1H), 6.98 - 6.88 (m, 1H), 4.46 - 4.33 (m, 2H), 4.12 - 4.01 (m, 1H), 3.96 - 3.86 (m, 1H), 3.82 - 3.68 (m, 1H), 3.32 - 3.30 (m, 0.5H), 3.24 - 3.18 (m, 1H), 3.18 - 3.15 (m, 1H), 3.15 - 3.09 (m, 0.5H), 2.72 (d, J = 0.9 Hz, 3H), 2.66 - 2.57 (m, 1H), 2.57 - 2.48 (m, 1H), 2.39 - 2.34 (m, 0.5H), 2.33 (s, 3H), 2.31 - 2.21 (m, 2H), 2.17 - 2.10 (m, 0.5H), 2.00 - 1.86 (m, 1H), 1.01 - 0.91 (m, 2H), 0.82 - 0.72 (m, 2H). 19 19F NMR (376 MHz, MeOD) δ -123.07 (d, J = 4.4 Hz).

[0743] Procedure 7: Synthesis of 1-((9R)-7-acetyl-3-oxo-2,7-diazaspiro[4.5]dec-9-yl)-1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)urea (G3)

[0744]

[0745] Step 1: Synthesis of G1

[0746] To a mixture of C11 (42 mg, 0.12 mmol) and TEA (36 mg, 0.36 mmol) in DCM (6 mL) at 0 °C was added Ac 2 o (26 mg, 0.18 mmol). The resulting mixture was then stirred at room temperature for 2 h and monitored by TLC. The mixture was then diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were separated, dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluting with PE / EtOAc = 100:0 to 3:1) to give G1 as a colorless oil (32 mg, 66.7% yield). LC / MS (ESI) m / z: 402 (M + H) + .

[0747] Synthesis of G2: A solution of G1 (32 mg, 0.08 mmol) in TFA (5 mL) was stirred at 80 °C for 2 h. Then the mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (15 mL) and washed with saturated NaHCO 3 solution (20 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give crude G2 (18 mg, 90.2% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 252 (M+H) + .

[0748] Synthesis of G3: To a mixture of G2 (18 mg, 0.07 mmol) in THF (5 mL) was added TEA (22 mg, 0.21 mmol) and A2 (32 mg, 0.11 mmol). The resulting mixture was stirred at 60 °C for 16 h. Then the mixture was diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give G3 (8 mg, 23.5% yield) as a white solid. LC / MS (ESI) m / z: 487 (M+H) + . 1 1H NMR (400 MHz, MeOD) δ 7.49 - 7.37 (m, 1H), 7.09 (t, J = 7.0 Hz, 2H), 4.53 (t, J = 11.8 Hz, 1H), 4.43 (t, J = 10.7 Hz, 2H), 3.90 - 3.77 (m, 2H), 3.71 - 3.47 (m, 1H), 3.43 - 3.34 (m, 1H), 3.28 - 3.21 (m, 1H), 3.19 (s, 2H), 3.17 - 2.93 (m, 1H), 2.57 - 2.45 (m, 2H), 2.39 - 2.22 (m, 2H), 2.20 (d, J = 17.4 Hz, 1H), 2.13 (d, J = 3.2 Hz, 2H), 2.09 (d, J = 2.3 Hz, 1H), 2.04 - 1.84 (m, 1H), 1.02 - 0.92 (m, 2H), 0.85 - 0.69 (m, 2H); 19 19F NMR (376 MHz, MeOH-d 4 ) δ -59.78 (s), -116.96 (s).

[0749] Procedure 8: Synthesis of 1-((9R)-7-acetyl-3-oxo-2,7-diazaspiro[4.5]dec-9-yl)-1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)urea (H8)

[0750]

[0751] Synthesis of H1: To a solution of methyl 3-hydroxypropionate (1 g, 9.61 mmol) in DCM (20 mL) at room temperature was added DHP (1.13 g, 13.45 mmol) and PPTS (121 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated under reduced pressure to afford crude H1 (1.78 g, 98.5% yield) as a colorless oil, which was used directly in the next step without further purification.

[0752] Synthesis of H2: To a solution of H1 (1.78 g, 9.47 mmol) in MeOH (12 mL) and H 2 2O (12 mL) was added LiOH (453 mg, 18.91 mmol) portionwise. The resulting mixture was stirred at room temperature for 2 h. Then the mixture was adjusted to pH = 5 with aqueous HCl (1 M) and extracted twice with EtOAc (30 mL). The combined organic layers were separated, washed with water (30 mL) and brine (30 mL), dried over anhydrous Na 2 2SO 4 4, filtered and concentrated under reduced pressure to afford crude H2 (1.59 g, 96.5% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 173 (M - H)-.

[0753] Synthesis of H3: To a solution of C11 (102 mg, 0.28 mmol) in DCM (6 mL) at 0 °C was added dropwise TEA (85 mg, 0.84 mmol) and NsCl (82 mg, 0.36 mmol), and the resulting mixture was stirred at room temperature for 18 h. Then the mixture was diluted with water (20 mL) and extracted twice with DCM (15 mL). The combined organic layers were separated, washed with brine (20 mL), dried over anhydrous Na 2 2SO 4Dry, filter and concentrate the filtrate to dryness in vacuo. Purify the residue by flash column chromatography on silica gel (eluting with PE / EtOAc = 100:0 to 2:1) to afford H3 as a yellow oil (116 mg, 75% yield). LC / MS (ESI) m / z: 545 (M+H) + .

[0754] Synthesis of H4: A mixture of H3 (116 mg, 0.21 mmol) in TFA (4 mL) was stirred at 80 °C for 3 h. The mixture was then concentrated under reduced pressure to give crude H4 as a purple oil (76 mg, 90.5% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 395 (M+H) + .

[0755] Synthesis of H5: To a solution of H4 (76 mg, 0.19 mmol) in MeCN (6 mL) at 0 °C was added TEA (0.08 mL, 0.57 mmol) and B1 (64 mg, 0.21 mmol), and the resulting mixture was stirred at 80 °C for 18 h. The mixture was then diluted with water (20 mL) and extracted twice with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated to dryness in vacuo. Purify the residue by flash column chromatography on silica gel (eluting with DCM / MeOH = 100:0 to 12:1) to afford H5 as a yellow solid (74 mg, 61% yield). LC / MS (ESI) m / z: 630 (M+H) + .

[0756] Synthesis of H6: To a mixture of H5 (74 mg, 0.12 mmol) and K 2 CO 3 (162 mg, 1.2 mmol) in MeCN (8 mL) at 0 °C was added dropwise PhSH (73 mg, 0.6 mmol), and the resulting mixture was stirred at 70 °C for 18 h. The mixture was then diluted with EtOAc (20 mL), filtered, and the filtrate was concentrated to dryness in vacuo. Purify the residue by flash column chromatography on silica gel (eluting with DCM / MeOH = 100:0 to 10:1) to afford H6 as a yellow oil (50 mg, 95.1% yield). LC / MS (ESI) m / z: 445 (M+H) + .

[0757] Synthesis of H7: At 0 °C, H2 (31 mg, 0.18 mmol) and HATU (67 mg, 0.18 mmol) were added to a mixture of H6 (50 mg, 0.12 mmol) and DIEA (0.1 mL, 0.6 mmol) in DMF (5 mL), and the resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to give crude H7 (70 mg, 99.0% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 601 (M+H) + .

[0758] Synthesis of H8: At 0 °C, PPTS (90 mg, 0.36 mmol) was added to a solution of H7 (70 mg, 0.12 mmol) in MeOH (5 mL), and the resulting mixture was stirred at room temperature for 18 h. Then the mixture was diluted with water (20 mL) and extracted twice with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by preparative HPLC to give H8 (17 mg, 27.4% yield) as a white solid. LC / MS (ESI) m / z: 517 (M+H) + . 1 1H NMR (400 MHz, MeOH-d 4 6) δ 7.48 - 7.39 (m, 1H), 7.09 (t, J = 7.6 Hz, 2H), 7.03 - 6.92 (m, 1H), 4.57 (t, J = 11.6 Hz, 1H), 4.50 - 4.37 (m, 2H), 3.99 (d, J = 8.2 Hz, 1H), 3.93 - 3.72 (m, 3H), 3.61 (d, J = 12.6 Hz, 1H), 3.49 - 3.32 (m, 1H), 3.25 - 3.12 (m, 2H), 3.08 - 2.94 (m, 1H), 2.74 (dt, J = 14.9, 6.1 Hz, 1H), 2.66 - 2.43 (m, 3H), 2.37 - 2.10 (m, 3H), 2.03 - 1.84 (m, 1H), 0.96 (d, J = 6.2 Hz, 2H), 0.78 (d, J = 12.1 Hz, 2H); 19 19FNMR (376 MHz, MeOH-d 4) δ - 59.78 (s), -116.98 (s).

[0759] Procedure 9: Synthesis of (9R)-9-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-methyl-2-oxo-1,3,7-triazaspiro[4.5]decane-7-carboxamide (I10)

[0760]

[0761] Synthesis of I1: To a mixture of C3 (470 mg, 1.35 mmol) and Ti(Oi-Pr) 4 (422 mg, 1.49 mmol) in DCM (10 mL) at 0 °C was added NH 3 / MeOH (7N, 1.9 mL), and the mixture was stirred at room temperature for 2 h. Then at 0 °C, TMSCN (161 mg, 1.62 mmol) was added to the above mixture, and the resulting mixture was stirred in a sealed tube at room temperature for another 16 h. Then the mixture was diluted with H 2 O (30 mL), filtered and the filtrate was extracted with DCM (20 mL × 2). The combined organic layers were separated, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:EtOAc = 100:0 to 25:1) to give I1 as a colorless oil (428 mg, 84.73% yield). LC / MS (ESI) m / z: 375 (M + H) + .

[0762] Synthesis of I2: To a solution of I1 (428 mg, 1.14 mmol) in MeOH (10 mL) at 0 °C was added CoCl 2 (14 mg, 0.11 mmol) and NaBH 4 (87 mg, 2.28 mmol), and the resulting mixture was stirred at 0 °C for 1 h. Then the mixture was quenched with aqueous NaOH (30 mL, 1N) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure to give crude I2 as a colorless oil (401 mg, 92.47% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 379 (M + H) + .

[0763] Synthesis of I3: CDI (76 mg, 0.74 mmol) was added to a solution of I2 (401 mg, 1.06 mmol) in THF (10 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. LCMS indicated complete consumption of the starting material. Then the mixture was stirred at 50 °C for another 2 h. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:EtOAc = 100:0 to 16:1) to give I3 (305 mg, 71.34% yield) as a colorless oil. LC / MS (ESI) m / z: 405 (M+H) + 。

[0764] Synthesis of I4: Pd / C (300 mg, 10% weight / weight) was added to a solution of 4 (305 mg, 0.75 mmol) in MeOH (10 mL), and the resulting mixture was degassed three times under N 2 atmosphere and stirred at room temperature under H 2 atmosphere for 2 h. Then the mixture was filtered, and the filtrate was concentrated to give crude I4 (193 mg, 94.69% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 271 (M+H) + 。

[0765] Synthesis of I5: AcOH (85 mg, 1.42 mmol) was added to a mixture of I4 (193 mg, 0.71 mmol) and 2,4-dimethoxybenzaldehyde (118 mg, 0.71 mmol) in DCM (8 mL), and the mixture was stirred at room temperature for 1 h. Then NaBH(OAc) 3 (452 mg, 2.13 mmol) was added to the above mixture at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. Then the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 10:1) to give I5 (288 mg, 95.83% yield) as a colorless oil. LC / MS (ESI) m / z: 421 (M+H) + 。

[0766] Synthesis of I6: C9 (300 mg, 1.73 mmol) and NaBH 3CN (152 mg, 2.42 mmol). The resulting mixture was stirred at 80 °C for 3 h. Then the mixture was concentrated to dryness, the residue was diluted with EtOAc (30 mL) and washed with saturated NaHCO 3 solution (30 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 25:1) to afford I6 as a colorless oil (235 mg, 74.50% yield). LC / MS (ESI) m / z: 461 (M+H) + .

[0767] Synthesis of I7: TFA (2 mL) was added to a solution of I6 (235 mg, 0.51 mmol) in DCM (8 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. LCMS indicated complete consumption of the starting material. Then the mixture was concentrated to afford crude I7 as a colorless oil (179 mg, 97.33% yield). LC / MS (ESI) m / z: 36l (M+H) + .

[0768] Synthesis of I8: N-Methyl-1H-imidazole-1-carboxamide (313 mg, 2.5 mmol) was added to a mixture of I7 (179 mg, 0.50 mmol) and DIEA (323 mg, 2.5 mmol) in MeCN (10 mL), and the resulting mixture was stirred at 60 °C for 16 h. Then the mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 9:1) to afford I8 as a colorless oil (110 mg, 53.05% yield). LC / MS (ESI) m / z: 418 (M+H) + .

[0769] Synthesis of I9: I8 (110 mg, 0.26 mmol) and TFA (5 mL) were charged into a round-bottom flask, and the resulting mixture was stirred at 80 °C for 4 h. LCMS indicated complete consumption of the starting material. Then the mixture was concentrated to afford crude I9 as a purple oil (58 mg, 82.35% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 268 (M+H) + .

[0770] Synthesis of I10: At 0 °C, B1 (67 mg, 0.22 mmol) was added to a mixture of I9 (58 mg, 0.22 mmol) and TEA (111 mg, 1.10 mmol) in THF (8 mL). The resulting mixture was stirred at 65 °C for 6 hours. The mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered, then concentrated to dryness. The residue was purified by preparative HPLC to give I10 (41.9 mg, 38.42% yield) as a white solid. LC / MS (ESI) m / z: 503 (M+H) + . 1 1H NMR (400 MHz, MeOD) δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 2H), 7.04 - 6.94 (m, 1H), 4.51 - 4.37 (m, 2H), 4.14 - 4.00 (m, 1H), 4.00 - 3.93 (m, 0.5H), 3.91 - 3.84 (m, 0.5H), 3.83 - 3.75 (m, 0.5H), 3.72 - 3.61 (m, 0.5H), 3.40 - 3.34 (m, 0.5H), 3.29 - 3.24 (m, 1H), 3.23 - 3.16 (m, 1H), 3.12 - 3.05 (m, 0.5H), 2.73 - 2.69 (m, 3H), 2.67 (s, 0.5H), 2.62 - 2.56 (m, 1H), 2.56 - 2.50 (m, 0.5H), 2.43 - 2.29 (m, 1H), 2.04 - 1.88 (m, 1H), 1.00 - 0.89 (m, 2H), 0.83 - 0.68 (m, 2H). 19 19F NMR (377 MHz, MeOD) δ -59.77 (s), -116.97 (s).

[0771] Procedure 10: Synthesis of 9-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-methyl-2-oxa-7-azaspiro[4.5]decane-7-carboxamide (J15)

[0772]

[0773] Synthesis of J1: At 0 °C, in N 2Under an atmosphere, TBDPSCl (3.02 g, 10.976 mmol) was added dropwise to a mixture of 1-(tert-butyl) 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (2 g, 7.713 mmol) and imidazole (1.49 g, 21.951 mmol) in DMF (25 mL). The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 hours. Then the mixture was diluted with EtOAc (80 mL) and washed twice with saturated NH 4 Cl solution (80 mL) and washed with brine (100 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 10:1) to give J1 (3.56 g, 95.1% yield) as a colorless oil. LC / MS (ESI) m / z: 498 (M+H) + .

[0774] Synthesis of J2: At -78 °C under an N 2 atmosphere, LDA (6.1 mL, 2 M in THF) was added dropwise to a solution of J1 (2.5 g, 4.885 mmol) in anhydrous THF (60 mL). The resulting mixture was stirred at -78 °C under an N 2 atmosphere for 1.5 hours. Then 3-bromoprop-1-ene (0.64 mL, 7.328 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at -78 °C under an N 2 atmosphere for another 2 hours. Then the mixture was quenched with saturated NH 4 Cl solution (60 mL) and extracted twice with EtOAc (60 mL). The combined organic layers were separated, washed with brine (80 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 20:1) to give J2 (2.2 g, 81.6% yield) as a colorless oil. LC / MS (ESI) m / z: 538 (M+H) + .

[0775] Synthesis of J3: At -78 °C under an N 2 atmosphere, O 2 was bubbled through a mixture of J2 (2.2 g, 4.091 mmol) in DCM (30 mL) and MeOH (20 mL) for 3 minutes, and then O 3 was bubbled through for another 1 hour. Then the mixture was treated with O 2Purge for 3 minutes, then with N 2 Purge for 3 minutes, then add NaBH 4 (0.40 g, 11.961 mmol) to the above mixture. Stir the resulting mixture at 0 °C under N 2 atmosphere for an additional 2 hours. Then quench the mixture with saturated NH 4 Cl solution (100 mL) and extract twice with EtOAc (80 mL). Separate the combined organic layers, wash with brine (100 mL), dry over anhydrous Na 2 SO 4 and filter. Evaporate the filtrate to dryness to obtain crude J3 (2.0 g, 70% purity, 68.9% yield) as a colorless oil, which is used directly in the next step without further purification. LC / MS (ESI) m / z: 510 (M+H) + .

[0776] Synthesis of J4: Add NaBH 2 (930 mg, 27.47 mmol) to a solution of J3 (2 g, 2.747 mmol) in MeOH (20 mL) at 0 °C under N 4 atmosphere. Stir the resulting mixture at room temperature under N 2 atmosphere for 16 hours. Then quench the mixture with saturated NH 4 Cl solution (80 mL) and extract twice with DCM (60 mL). Separate the combined organic layers, wash with water (100 mL) and brine (100 mL), dry over anhydrous Na 2 SO 4 and filter. Evaporate the filtrate to dryness. Purify the residue by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 1:1) to obtain J4 (1.2 g, 85.0% yield) as a colorless oil. LC / MS (ESI) m / z: 514 (M+H) + .

[0777] Synthesis of J5: Add MsCl (803 mg, 7.01 mmol) dropwise to a mixture of J4 (1.2 g, 2.42 mmol) and pyridine (1.11 g, 14.02 mmol) in DCM (25 mL) at 0 °C. Stir the resulting mixture at room temperature under N 2 atmosphere for 22 hours. Then quench the mixture with saturated NaHCO 3 solution (80 mL) and extract twice with EtOAc (60 mL). Separate the combined organic layers, wash with water (100 mL) and brine (100 mL), dry over anhydrous Na 2 SO 4Dry and filter. Evaporate the filtrate to dryness. Purify the residue by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 8:1) to obtain J5 as a colorless oil (860 mg, 74.27% yield). LC / MS (ESI) m / z: 496 (M+H) + .

[0778] Synthesis of J6: Add TBAF (3.5 mL, 3.50 mmol, 1 M in THF) to a solution of J5 (860 mg, 1.735 mmol) in THF (20 mL) at 0 °C. Stir the resulting mixture at room temperature under N 2 atmosphere for 2 h. Then dilute the mixture with EtOAc (50 mL), and wash with water (50 mL × 4) and brine (50 mL × 2). Separate the organic layer, dry over anhydrous Na 2 SO 4 dry and filter. Evaporate the filtrate to dryness. Purify the residue by silica gel column chromatography (eluting with PE:EtOAc = 100:0 to 1:1) to obtain J6 as a colorless oil (420 mg, 94.1% yield). LC / MS (ESI) m / z: 258 (M+H) + .

[0779] Synthesis of J7: Add TEA (330 mg, 3.264 mmol) and MsCl (149 mg, 1.306 mmol) to a solution of J6 (280 mg, 1.088 mmol) in DCM (8 mL) at 0 °C. Stir the resulting mixture at room temperature under N 2 atmosphere for 2 h. Then dilute the mixture with DCM (30 mL), and wash with water (30 mL) and brine (30 mL). Separate the organic layer, dry over anhydrous Na 2 SO 4 dry and filter. Evaporate the filtrate to dryness to obtain crude J7 as a colorless oil (320 mg, 87.7% yield), which is used directly in the next step without further purification. LC / MS (ESI) m / z: 336 (M+H) + .

[0780] Synthesis of J8: Add NaN 2 (186 mg, 2.862 mmol) to a solution of J7 (320 mg, 0.954 mmol) in DMF (8 mL) at room temperature under N 3 (186 mg, 2.862 mmol). Stir the resulting mixture at 90 °C under N 2 atmosphere for 16 h. Then cool the mixture to room temperature and dilute with water (30 mL), extract twice with EtOAc (30 mL). Separate the combined organic layers, wash with saturated NH4 The Cl solution (30 mL × 2) and brine (30 mL × 2) were used for washing, and then dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness to obtain crude J8 (290 mg, 60% purity, 64.6% yield) as a colorless oil, which was directly used in the next step without further purification. LC / MS (ESI) m / z: 283 (M + H) + .

[0781] Synthesis of J9: To a solution of J8 (290 mg, 0.616 mmol) in EtOH (5 mL) was added Pd / C (100 mg, 10% weight / weight). The resulting mixture was stirred at room temperature under a N 2 atmosphere at 25 psi for 6 hours. Then the mixture was diluted with DCM (30 mL) and filtered through a Celite pad. The filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 10:1) to obtain J9 (145 mg, 91.8% yield) as a colorless oil. LC / MS (ESI) m / z: 257 (M + H) + .

[0782] Synthesis of J10: At 0 °C, AcOH (102 mg, 1.697 mmol) was added to a mixture of J9 (145 mg, 0.566 mmol) and 2,4 - dimethoxybenzaldehyde (94 mg, 0.566 mmol) in DCM (8 mL). The resulting mixture was stirred at room temperature for 1 hour. Then at 0 °C, NaBH(OAc) 3 (359.74 mg, 1.697 mmol) was added portionwise to the above mixture and the resulting mixture was stirred at room temperature under a N 2 atmosphere for 4 hours. The mixture was quenched with saturated NaHCO 3 solution (30 mL) and extracted twice with DCM (20 mL). The combined organic layers were separated, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 10:1) to obtain J10 (135 mg, 58.7% yield) as a colorless oil. LC / MS (ESI) m / z: 407 (M + H) + .

[0783] Synthesis of J11: To a mixture of J10 (125 mg, 0.307 mmol) and AcOH (55 mg, 0.922 mmol) in THF (6 mL) and EtOH (3 mL) was added C9 (134 mg, 0.769 mmol) and NaBH 3 CN (58 mg, 0.922 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 4 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and basified to pH = 8 with saturated NaHCO 3 solution (30 mL). Then the mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 25:1) to give J11 (95 mg, 67.9% yield) as a colorless oil. LC / MS (ESI) m / z: 447 (M+H) + .

[0784] Synthesis of J12: To a solution of J11 (95 mg, 0.213 mmol) in anhydrous DCM (6 mL) at 0 °C was added dropwise TFA (2 mL). The resulting mixture was stirred at room temperature under N 2 atmosphere for 2 h. Then the reaction mixture was concentrated under reduced pressure to give crude J12 (73 mg, 99.1% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 347 (M+H) + .

[0785] Synthesis of J13: To a mixture of J12 (73 mg, 0.211 mmol) and TEA (64 mg, 0.632 mmol) in anhydrous MeCN (6 mL) at room temperature was added N-methyl-1H-imidazole-1-carboxamide (53 mg, 0.421 mmol). The resulting mixture was stirred at 60 °C under N 2 atmosphere for 16 h. Then the mixture was diluted with water (30 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 20:1) to give 15 (80 mg, 94.1% yield) as a colorless oil. LC / MS (ESI) m / z: 404 (M+H) +。

[0786] Synthesis of J14: A solution of J13 (70 mg, 0.173 mmol) in TFA (5 mL) was stirred at 80 °C under N 2 atmosphere for 3 hours. After cooling, the mixture was evaporated to dryness under reduced pressure to give crude J14 (42 mg, 95.6% yield) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 254 (M+H) + 。

[0787] Synthesis of J15: At room temperature, a solution of B1 (75 mg, 0.249 mmol) in anhydrous THF (1 mL) was added to a mixture of J14 (42 mg, 0.166 mmol) and TEA (167 mg, 1.66 mmol) in anhydrous THF (4 mL). The resulting mixture was stirred at 60 °C under N 2 atmosphere for 16 hours. Then the mixture was diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were separated, washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC to give J15 (33.1 mg, 40.87% yield) as a white solid. LC / MS (ESI) m / z: 489 (M+H) + 。 1 1H NMR (400 MHz, CD 3 OD-d 4 ) δ 7.51 - 7.38 (m, 1H), 7.18 - 6.98 (m, 2H), 4.52 - 4.38 (m, 2H), 4.03 - 3.77 (m, 5H), 3.66 - 3.54 (m, 1H), 3.48 - 3.37 (m, 1H), 3.14 (t, J = 11.7 Hz, 1H), 2.72 (s, 3H), 2.64 - 2.50 (m, 2H), 2.36 - 2.13 (m, 1H), 2.01 - 1.82 (m, 1H), 1.80 - 1.63 (m, 2H), 1.04 - 0.89 (m, 2H), 0.84 - 0.69 (m, 2H). 19 19F NMR (376 MHz, CD 3 OD-d 4 ) δ -59.16--60.07 (m), -116.66--117.21 (m).

[0788] Procedure 11: Synthesis of 4-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-methyl-9-oxa-2-azaspiro[5.5]undecane-2-carboxamide (K7)

[0789]

[0790] Synthesis of K2: To a mixture of K1 (500 mg, 1.85 mmol) and 2,4-dimethoxybenzaldehyde (307 mg, 1.85 mmol) in MeOH (12 mL) was added AcOH (212 μL, 3.70 mmol), and the mixture was stirred at room temperature for 10 min. Then NaBH(OAc) 3 (784 mg, 3.70 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. Then the mixture was cooled to 0 °C, basified with 5% aqueous ammonia solution and the residue was extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness to give crude 2 (728 mg), which was used directly in the next step without purification. LC / MS (ESI) m / z: 421 (M+H) + .

[0791] Synthesis of K3: To a mixture of K2 (728 mg, 1.73 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (603 mg, 3.46 mmol) in EtOH (7.5 mL) were added AcOH (595 μL, 10.4 mmol) and NaBH 3 CN (218 mg, 3.46 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 18 h. Then the mixture was cooled to 0 °C, basified with 5% aqueous ammonia solution and the residue was extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with hexane:EtOAc = 100:0 to 0:100) to give K3 as a colorless oil (536 mg, 67.2% yield over 2 steps). LC / MS (ESI) m / z: 461 (M+H) + .

[0792] Synthesis of K4: 1 M HCl in dioxane (1 mL) was added dropwise to a solution of K3 (500 mg, 1.09 mmol) in DCM (5 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 3 h. LCMS indicated complete consumption of the starting material. The mixture was then concentrated to afford crude K4 as a white solid (430 mg, 99.9% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 361 (M+H) + 。

[0793] Synthesis of K5: N-Methyl-1H-imidazole-1-carboxamide (94 mg, 0.75 mmol) was added to a mixture of K4 (230 mg, 0.58 mmol) and DIPEA (303 μL, 1.74 mmol) in DCM (5 mL), and the resulting mixture was stirred at room temperature for 16 h. The mixture was then diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to afford crude K5 (182 mg, 75.4% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 418 (M+H) + 。

[0794] Synthesis of K6: K5 (182 mg, 0.44 mmol) and TFA (4 mL) were charged into a round-bottom flask, and the mixture was stirred at 80 °C for 1 h. LCMS indicated complete consumption of the starting material. The mixture was then concentrated to afford crude K6 as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 268 (M+H) + 。

[0795] Synthesis of K7: A solution of 8 (1.13 mL, 0.57 mmol) was added to a mixture of 7 and TEA (303 μL) in DMF (1.5 mL), and the resulting mixture was stirred at 50 °C for 2 h. The residue was then purified directly by preparative HPLC (eluting with H 2 O + 0.1% TFA: MeCN + 0.1% TFA = 100:0 to 0:100) to afford pure K7 as a white solid (38 mg, 17% yield over 2 steps). LC / MS (ESI) m / z: 503 (M+H) + 。 11H NMR (400 MHz, d-DMSO) δ 7.50 - 7.45 (m, 1H), 7.37 - 7.35 (m, 1H), 7.28 - 7.26 (m, 1H), 6.96 - 6.93 (m, 1H), 6.38 - 6.37 (m, 1H), 4.36 - 4.35 (m, 2H), 4.18 - 4.14 (m, 1H), 3.94 - 3.91 (m, 1H), 3.78 - 3.71 (m, 1H), 3.62 - 3.55 (m, 4H), 3.05 - 2.99 (m, 1H), 2.59 - 2.58 (m, 3H), 2.52 - 2.47 (m, 1H), 2.33 - 2.30 (m, 1H), 1.86 - 1.70 (m, 2H), 1.50 - 1.47 (m, 1H), 1.39 - 1.30 (m, 3H), 0.94 - 0.92 (m, 2H), 0.70 - 0.67 (m, 2H);

[0796] Procedure 12: Synthesis of 4-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-9-oxa-2-azaspiro[5.5]undecane-2-carboxamide (L3)

[0797]

[0798] Synthesis of L1: Trimethylsilyl isocyanate (26 μL, 0.19 mmol) was added to a mixture of K4 (63 mg, 0.16 mmol) and DIPEA (83 μL, 0.48 mmol) in THF (1.5 mL), and the resulting mixture was stirred at room temperature for 16 h. Then the mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give crude L1 (27 mg, 42% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 404 (M + H) + .

[0799] Synthesis of 10: L1 (27 mg, 68 μmol) and TFA (1 mL) were charged into a scintillation vial, and the mixture was stirred at 80 °C for 1 h. LCMS indicated complete consumption of the starting material. Then the mixture was concentrated to give crude L2 as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 254 (M + H) + .

[0800] Synthesis of L3: A solution of B1 (0.18 mL, 88 μmol) was added to a mixture of L2 and TEA (47 μL) in DMF (1 mL), and the resulting mixture was stirred at 50 °C for 2 h. Then the residue was purified directly by preparative HPLC (eluting with H 2 O + 0.1% TFA: MeCN + 0.1% TFA = 100:0 to 0:100) to give pure L3 as a white solid (6.9 mg, 21% yield over 2 steps). LC / MS (ESI) m / z: 489 (M + H) + . 1 H NMR (400 MHz, d-DMSO) δ 7.48 - 7.43 (m, 1H), 7.36 - 7.33 (m, 1H), 7.26 - 7.24 (m, 1H), 6.93 - 6.90 (m, 1H), 5.88 (s, 2H), 4.35 - 4.33 (m, 2H), 4.15 - 4.12 (m, 1H), 3.95 - 3.92 (m, 1H), 3.77 - 3.69 (m, 1H), 3.65 - 3.51 (m, 4H), 3.05 - 2.99 (m, 1H), 2.51 - 2.46 (m, 1H), 2.33 - 2.30 (m, 1H), 1.84 - 1.78 (m, 1H), 1.71 - 1.68 (m, 1H), 1.52 - 1.48 (m, 1H), 1.38 - 1.29 (m, 3H), 0.92 - 0.85 (m, 2H), 0.71 - 0.64 (m, 2H).

[0801] Table 1.

[0802]

[0803]

[0804]

[0805]

[0806]

[0807] Synthesis of common intermediate A5

[0808]

[0809] Step 1: Synthesis of A2

[0810] At -78 °C, in N 2To a solution of A1 (30 g, 116 mmol) in anhydrous THF (250 mL) was added dropwise isopropylmagnesium chloride-lithium chloride complex (223 mL, 1.3 M in THF) under an atmosphere. The mixture was stirred at -78 °C for 2 h. Then DMF (45 mL, 579 mmol) was added dropwise to the above mixture at -78 °C. Then the resulting mixture was warmed to room temperature and stirred for an additional 1 h under an N 2 atmosphere. After completion, the reaction mixture was quenched with saturated NH 4 Cl (200 mL) at 0 °C and extracted with TBME (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure to afford A2 (24 g, quantitative) as a brown oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 209 (M+H) + .

[0811] Step 2: Synthesis of A3

[0812] To a solution of A2 (24 g, 115 mmol) in THF (400 mL) was added sodium carbonate (24.5 g, 231 mmol) and hydroxylamine hydrochloride (10.4 g, 150 mmol). The resulting mixture was stirred at 40 °C overnight. Then the mixture was diluted with water (600 mL) and extracted with DCM (400 mL × 2). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness under reduced pressure to afford A3 (25.7 g, 99% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 224 (M+H) + .

[0813] Step 3: Synthesis of A4

[0814] To a solution of A3 (25.7 g, 115 mmol) in AcOH (250 mL) was added Zn (37.7 g, 576 mmol) portionwise. The resulting mixture was stirred at 70 °C for 6 h under an N 2 atmosphere. After completion, the mixture was basified to pH = 8 with aqueous NaOH (1 N) and extracted with DCM (400 mL x 2). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 6% MeOH in DCM) to afford A4 as a colorless oil (14.1 g, 59% yield). LC / MS (ESI) m / z: 210 (M+H) + .

[0815] Step 4: Synthesis of A5

[0816] To a solution of A4 (2.6 g, 12.4 mmol) in THF (100 mL) at 0 °C was added triethylamine (1.25 g, 12.4 mmol) and CDI (2.2 g, 13.7 mmol). The resulting mixture was stirred at 0 °C under N 2 atmosphere for 1 h. Upon completion, the mixture was diluted with water (120 mL) and extracted with DCM (70 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered, then concentrated under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 20% EtOAc in PE) to afford A5 as a white solid (2.6 g, 69% yield). LC / MS (ESI) m / z: 304 (M+H) + .

[0817] Synthesis of Example 1 / B13

[0818]

[0819] Step 1: Synthesis of A2

[0820] To a solution of B1 (50 g, 256.2 mmol) in AcOH (120 mL) was added PtO 2 (5 g, 22.0 mmol). The resulting mixture was stirred at 50 °C under H 2 atmosphere (20 atm) for 16 h. Then the mixture was filtered and concentrated under reduced pressure to give crude B2 (50 g, 97% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 202 (M+H) + .

[0821] Step 2: Synthesis of B3

[0822] To a solution of B2 (50 g, 248.5 mmol) in DCM (500 mL) at 0 °C was added NaHHCO 3 (76 g, 904.7 mmol) and Boc 2O (66.4 g, 304.2 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water (500 mL) and extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 15% EtOAc in PE) to afford cis-isomer B3 as a white solid (24.0 g, 32% yield). LC / MS (ESI) m / z: 246 (M+H-56) + . 1 1H NMR (400 MHz, CDCl 3 ) δ 4.35 (br s, 2H), 3.69 (s, 6H), 2.88 - 2.36 (m, 6H), 1.45 (s, 9H); and the trans-isomer was obtained as a colorless oil (9.1 g, 12% yield). LC / MS (ESI) m / z: 246 (M+H-56) + . 1 1H NMR (400 MHz, CDCl 3 ) δ 3.82 - 3.70 (m, 2H), 3.68 (s, 6H), 3.60 - 3.42 (m, 2H), 2.85 - 2.77 (m, 2H), 2.15 - 1.96 (m, 2H), 1.44 (s, 9H).

[0823] Step 3: Synthesis of B4

[0824] To a solution of B3 (24 g, 79.6 mmol) in MeOH (240 mL) at 0 °C was added 2 M NaOH (42 mL, 84.0 mmol, aqueous solution). The resulting mixture was stirred at room temperature for 16 h. Then the mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL). The aqueous layer was adjusted to pH = 4 with HCl (1 M), then extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 70% EtOAc in PE) to afford B4 as a white solid (16 g, 70% yield). LC / MS (ESI) m / z: 232 (M+H-56) + .

[0825] Step 4: Synthesis of B5

[0826] At 0 °C, DPPA (18.4 g, 66.8 mmol) and TEA (6.8 g, 66.8 mmol) were added to a solution of B4 (16 g, 55.7 mmol) in toluene (160 mL). The resulting mixture was stirred at 110 °C under N 2 atmosphere for 2 h. Then, BnOH (30.1 g, 278.5 mmol) and TEA (6.8 g, 66.8 mmol) were added to the above mixture at 0 °C. The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 40% EtOAc in PE) to afford B5 (12.8 g, 59% yield) as a white solid. LC / MS (ESI) m / z: 293 (M+H-100) + .

[0827] Step 5: Synthesis of B6

[0828] NaBH 4 (3.0 g, 81.5 mmol) was added portionwise to a solution of B5 (12.8 g, 32.6 mmol) in EtOH (150 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. Then the mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 60% EtOAc in PE) to afford B6 (10.2 g, 28.0 mmol) as a white solid. LC / MS (ESI) m / z: 265 (M+H-100) + .

[0829] Step 6: Synthesis of B7

[0830] At room temperature, under a nitrogen atmosphere, Pd / C (1.0 g, 10 wt%) was added to a solution of B6 (10.0 g, 27.5 mmol) in i-PrOH (150 mL). The suspension was degassed under vacuum and purged with H 2 several times. The resulting mixture was stirred at room temperature under H 2 atmosphere for 18 h. Then the mixture was filtered through Pad filtration, and wash the filter cake with MeOH (100 mL). Concentrate the combined filtrates to dryness to obtain crude B7 (6.1 g, 97% yield), which is used directly in the next step without further purification. LC / MS (ESI) m / z: 231 (M+H) + 。

[0831] Step 7: Synthesis of A8

[0832] Add AcOH (1.2 g, 20.8 mmol) and 2,4-dimethoxybenzaldehyde (8.9 g, 71.5 mmol) to a solution of B7 (2.4 g, 10.4 mmol) in DCM (50 mL) at room temperature. Stir the resulting mixture under N 2 atmosphere for 1 h. Then add NaBH(OAc) 3 (2.65 g, 12.48 mmol) portionwise to the above mixture and stir the resulting mixture at room temperature under N 2 atmosphere for 3 h. Then filter the mixture and rinse with DCM (50 mL x 2). Dilute the filtrate with water (70 mL) and extract with DCM (40 mL x 2). Wash the combined organic layers with brine (80 mL), dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure. Purify the residue by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to obtain B8 (2.7 g, 68% yield) as a pale yellow oil. LC / MS (ESI) m / z: 381 (M+H) + 。

[0833] Step 8: Synthesis of B9

[0834] Add AcOH (4.3 g, 71 mmol), (1-ethoxycyclopropoxy)trimethylsilane (2.5 g, 14.2 mmol), and NaBH 3 CN (1.3 g, 21.3 mmol) to a solution of B8 (2.7 g, 7.1 mmol) in THF / EtOH (60 mL, volume / volume = 2:1). Stir the resulting mixture at 80 °C under N 2 atmosphere for 4 h. Then neutralize the mixture with NaHCO 3 (aqueous solution) until the pH is adjusted to pH = 8. Dilute the mixture with water (80 mL) and extract with EtOAc (70 mL x 2). Wash the combined organic layers with brine (80 mL), dry over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. Purify the residue by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford B9 as a colorless oil (2.0 g, 67% yield). LC / MS (ESI) m / z: 421 (M+H) + .

[0835] Step 9: Synthesis of B10

[0836] At 0 °C, add TFA (4 mL) to a solution of B9 (2.0 g, 4.8 mmol) in DCM (20 mL) under a N 2 atmosphere. Stir the resulting mixture at room temperature for 6 h. Then concentrate the reaction mixture under reduced pressure. Dilute the residue with DCM (20 mL), and neutralize with NaHCO 3 (aqueous solution) until the pH is adjusted to pH = 8. Then extract the mixture with DCM (40 mL × 2). Wash the combined organic layers with brine (40 mL), dry over anhydrous Na 2 SO 4 dry and concentrate under reduced pressure. Purify the residue by flash column chromatography (eluting with 10 to 15% MeOH in DCM) to afford B10 as a pale yellow oil (1.3 g, 86% yield). LC / MS (ESI) m / z: 321 (M+H) + .

[0837] Step 10: Synthesis of B11

[0838] At 0 °C, add TEA (322 mg, 3.18 mmol) and N-methyl-1H-imidazole-1-carboxamide (796 mg, 6.36 mmol) to a solution of B10 (680 mg, 2.12 mmol) in MeCN (12 mL). Heat the resulting mixture to 50 °C and stir for 4 h. Then dilute the mixture with water (30 mL) and extract with EtOAc (20 mL x 2). Wash the combined organic layers with brine (30 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness under reduced pressure. Purify the residue by flash column chromatography (eluting with 0 to 50% EtOAc in PE) to afford B11 as a pale yellow oil (690 g, 86% yield). LC / MS (ESI) m / z: 378 (M+H) + .

[0839] Step 11: Synthesis of B12

[0840] A solution of B11 (690 mg, 1.83 mmol) in TFA (8 mL) was stirred at 80 °C for 4 h. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in DCM (20 mL) and neutralized with NaHCO 3 (saturated aqueous solution) until the pH was adjusted to pH = 8. The mixture was then diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 20 to 30% MeOH in DCM) to afford B12 (470 mg, 98% yield) as a pale yellow oil. LC / MS (ESI) m / z: 228 (M+H) + .

[0841] Step 3: Synthesis of Example 1 / B13

[0842] To a solution of B12 (470 mg, 1.80 mmol) in anhydrous THF (15 mL) at 0 °C was added TEA (364 mg, 3.60 mmol) and A5 (546 mg, 1.80 mmol). The resulting mixture was stirred at 50 °C under N 2 atmosphere for 18 h. The mixture was then diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 6% MeOH in DCM) to afford racemic-Example 1 / B13 (292 mg, 35% yield) as a white solid. LC / MS (ESI) m / z: 463 (M+H) + . This material (200 mg, 0.43 mmol) was further separated by SFC (SHIMADZU preparative solution SFC; ChiralCel OX, 250×21.2 mm I.D., 5 μm; OZ-M-D-20-8MIN) to afford Example 1 / B13 (76 mg, 38% yield, 100% enantiomeric excess) as a white solid. 1 H NMR (400 MHz, CD 3OD) δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 2H), 4.50 - 4.37 (m, 2H), 4.07 (d, J = 9.9 Hz, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.74 - 3.61 (m, 1H), 3.49 - 3.39 (m, 2H), 3.08 (s, 1H), 2.70 (s, 3H), 2.59 - 2.49 (m, 1H), 2.44 - 2.34 (m, 1H), 1.94 - 1.78 (m, 2H), 1.77 - 1.64 (m, 1H), 1.00 - 0.89 (m, 2H), 0.80 - 0.68 (m, 2H). 1 9 F NMR (377 MHz, CD 3 OD) δ -59.78 (s), -117.03 (s).

[0843] Synthesis of Example 2 / C10

[0844]

[0845] Step 1: Synthesis of C1

[0846] At 0 °C under N 2 atmosphere, TEA (4.0 g, 40.0 mmol) and NsCl (6.4 g, 29.1 mmol) were added to a solution of B7 (6.1 g, 26.5 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (150 mL) and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford C1 (6.5 g, 59% yield) as a white solid. LC / MS (ESI) m / z: 360 (M + H - 56) + .

[0847] Step 2: Synthesis of C2

[0848] At 0 °C, allyl bromide (3.8 g, 31.4 mmol) was added portionwise to a mixture of C1 (6.5 g, 15.7 mmol) and K 2 CO 3 (4.3 g, 31.4 mmol) in DMF (100 mL) and the resulting mixture was stirred at room temperature under N 2Stir for 18 h under [atmosphere]. Then filter the mixture and wash with DCM (50 mL x 2). Dilute the filtrate with water (150 mL) and extract with DCM (100 mL x 2). Wash the combined organic layers with brine (100 mL), dry over anhydrous Na 2 SO 4 and concentrate to dryness under reduced pressure. Purify the residue by flash column chromatography (eluting with 0 to 5% MeOH in DCM) to afford C2 as a yellow oil (6.5 g, 91% yield). LC / MS (ESI) m / z: 400 (M+H-56) + .

[0849] Step 3: Synthesis of C3

[0850] To a solution of C2 (6.5 g, 14.3 mmol) in MeCN (120 mL) was added K 2 CO 3 (9.9 g, 71.5 mmol) and benzenethiol (8.9 g, 71.5 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 18 h. Then dilute the mixture with water (150 mL) and extract with DCM (100 mL × 2). Wash the combined organic layers with brine (100 mL), dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure. Purify the residue by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford C3 as a pale yellow oil (3.1 g, 83% yield). LC / MS (ESI) m / z: 271 (M+H) + .

[0851] Step 4: Synthesis of C4

[0852] A mixture of C3 (3.1 g, 11.5 mmol), (1-ethoxycyclopropoxy)trimethylsilane (4.0 g, 23.0 mmol), AcOH (6.9 g, 115 mmol) and NaBH 3 CN (2.2 g, 34.5 mmol) in a solution of THF / EtOH (90 mL, volume / volume = 2:1) was stirred at 80 °C under N 2 atmosphere for 4 h. Then neutralize the mixture with NaHCO 3 (saturated aqueous solution) until the pH is adjusted to pH = 8. Dilute the mixture with water (60 mL) and extract with EtOAc (40 mL x 2). Wash the combined organic layers with brine (40 mL), dry over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. Purify the residue by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford C4 as a colorless oil (3.2 g, 90% yield). LC / MS (ESI) m / z: 311 (M+H) + .

[0853] Step 5: Synthesis of C5

[0854] At 0 °C under N 2 atmosphere, to a solution of C4 (1.6 g, 5.1 mmol) in DCM (30 mL) was added 1,3-dimethylbarbituric acid (1.2 g, 7.6 mmol) and Pd(PPh 3 ). 4 (596 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 1 h. Then the mixture was diluted with water (40 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness under reduced pressure. Purify the residue by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to afford C5 as a yellow oil (1.2 g, 85% yield). LC / MS (ESI) m / z: 271 (M+H) + .

[0855] Step 6: Synthesis of C6

[0856] At 0 °C to a solution of C5 (1.2 g, 4.4 mmol) in anhydrous THF (30 mL) was added TEA (897 mg, 8.8 mmol) and A5 (22 mg, 0.12 mmol). The resulting mixture was stirred at 60 °C under N 2 atmosphere for 3 h. Then the mixture was diluted with water (40 mL) and extracted with EtOAc (30 mLx2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness under reduced pressure. Purify the residue by flash column chromatography (eluting with 0 to 5% MeOH in DCM) to afford C6 as a colorless oil (1.23 g, 54% yield). LC / MS (ESI) m / z: 506 (M+H) + .

[0857] Step 7: Synthesis of C7

[0858] To a solution of C6 (1.23 g, 2.4 mmol) in anhydrous DCM (30 mL) at 0 °C was added TEA (737 mg, 7.2 mmol) and MsCl (334 mg, 2.8 mmol). The resulting mixture was stirred at 0 °C under N 2 atmosphere for 2 h. Then the mixture was quenched with water (40 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 5% MeOH in DCM) to afford C7 (1.2 g, 84% yield) as a colorless oil. LC / MS (ESI) m / z: 584 (M+H) + .

[0859] Step 8: Synthesis of C8

[0860] To a solution of C7 (1.2 g, 2.0 mmol) in DMF (16 mL) at room temperature was added NaCN (121 mg, 2.4 mmol). The resulting mixture was stirred at 90 °C under N 2 atmosphere for 2 h. Then the mixture was diluted with saturated NH 4 4Cl solution (50 mL) and extracted with EtOAc (30 mL x2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 5% MeOH in DCM) to afford C8 (1.0 g, 95% yield) as a white solid. LC / MS (ESI) m / z: 515 (M+H) + . C8 (1.0 g, 1.9 mmol) was further separated by SFC (Waters Thar 80 preparative SFC; ChiralPak AD, 250×4.6 mm ID 5 μm; AD_MeOH_DEA_40) to give C8-P1 (390 mg, 39% yield, 99% enantiomeric excess) and C8-P2 (450 mg, 45% yield, 99% enantiomeric excess) as white solids. LC / MS (ESI) m / z: 515 (M+H) + .

[0861] Step 9: Synthesis of C9

[0862] To a solution of C8-P2 (40 mg, 78 μmol) in DCM (3 mL) at 0 °C was added dropwise TFA (1 mL). The resulting mixture was stirred at 0 °C under N2 Stir for 1 hour under an atmosphere. Then concentrate the mixture under reduced pressure to obtain crude C9 as a purple oil (30 mg, 93% yield), which is used directly in the next step without further purification. LC / MS (ESI) m / z: 415 (M+H) + .

[0863] Step 10: Synthesis of Example 2 / C10

[0864] Add TMSNCO (12 mg, 0.1 mmol) dropwise to a mixture of C9 (30 mg, 72 μmol) and DIEA (19 mg, 0.14 mmol) in anhydrous THF (5 mL) at 0 °C. Stir the resulting mixture at room temperature under N 2 atmosphere for 16 hours. Then dilute the mixture with water (30 mL) and extract with EtOAc (20 mL x 2). Wash the combined organic layers with brine (20 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness under reduced pressure. Purify the residue by preparative HPLC to obtain Example 2 / C10 as a white solid (18 mg, 54% yield). LC / MS (ESI) m / z: 458 (M+H) + . 1 1H NMR (400 MHz, MeOD) δ 7.46 - 7.40 (m, 1H), 7.12 - 7.05 (m, 2H), 6.98 (t, J = 5.9 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.15 - 4.05 (m, 1H), 3.93 - 3 - 83 (m, 1H), 3.74 - 3.64 (m, 1H), 3.25 - 3.17 (m, 1H), 2.59 - 2.54 (m, 1H), 2.52 - 2.41 (m, 3H), 2.08 - 1.96 (m, 2H), 1.95 - 1.86 (m, 1H), 0.99 - 0.91 (m, 2H), 0.81 - 0.73 (m, 2H). 19 19F NMR (377 MHz, MeOD) δ -59.78 (s), -117.01 (s).

[0865] Synthesis of Example 3 / D5

[0866]

[0867] Step 1: Synthesis of D1

[0868] At 0 °C, under N 2Under an atmosphere, NaH (32 mg, 1.3 mmol) was added portionwise to a solution of B9 (365 mg, 0.87 mmol) in anhydrous DMF (8 mL). The mixture was stirred at 0 °C for 30 min, and then MeI (71 mg, 0.96 mmol) was added dropwise to the above mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for 4 h. Then the mixture was quenched with saturated NH 4 Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography (eluting with 30 to 35% EtOAc in PE) to give D1 as a colorless oil (299 mg, 79% yield). LC / MS (ESI) m / z: 435 (M+H) + .

[0869] Step 2: Synthesis of D2

[0870] TFA (2 mL) was added dropwise to a solution of D1 (299 mg, 0.69 mmol) in DCM (8 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Then the mixture was concentrated in vacuo to give crude D2 as a purple oil (205 mg, 89% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 335 (M+H) + .

[0871] Step 3: Synthesis of D3

[0872] TMSNCO (91 mg, 0.79 mmol) was added dropwise to a mixture of D2 (205 mg, 0.61 mmol) and DIEA (155 mg, 1.2 mmol) in anhydrous DCM (10 mL) under N 2 atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography (eluting with 20 to 25% MeOH in DCM) to give D3 as a pale yellow oil (177 mg, 76% yield). LC / MS (ESI) m / z: 378 (M+H) + .

[0873] Step 4: Synthesis of D4

[0874] D3 (177 mg, 0.47 mmol) and TFA (4 mL) were charged into a round-bottom flask, and the reaction mixture was stirred at 80 °C under N 2 atmosphere for 2 h. Then the mixture was concentrated under reduced pressure to afford crude D4 (104 mg, quantitative) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 228 (M+H) + .

[0875] Step 5: Synthesis of Example 3 / D5

[0876] To a mixture of D4 (104 mg, 0.46 mmol) and TEA (70 mg, 0.69 mmol) in anhydrous THF (6 mL) at 0 °C was added A5 (139 mg, 0.46 mmol). The resulting mixture was stirred at 60 °C for 4 h. Then the mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to afford racemic-Example 3 / D5 (146 mg, 69% yield) as a white solid. LC / MS (ESI) m / z: 463 (M+H) + . The material (146 mg, 0.32 mmol) was further separated by SFC (Waters Thar 80 preparative SFC; ChiralPak IB, 100 × 4.6 mm I.D. 5 μm; IB_EtOH_DEA_20) to obtain Example 3 / D5 (46 mg, 32% yield, 100% enantiomeric excess) as a white solid. 1 1H NMR (400 MHz, MeOD) δ 7.44 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.7 Hz, 2H), 4.44 (s, 2H), 4.07 (d, J = 12.3 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.68 (d, J = 4.1 Hz, 1H), 3.33 (s, 3H), 3.30 - 3.24 (m, 2H), 3.21 - 3.12 (m, 1H), 2.59 - 2.51 (m, 1H), 2.49 - 2.39 (m, 1H), 1.89 (d, J = 7.2 Hz, 3H), 0.97 - 0.91 (m, 2H), 0.81 - 0.70 (m, 2H). 19 19F NMR (377 MHz, MeOD) δ -59.78 (s), -117.04 (s).

[0877] Synthesis of Example 4 / E14

[0878]

[0879] Step 1: Synthesis of E2

[0880] To a mixture of TEA (16 mL, 116 mmol) and E1 (10.0 g, 46.2 mmol) in DCM (100 mL) at 0 °C was added Cbz-OSu (17.3 g, 69.4 mmol) portionwise. The resulting mixture was warmed to room temperature and stirred for 20 h. The mixture was diluted with H 2 O (300 mL) and extracted with DCM (400 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:3) to afford E2 (15.9 g, 98% yield) as a white solid. LC / MS (ESI) m / z: 295 (M+H-56) + .

[0881] Step 2: Synthesis of E3

[0882] To a solution of E2 (8.0 g, 22.8 mmol) in anhydrous DCM (80 mL) at 0 °C was added Dess-Martin periodinane (19.4 g, 45.7 mmol) portionwise. The resulting mixture was stirred at room temperature for 2 h. Then the mixture was quenched with saturated NaHCO 3 (aqueous solution) (200 mL) and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:2) to afford E3 (7.9 g, 99% yield) as a white solid. LC / MS (ESI) m / z: 249 (M+H-100) + .

[0883] Step 3: Synthesis of E4

[0884] To a solution of trimethyl phosphonoacetate (4.0 mL, 27.2 mmol) in anhydrous THF (100 mL) at 0 °C was added NaHH (1.1 g, 27.2 mmol) portionwise. At 0 °C under N 2The reaction mixture was stirred for 30 min under the atmosphere. Then a solution of E3 (7.9 g, 22.7 mmol) in THF (50 mL) was added to the above mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for an additional 16 h. Then the mixture was quenched with saturated NH 4 Cl (200 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc = 100:0 to 100:35) to afford E4 (7.2 g, 79% yield) as a colorless oil. LC / MS (ESI) m / z: 304 (M+H-l00) + .

[0885] Step 4: Synthesis of E5

[0886] To a mixture of E4 (7.2 g, 17.8 mmol) and K 2 CO 3 (2.5 g, 17.8 mmol) in DMSO (100 mL) was added nitromethane (10.8 g, 178 mmol). The resulting mixture was stirred at 100 °C under N 2 atmosphere for 16 h. Then the mixture was diluted with H 2 O (300 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE:EtOAc = 100:0 to 100:25) to afford E5 (3.8 g, 46% yield) as a colorless oil. LC / MS (ESI) m / z: 366 (M+H-100) + .

[0887] Step 5: Synthesis of E6

[0888] To a solution of E5 (3.8 g, 8.0 mmol) in EtOH (100 mL) at 0 °C was added nickel chloride (10.4 g, 80.1 mmol) and NaBH 4 (3.0 g, 80.1 mmol) portionwise. The resulting mixture was stirred at room temperature for 2 h. Then the mixture was quenched with saturated NH 4 Cl (aqueous solution) (150 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2 SO 4 Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by silica gel column chromatography (DCM:MeOH = 100:0 to 100:4) to obtain E6 as a colorless oil (2.2 g, 68% yield). LC / MS (ESI) m / z: 304 (M+H-100) + 。

[0889] Step 6: Synthesis of E7

[0890] Add Pd / C (10 wt%) (440 mg) to a solution of E6 (2.2 g, 5.5 mmol) in MeOH (30 mL) and degas the mixture three times under N 2 atmosphere. Stir the resulting mixture under H 2 atmosphere at 20 psi for 2 h at room temperature. Then dilute the mixture with DCM (100 mL) and filter through a pad, washing the cake with MeOH (25 mL). Dry the combined filtrate over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness to obtain crude E7 as a colorless oil (1.4 g, 95% yield), which is used directly in the next step without further purification. LC / MS (ESI) m / z: 270 (M+H) + 。

[0891] Step 7: Synthesis of E8

[0892] Add AcOH (614 mg, 10.4 mmol) to a mixture of E7 (1.4 g, 5.2 mmol) and 2,4-dimethoxybenzaldehyde (860 mg, 5.2 mmol) in DCM (50 mL) and stir the mixture at room temperature for 1 h. Then cool the reaction mixture to 0 °C and add NaBH(OAc) 3 (3.3 g, 15.5 mmol) portionwise to the above mixture. Stir the resulting mixture at room temperature for 16 h. After completion, concentrate the reaction mixture under reduced pressure to dryness. Purify the residue by flash silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 100:10) to obtain E8 as a colorless oil (2.1 g, 96% yield). LC / MS (ESI) m / z: 420 (M+H) + 。

[0893] Step 8: Synthesis of E9

[0894] To a mixture of E8 (2.1 g, 5.0 mmol) and AcOH (3 mL, 54.4 mmol) in EtOH (20 mL) and THF (40 mL) was added (1-ethoxycyclopropoxy)trimethylsilane (3 mL, 13.6 mmol) and NaBH 3 CN (1.2 g, 19.0 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 3 h. Then the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (80 mL) and washed with saturated NaHCO 3 (aqueous solution) (80 mL). The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:5) to afford E9 (2.1 g, 91% yield) as a colorless oil. LC / MS (ESI) m / z: 460 (M+H) + .

[0895] Step 9: Synthesis of E10

[0896] To a solution of E9 (2.1 g, 4.6 mmol) in DCM (20 mL) at 0 °C was added dropwise TFA (5 mL), and the resulting mixture was stirred at room temperature for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude E10 (1.6 g, quantitative) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 360 (M+H) + .

[0897] Step 10: Synthesis of E11

[0898] To a mixture of E10 (1.6 g, 4.5 mmol) and DIEA (3.0 mL, 20.8 mmol) in anhydrous MeCN (80 mL) was added N-methyl-1H-imidazole-1-carboxamide (3.3 g, 26.0 mmol). The resulting mixture was stirred at 60 °C for 16 h. Then the mixture was diluted with H 2 O (150 mL) and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column chromatography (eluting with DCM:MeOH = 100:0 to 100:8) to afford E11 (1.6 g, 86% yield) as a colorless oil. LC / MS (ESI) m / z: 417 (M+H)+ .

[0899] Step 11: Synthesis of E12

[0900] Charge E11 (1.6 g, 3.8 mmol) and TFA (20 mL) into a round-bottom flask, and stir the reaction mixture at 80 °C under N 2 atmosphere for 4 hours. Then concentrate the mixture under reduced pressure to obtain crude E12 (980 mg, quantitative) as a purple oil, which is used directly in the next step without further purification. LC / MS (ESI) m / z: 267 (M+H) + .

[0901] Step 12: Synthesis of Example 4 / E14

[0902] At 0 °C under N 2 atmosphere, add dropwise a solution of E13 (282 mg, 1.2 mmol) in DCM (5 mL) to a mixture of E12 (310 mg, 1.2 mmol) and TEA (0.7 mL, 4.8 mmol) in anhydrous DCM (12 mL). Stir the resulting mixture at room temperature for 30 min. Then dilute the mixture with H 2 O (30 mL), and extract with DCM (20 mL×2). Wash the combined organic layers with brine (30 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness under reduced pressure. Purify the residue by flash column chromatography on silica gel (eluting with DCM:MeOH = 100:0 to 100:15) to obtain racemic-Example 4 / E14 (330 mg). LC / MS (ESI) m / z: 502 (M+H) + . Further separate this sample by SFC (ChiralCel OZ, 250×21.2 mm I.D., 5 μm; mobile phase: A is CO 2 and B is MeOH + 0.1% NH 3 H 2 O; B%: 40% - 40%, 4.0 min; 120 min) to obtain Example 4 / E14 (98 mg, 17% yield) as a white solid. 11H NMR (400 MHz, MeOD) δ 7.49 - 7.41 (m, 1H), 7.16 - 7.07 (m, 2H), 4.51 - 4.39 (m, 2H), 4.09 - 4.02 (m, 1H), 3.97 - 3.88 (m, 1H), 3.80 - 3.67 (m, 1H), 3.22 - 3.14 (m, 3H), 2.72 (s, 3H), 2.66 - 2.60 (m, 1H), 2.59 - 2.53 (m, 1H), 2.38 - 2.31 (m, 1H), 2.30 - 2.21 (m, 2H), 1.94 - 1.86 (m, 1H), 1.02 - 0.95 (m, 2H), 0.82 - 0.75 (m, 2H). 19 19F NMR (377 MHz, MeOD) δ -59.77 (s), -116.97 (s).

[0903] Synthesis of Example 5 / F17

[0904]

[0905] Step 2: Synthesis of F1

[0906] At 0 °C, under N 2 atmosphere, BH 3 -THF (65.3 mL, 1 M in THF) was added dropwise to a solution of B4 (7.5 g, 26.1 mmol) in anhydrous THF (100 mL). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was slowly poured into ice water (150 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 5% MeOH in DCM) to afford F1 as a colorless oil (4.8 g, 67% yield). LC / MS (ESI) m / z: 274 (M+H) + .

[0907] Step 3: Synthesis of F2

[0908] At 0 °C, TEMPO (375 mg, 1.76 mmol) was added to a solution of F1 (4.8 g, 17.6 mmol) in DCM (60 mL)

[0909] and PhI(OAc) 2(8.54 g, 26.3 mmol). The resulting mixture was stirred at room temperature for 4 h. Then the mixture was diluted with water (120 mL) and extracted with DCM (80 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 40% EA in PE) to afford F2 as a yellow oil (4.3 g, 90% yield). LC / MS (ESI) m / z: 272 (M+H) + .

[0910] Step 4: Synthesis of F3

[0911] To a mixture of methoxymethylenetriphenylphosphonium chloride (5.6 g, 16.4 mmol) in anhydrous THF (70 mL) at 0 °C was added t-BuOK (15.3 mL, 1 M in THF), and the mixture was stirred at 0 °C under N 2 atmosphere for 30 min. Then a solution of F2 (2.96 g, 10.9 mmol) in THF (70 mL) was added to the above mixture at 0 °C under N 2 atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. Then the mixture was diluted with water (120 mL) and extracted with EtOAc (70 mL x 2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 10% EA in PE) to afford F3 as a yellow oil (2.5 g, 76% yield). LC / MS (ESI) m / z: 300 (M+H) + .

[0912] Step 5: Synthesis of F4

[0913] To a solution of F3 (3.9 g, 13 mmol) in acetone (60 mL) was added PPTS (6.55 g, 26 mmol). The resulting mixture was stirred at 50 °C for 24 h. Then the mixture was diluted with water (120 mL) and extracted with EtOAc (70 mL x 2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness under reduced pressure. This residue was dissolved in THF (60 mL), and at 0 °C, NaBH 4(696 mg, 18.4 mmol) was added portionwise to the above solution. The resulting mixture was stirred at 0 °C for 20 min. Then the mixture was quenched with water (100 mL) and extracted with EtOAc (70 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 to 4% MeOH in DCM) to afford F4 as a yellow oil (2.7 g, 76% yield). LC / MS (ESI) m / z: 288 (M+H) + .

[0914] Step 6: Synthesis of F5

[0915] To a mixture of F4 (2.7 g, 9.4 mmol) and TEA (3.9 mL, 28.2 mmol) in DCM (50 mL) at 0 °C was added DMAP (574 mg, 4.7 mmol) and TBDPSCl (3.2 mL, 12.2 mmol). The resulting mixture was stirred at room temperature for 18 h. Then the mixture was diluted with water (120 mL) and extracted with DCM (80 mL×2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography (eluting with 0 to 7% EtOAc in PE) to afford F5 as a colorless oil (3.4 g, 69% yield). LC / MS (ESI) m / z: 526 (M+H) + .

[0916] Step 7: Synthesis of F6

[0917] To a solution of F5 (3.4 g, 6.5 mmol) in MeOH (50 mL) at 0 °C was added 2 M NaOH (6.5 mL, 13 mmol, aqueous solution). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (100 mL) and extracted with TBME (100 mL). The aqueous layer was separated, adjusted to pH = 4 with HCl (1 N) aqueous solution and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude F6 as a white solid (2.4 g, 70% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 512 (M+H).

[0918] Step 8: Synthesis of F7

[0919] At 0 °C, DPPA (1.3 mL, 6.1 mmol) and TEA (1.96 mL, 14.1 mmol) were added to a solution of F6 (2.4 g, 4.7 mmol) in toluene (50 mL). The resulting mixture was stirred at 110 °C under N 2 atmosphere for 2 h. Then, BnOH (1.45 mL, 14.1 mmol) was added to the above mixture at 0 °C. The resulting mixture was stirred at 90 °C under N 2 atmosphere for another 6 h. After cooling to room temperature, the mixture was diluted with water (120 mL) and extracted with EtOAc (70 mL x 2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 18% EtOAc in PE) to give F7 (1.6 g, 55% yield) as a white solid. LC / MS (ESI) m / z: 517 (M+H-100) + .

[0920] Step 9: Synthesis of F8

[0921] At room temperature, Pd / C (0.4 g, 10 wt%) was added to a solution of F7 (1.6 g, 2.6 mmol) in i-PrOH (40 mL). The resulting mixture was stirred at room temperature under H 2 atmosphere at 20 psi for 4 h. Then the mixture was filtered through a pad, and the filter cake was washed with MeOH (40 mL). The combined filtrates were concentrated to dryness to give crude F8 (1.2 g, 96% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 483 (M+H) + .

[0922] Step 10: Synthesis of F9

[0923] At 0 °C under N 2 atmosphere, NsCl (580 mg, 2.63 mmol) was added portionwise to a mixture of F8 (1.2 g, 2.5 mmol) and TEA (1 mL, 7.5 mmol) in anhydrous DCM (50 mL). The resulting mixture was stirred at room temperature for 7 h. Then the mixture was diluted with water (80 mL) and extracted with DCM (50 mL×2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 22% EtOAc in PE) to give F9 as a yellow solid (1.4 g, 84% yield). LC / MS (ESI) m / z: 668 (M+H) + .

[0924] Step 11: Synthesis of F10

[0925] To a mixture of F9 (1.4 g, 2.1 mmol) and CO 3 (869 mg, 6.3 mmol) in DMF (40 mL) at 0 °C was added dropwise allyl bromide (0.27 mL, 3.1 mmol) and the resulting mixture was stirred at room temperature under N 2 atmosphere for 18 h. Then the mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 18% EtOAc in PE) to give F10 as a yellow oil (1.4 g, 94% yield). LC / MS (ESI) m / z: 652 (M+H-56) + .

[0926] Step 12: Synthesis of F11

[0927] To a solution of F10 (1.4 g, 1.84 mmol) in MeCN (50 mL) was added K 2 CO 3 (2.54 g, 18.4 mmol) and benzenethiol (1.1 g, 9.2 mmol). The resulting mixture was stirred at 70 °C under N 2 atmosphere for 18 h. Then the mixture was diluted with water (80 mL) and extracted with DCM (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to give F11 as a pale yellow oil (875 mg, 91% yield). LC / MS (ESI) m / z: 523 (M+H) + .

[0928] Step 13: Synthesis of F12

[0929] To a mixture of F11 (875 mg, 1.67 mmol) and AcOH (0.96 mL, 16.7 mmol) in THF / EtOH (48 mL, volume / volume = 2:1) was added (1-ethoxycyclopropoxy)trimethylsilane (870 mg, 5.01 mmol) and NaBH 3 CN (316 mg, 5.01 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 4 h. Then the mixture was basified with NaHCO 3 solution (saturated aqueous solution) until the pH was adjusted to pH = 8. The mixture was diluted with water (80 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography (eluting with 0 to 3% MeOH in DCM) to afford F12 (730 mg, 77% yield) as a colorless oil. LC / MS (ESI) m / z: 563 (M+H) + .

[0930] Step 14: Synthesis of F13

[0931] To a solution of F12 (330 mg, 0.6 mmol) in DCM (10 mL) at 0 °C under N 2 atmosphere was added dropwise TFA (2 mL). The resulting mixture was stirred at room temperature for 2 h. Then the reaction mixture was concentrated in vacuo to afford crude F13 (270 mg, quantitative) as a brown oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 463 (M+H) + .

[0932] Step 15: Synthesis of F14

[0933] To a mixture of F13 (270 mg, 0.58 mmol) and TEA (0.24 mL, 1.75 mmol) in anhydrous DCM (15 mL) at 0 °C under N 2 atmosphere was added dropwise 2,5-dioxopyrrolidin-1-ylmethyl carbamate (150 mg, 0.87 mmol). The resulting mixture was stirred at room temperature for 1 h. Then the mixture was diluted with water (50 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 5% MeOH in DCM) to afford F14 as a colorless oil (235 mg, 77% yield). LC / MS (ESI) m / z: 520 (M+H) + .

[0934] Step 16: Synthesis of F15

[0935] At 0 °C, to a solution of F14 (235 mg, 0.45 mmol) in DCM (14 mL) was added 1,3-dimethylbarbituric acid (141 mg, 0.9 mmol) and Pd(PPh 3 ) 4 (104 mg, 0.09 mmol). The resulting mixture was stirred at room temperature under N 2 atmosphere for 2 h. Then the mixture was concentrated to afford crude F15 as an orange oil (226 mg, quantitative), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 480 (M+H) + .

[0936] Step 17: Synthesis of F16

[0937] At room temperature under N 2 atmosphere, to a mixture of F15 (226 mg, 0.47 mmol) and TEA (0.2 mL, 1.41 mmol) in THF (15 mL) was added A5 (150 mg, 0.5 mmol). The resulting mixture was stirred at 60 °C for 4 h. Then the mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 3% MeOH in DCM) to afford F16 as a white solid (315 mg, 94% yield). LC / MS (ESI) m / z: 737 (M+Na) + .

[0938] Step 18: Synthesis of Example 5 / F17

[0939] To a solution of 21 (315 mg, 0.44 mmol) in THF (15 mL) was added TBAF (230 mg, 0.88 mmol). The resulting mixture was stirred at room temperature for 1 h. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2 SO 4 Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 8% MeOH in DCM) to afford racemic-Example 5 as a white solid (155 mg, 74% yield). LC / MS (ESI) m / z: 477 (M+H) + . Further separate the material (155 mg, 0.33 mmol) by SFC (Waters Thar 80 preparative SFC; ChiralCel OX, 250×20 mm I.D., 5 μm; 40 mL / min) to obtain Example 5 / (65 mg, 31% yield, 99% enantiomeric excess). 1 H NMR (400 MHz, CD 3 OD) δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 2H), 4.44 (d, J = 4.7 Hz, 2H), 4.02 - 3.94 (m, 1H), 3.91 - 3.82 (m, 1H), 3.69 - 3.58 (m, 3H), 3.16 - 3.08 (m, 1H), 2.69 (d, J = 3.9 Hz, 3H), 2.58 - 2.50 (m, 1H), 2.33 (dd, J = 13.1, 11.4 Hz, 1H), 1.95 (d, J = 12.1 Hz, 1H), 1.79 (q, J = 11.9 Hz, 1H), 1.71 - 1.60 (m, 1H), 1.58 - 1.37 (m, 2H), 1.00 - 0.88 (m, 2H), 0.81 - 0.70 (m, 2H). 19 F NMR (376 MHz, CD 3 OD) δ -59.71--59.83 (m), -117.01 (d, J = 4.2 Hz).

[0940] Synthesis of Example 6 / G12

[0941]

[0942] Step 1: Synthesis of G2

[0943] Add NIS (46.7 g, 207.6 mmol) portionwise to a solution of G1 (30.0 g, 207.6 mmol) in TFA (300 mL) at 0 °C. Stir the resulting mixture at room temperature for 16 h. Then concentrate the mixture under reduced pressure, dissolve the residue in DCM (600 mL) and wash with aqueous NaHCO 3 solution (400 mL * 2) and brine (400 mL), over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography on silica gel (eluting with PE:EtOAc = 100:0 to 95:5) to afford G2 as a white solid (36.0 g, 64% yield). 1 1H NMR (400 MHz, MeOD) δ 7.72 (dd, J = 6.8, 0.4 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 2.30 (s, 3H).

[0944] Step 2: Synthesis of G3

[0945] To a solution of G2 (27 g, 99.8 mmol) in anhydrous DMF (270 mL) was added Zn(CN) 2 (12.9 g, 109.8 mmol), followed by the addition of Pd(PPh 3 ) 4 (5.7 g, 4.9 mmol). The resulting mixture was stirred at 100 °C under N 2 atmosphere for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (400 mL) and filtered. The filtrate was washed twice with aqueous saturated NH 4 Cl (200 mL). Then the organic layer was separated, washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to dryness. Purify the residue by flash column chromatography on silica gel (eluting with PE:EtOAc = 100:0 to 95:5) to afford G3 as a white solid (10.0 g, 59.1% yield).

[0946] Step 3: Synthesis of G4

[0947] To a solution of G3 (10 g, 58.9 mmol) in anhydrous THF (100 mL) at 0 °C was added dropwise BH 3 -THF (295 mL, 1 M in THF). The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 h. LCMS showed complete consumption of the starting material. Then the mixture was quenched dropwise with MeOH (80 mL) and concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (150 mL) and washed with aqueous HCl (100 mL, 1 N). The aqueous layer was separated, basified to pH = 10 with 15% aqueous NaOH. Then the mixture was extracted with EtOAc (100 mL * 3), the combined organic layers were separated, washed with brine (100 mL), dried over Na 2 SO 4Dry, filter and concentrate under reduced pressure to obtain crude G4 as a colorless oil (5.5 g, 53.4% yield), which is used directly in the next step without further purification. LCMS: ESI m / z: 174 (M+H) + 。

[0948] Step 4: Synthesis of G5

[0949] To a solution of G4 (36 mg, 0.21 mmol) in THF (3 mL) at 0 °C was added CDI (36 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 50 min. Then the mixture was concentrated under reduced pressure to obtain crude G5 as a colorless oil (55 mg, 98.99% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 268 (M+H) + 。

[0950] Step 5: Synthesis of G7

[0951] To a solution of G6 (400 mg, 1.85 mmol) in DCM (20 mL) was added 2,4-dimethoxybenzaldehyde (338 mg, 2.04 mmol), NaBH(OAc) 3 (785 mg, 3.70 mmol) and AcOH (catalyst). The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 h. Then the mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to obtain G7 as a white solid (550 mg, 81% yield). LC / MS (ESI) m / z: 367 (M+H) + 。

[0952] Step 6: Synthesis of G8

[0953] To a mixture of G7 (550 mg, 1.50 mmol) and AcOH (1.35 g, 22.5 mmol) in THF / EtOH (30 mL, volume / volume = 1:1) was added (1-ethoxycyclopropoxy)trimethylsilane (915 mg, 5.26 mmol) and NaBH 3 CN (284 mg, 4.51 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 2 h. The mixture was treated with saturated NaHCO 3The solution was alkalized to pH = 8 and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 100% EtOAc in PE) to afford G8 as a white solid (450 mg, 74% yield). LC / MS (ESI) m / z: 407 (M+H) + 。

[0954] Step 7: Synthesis of G9

[0955] To a solution of G8 (450 mg, 1.11 mmol) in DCM (20 mL) at 0 °C was added dropwise TFA (4 mL). The resulting mixture was stirred at room temperature under N 2 atmosphere for 2 h. Then the mixture was alkalized with saturated NaHCO 3 solution to adjust the pH = 8 and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to afford G9 as a yellow oil (285 mg, 84% yield). LC / MS (ESI) m / z: 307 (M+H) + 。

[0956] Step 8: Synthesis of G10

[0957] To a solution of G9 (285 mg, 0.93 mmol) in DCM (15 mL) at 0 °C was added dropwise TEA (282 mg, 2.79 mmol) and 2,5-dioxopyrrolidin-1-ylmethyl carbamate (320 mg, 1.86 mmol). The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 h. Then the mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to afford G10 as a white solid (250 mg, 74% yield). LC / MS (ESI) m / z: 364 (M+H) + 。

[0958] Step 9: Synthesis of G11

[0959] A solution of G10 (250 mg, 0.69 mmol) in TFA (10 mL) was stirred at 80 °C under a nitrogen 2 atmosphere for 2 h. The mixture was then basified with saturated NaHCO 3 solution to adjust the pH to 8 and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to afford G11 as a yellow oil (120 mg, 82% yield). LC / MS (ESI) m / z: 214 (M+H) + .

[0960] Step 10: Synthesis of Example 6 / G12

[0961] To a mixture of G11 (40 mg, 0.19 mmol) and TEA (57 mg, 0.56 mmol) in MeCN (10 mL) at room temperature was added G5 (150 mg, 0.28 mmol). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 h. The mixture was then quenched with NH 4 Cl (20 mL, saturated aqueous solution) and extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to afford Example 6 / G12 as a white solid (8 mg, 10% yield). LC / MS (ESI) m / z: 413 (M+H) + . 1 1H NMR (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.90 (t, J = 5.9 Hz, 1H), 4.42 - 4.31 (m, 2H), 4.17 - 4.06 (m, 1H), 3.83 - 3.74 (m, 1H), 3.73 - 3.63 (m, 1H), 3.60 - 3.45 (m, 1H), 3.11 - 3.02 (m, 1H), 2.69 (s, 3H), 2.55 - 2.48 (m, 1H), 2.46 - 2.36 (m, 1H), 2.32 (s, 3H), 2.14 (d, J = 11.4 Hz, 1H), 2.09 - 1.97 (m, 1H), 1.00 - 0.88 (m, 2H), 0.80 - 0.70 (m, 2H). 1 919F NMR (376 MHz, MeOD) δ -123.11 (s).

[0962] Synthesis of Example 7 / H1

[0963]

[0964] Step 1: Synthesis of Example 7 / H1

[0965] At 0 °C, Meerwein’s salt (24 mg, 0.16 mmol) and proton sponge (46.4 mg, 0.22 mmol) were added to a solution of racemic-B13 (50 mg, 0.11 mmol) in anhydrous DCM (6 mL). The resulting mixture was stirred at room temperature under a N 2 atmosphere for 48 h. The mixture was then diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 2SO 4 4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to afford racemic-Example 7 / H1 as a white solid (13 mg, 25% yield). LC / MS (ESI) m / z: 477 (M+H) + . The material (13 mg, 0.027 mmol) was further separated by SFC (SHIMADZU preparative solution SFC; ChiralCel OZ, 250×21.2 mm I.D., 5 μm; OZ-M-D-20-8MIN) to give Example 7 / H1 as a white solid (4.0 mg, 31% yield, 100% enantiomeric excess). 1 1H NMR (400 MHz, CD 3 3OD) δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 2H), 4.43 (s, 2H), 4.05 (d, J = 14.0 Hz, 1H), 3.88 (dd, J = 12.5, 4.0 Hz, 1H), 3.74 - 3.58 (m, 1H), 3.32 (s, 3H), 3.28 (t, J = 5.5 Hz, 2H), 3.16 - 3.02 (m, 1H), 2.70 (s, 3H), 2.57 - 2.50 (m, 1H), 2.40 (dd, J = 13.3, 10.8 Hz, 1H), 1.97 - 1.75 (m, 3H), 0.97 - 0.91 (m, 2H), 0.79 - 0.71 (m, 2H). 19 19F NMR (377 MHz, CD 3OD) δ -59.77 (s), -117.01 (s).

[0966] Synthesis of Example 8 / I1

[0967]

[0968] Step 1: Synthesis of Example 8 / I1

[0969] To a mixture of E13 (42 mg, 0.16 mmol) and TEA (162 mg, 1.60 mmol) in THF (6 mL) at 0 °C was added G5 (55 mg, 0.21 mmol). The resulting mixture was stirred at 60 °C under N 2 atmosphere for 16 h. Then the mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to dryness. The residue was purified by preparative HPLC to give Example 8 / 11 as a white solid (20.7 mg, 28% yield). LC / MS (ESI) m / z: 466 (M + H) + . 1 1H NMR (400 MHz, MeOD) δ 7.26 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 9.8 Hz, 1H), 6.98 - 6.88 (m, 1H), 4.46 - 4.33 (m, 2H), 4.12 - 4.01 (m, 1H), 3.96 - 3.86 (m, 1H), 3.82 - 3.68 (m, 1H), 3.32 - 3.30 (m, 0.5H), 3.24 - 3.18 (m, 1H), 3.18 - 3.15 (m, 1H), 3.15 - 3.09 (m, 0.5H), 2.72 (d, J = 0.9 Hz, 3H), 2.66 - 2.57 (m, 1H), 2.57 - 2.48 (m, 1H), 2.39 - 2.34 (m, 0.5H), 2.33 (s, 3H), 2.31 - 2.21 (m, 2H), 2.17 - 2.10 (m, 0.5H), 2.00 - 1.86 (m, 1H), 1.01 - 0.91 (m, 2H), 0.82 - 0.72 (m, 2H). 19 19F NMR (376 MHz, MeOD) δ -123.07 (d, J = 4.4 Hz).

[0970] Synthesis of Example 9 / J10

[0971]

[0972] Step 1: Synthesis of J1

[0973] Under a nitrogen atmosphere, Pd / C (260 mg, 10 wt%) was added to a solution of B5 (1.3 g, 3.3 mmol) in i-PrOH (30 mL). The suspension was degassed under vacuum and purged with H 2 several times. The resulting mixture was stirred at room temperature under an H 2 atmosphere of 20 psi for 16 hours. Then the mixture was filtered through a pad, and the filter cake was washed with MeOH (30 mL). The combined filtrates were concentrated to dryness to afford crude J1 (840 mg, 98% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 259 (M+H) + .

[0974] Step 2: Synthesis of J2

[0975] AcOH (396 mg, 6.6 mmol) and 2,4-dimethoxybenzaldehyde (531 mg, 3.2 mmol) were added to a solution of J1 (840 mg, 3.3 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature under an N 2 atmosphere for 1 hour. Then NaBH(OAc) 3 (2.1 g, 9.9 mmol) was added portionwise to the above mixture at 0 °C and the resulting mixture was stirred at room temperature under an N 2 atmosphere for an additional 3 hours. Then the mixture was filtered and rinsed with DCM (30 mL x 2). The filtrate was diluted with water (50 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford J2 (1.1 g, 83% yield) as a pale yellow oil. LC / MS (ESI) m / z: 409 (M+H) + .

[0976] Step 3: Synthesis of J3

[0977] (1-Ethoxycyclopropoxy)trimethylsilane (940 mg, 5.4 mmol) and NaBH 3CN (509 mg, 8.1 mmol). The resulting mixture was stirred at 80 °C under N 2 atmosphere for 4 h. Then the mixture was neutralized with NaHCO 3 (aqueous solution) until the pH was adjusted to pH = 8 and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 25 to 35% EtOAc in PE) to afford J3 (830 mg, 69% yield) as a colorless oil. LC / MS (ESI) m / z: 449 (M+H)+.

[0978] Step 4: Synthesis of J4

[0979] To a solution of J3 (830 mg, 1.85 mmol) in DCM (20 mL) at 0 °C was added dropwise TFA (4 mL). The resulting mixture was stirred at room temperature under N 2 atmosphere for 1 h. Then the mixture was concentrated under reduced pressure to afford crude J4 (572 mg, 89% yield) as a purple oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 349 (M+H) + .

[0980] Step 5: Synthesis of J5

[0981] At 0 °C under N 2 atmosphere, N-methyl-1H-imidazole-1-carboxamide (263 mg, 2.1 mmol) was added dropwise to a mixture of J4 (572 mg, 1.6 mmol) and TEA (646 mg, 6.4 mmol) in anhydrous DCM (20 mL). The resulting mixture was stirred at room temperature for 12 h. Then the mixture was diluted with water (50 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford J5 (606 mg, 91% yield) as a colorless oil. LC / MS (ESI) m / z: 406 (M+H) + .

[0982] Step 6: Synthesis of J6

[0983] J5 (606 mg, 1.5 mmol) and TFA (5 mL) were charged into a round-bottom flask and the reaction mixture was heated at 80 °C under N2 Stir for 2 hours under an atmosphere. Then concentrate the mixture under reduced pressure to obtain crude J6 (350 mg, quantitative) as a purple oil, which is used directly in the next step without further purification. LC / MS (ESI) m / z: 256 (M+H) + .

[0984] Step 7: Synthesis of J7

[0985] Add A5 (415 mg, 1.37 mmol) to a mixture of J6 (350 mg, 1.37 mmol) and TEA (208 mg, 2.06 mmol) in anhydrous THF (10 mL) at 0 °C. Stir the resulting mixture at 60 °C under an N 2 atmosphere for 4 hours. Then quench the mixture with water (50 mL) and extract with EtOAc (30 mL x 2). Wash the combined organic layers with brine (50 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness under reduced pressure. Purify the residue by flash column chromatography (eluting with 10 to 15% MeOH in DCM) to obtain J7 (534 mg, 79% yield) as a colorless oil. LC / MS (ESI) m / z: 491 (M+H) + .

[0986] Step 8: Synthesis of J8

[0987] Add 2 M NaOH (1.1 mL, 2.2 mmol, aqueous solution) to a solution of J7 (534 mg, 1.1 mmol) in MeOH (10 mL) at 0 °C. Stir the resulting mixture at room temperature for 2 hours. Then dilute the mixture with water (40 mL) and extract with TBME (30 mL). Separate the aqueous layer, adjust to pH = 5 with HCl (1 N) aqueous solution and extract with EtOAc (30 mL x 2). Wash the combined organic layers with brine (50 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate to dryness under reduced pressure. Purify the residue by flash column chromatography (eluting with 0 to 80% EtOAc in PE) to obtain J8 (460 mg, 89% yield) as a white solid. LC / MS (ESI) m / z: 477 (M+H) + .

[0988] Step 9: Synthesis of J9

[0989] To a solution of J8 (460 mg, 0.97 mmol) in DMF (15 mL) was added DIEA (250 mg, 1.94 mmol) and HATU (380 mg, 1.1 mmol). The resulting mixture was stirred at room temperature under N 2 atmosphere for 15 min. Then NH 4 Cl (81 mg, 1.5 mmol) was added portionwise to the above mixture at 0 °C and the resulting mixture was stirred at room temperature under N 2 atmosphere for an additional 6 h. The mixture was then quenched with NH 4 Cl (60 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography (eluting with 15 to 20% MeOH in DCM) to afford J9 (402 mg, 88% yield) as a pale yellow oil. LC / MS (ESI) m / z: 476 (M+H) + .

[0990] Step 10: Synthesis of Example 9 / J10

[0991] To a mixture of 12 (402 mg, 0.85 mmol) and TEA (172 mg, 1.7 mmol) in anhydrous DCM (15 mL) at 0 °C was added dropwise TFAA (273 mg, 1.3 mmol) and the resulting mixture was stirred at room temperature under N 2 atmosphere for an additional 3 h. The mixture was then diluted with water (50 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to dryness. The residue was purified by preparative HPLC to afford racemic-Example 9 / J10 (220 mg, 57% yield) as a white solid. LC / MS (ESI) m / z: 458 (M+H) + . The material was further separated by SFC (Waters Thar 80 preparative SFC; ChiralPak IG, 100×4.6 mm I.D. 5 μm; IG_MeOH_DEA_20) to afford Example 9 / J10 (63 mg, 29% yield, 100% enantiomeric excess) as a white solid. 1HNMR(400 MHz, MeOD) δ 7.43 (t, J = 8.6 Hz, 1H), 7.10 (t, J = 7.7 Hz, 2H), 4.44 (s, 2H), 4.29 (d, J = 9.4 Hz, 1H), 3.85 (d, J = 9.3 Hz, 1H), 3.63 - 3.51 (m, 1H), 3.26 (s, 1H), 2.90 - 2.79 (m, 2H), 2.70 (s, 3H), 2.62 - 2.52 (m, 1H), 2.48 - 2.34 (m, 1H), 2.30 - 2.20 (m, 1H), 1.04 - 0.94 (m, 2H), 0.83 - 0.73 (m, 2H). 19 F NMR(377 MHz, MeOD) δ -59.78 (s), -116.98 (s).

[0992] Synthesis of Example 10 / K4

[0993]

[0994] Step 1: Synthesis of K1

[0995] To a solution of B9 (1.5 g, 3.57 mmol) in DCM (25 mL) at 0 °C was added dropwise TFA (5 mL). The resulting mixture was stirred at room temperature under N 2 atmosphere for 5 h. Then the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (30 mL) and basified with saturated NaHCO 3 solution until the pH was adjusted to pH = 8. The resulting mixture was diluted with H 2 O (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 and filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 10 to 20% MeOH in DCM) to give K1 as a pale yellow oil (1.13 g, 99% yield). LC / MS (ESI) m / z: 321 (M + H) + .

[0996] Step 2: Synthesis of K2

[0997] At 0 °C under N 2Under an atmosphere, methyl chloroformate (334 mg, 3.53 mmol) was added dropwise to a mixture of K1 (1.13 g, 3.53 mmol) and TEA (714 mg, 7.06 mmol) in dry DCM (30 mL). The resulting mixture was stirred at room temperature for 2 hours. Then the mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 5 to 10% MeOH in DCM) to afford K2 (1.32 g, 99% yield) as a colorless oil. LC / MS (ESI) m / z: 379 (M+H) + .

[0998] Step 3: Synthesis of K3

[0999] A solution of K2 (400 mg, 1.06 mmol) in TFA (6 mL) was stirred at 80 °C under N 2 atmosphere for 3 hours. After completion, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (20 mL) and basified with saturated NaHCO 3 solution until the pH was adjusted to pH = 8. The resulting mixture was diluted with H 2 O (50 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 10 to 20% MeOH in DCM) to afford K3 (190 mg, 79% yield) as a colorless oil. LC / MS (ESI) m / z: 229 (M+H) + .

[1000] Step 4: Synthesis of Example 10 / K4

[1001] At 0 °C, A5 (265 mg, 0.83 mmol) was added to a mixture of K3 (190 mg, 0.83 mmol) and TEA (168 mg, 1.66 mmol) in anhydrous THF (12 mL). The resulting mixture was stirred at 50 °C under N 2 atmosphere for 18 hours. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 10% MeOH in DCM) to give racemic-Example 10 / K4 as a white solid (160 mg, 42% yield). LC / MS (ESI) m / z: 464 (M+H) + The material was further separated by SFC (SHIMADZU preparative solution SFC; ChiralCel OX, 250×21.2 mm I.D., 5 μm; IC_EtOH_DEA_30_8 min) to give Example 10 / K4 as a white solid (55 mg, 34% yield, enantiomeric excess 100%). 1 1H NMR (400 MHz, CD 3 OD) δ 7.42 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 8.4 Hz, 2H), 4.43 (s, 2H), 4.26 - 4.16 (m, 1H), 4.10 - 3.98 (m, 1H), 3.76 - 3.66 (m, 1H), 3.68 (s, 3H), 3.48 - 3.36 (m, 2H), 3.17 (t, J = 12.2 Hz, 1H), 2.58 - 2.32 (m, 2H), 1.92 - 1.80 (m, 2H), 1.76 - 1.68 (m, 1H), 0.99 - 0.87 (m, 2H), 0.80 - 0.68 (m, 2H).1 9 19F NMR (377 MHz, CD 3 OD) δ -59.78 (s), -117.08 (s).

[1002] Synthesis of Example 11 / L8

[1003]

[1004] Step 1: Synthesis of L2

[1005] To a solution of L1 (1.59 g, 10 mmol) in THF (100 mL) at 0 °C was added triethylamine (1.01 g, 10 mmol) and CDI (1.78 g, 11 mmol). The resulting mixture was stirred at 0 °C under N 2 atmosphere for 1 h. Upon completion, the mixture was diluted with water (80 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 2SO 4Dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 0 to 20% EtOAc in PE) to give L2 as a white solid (2.6 g, 69% yield). LC / MS (ESI) m / z: 254 (M+H) + .

[1006] Step 2: Synthesis of L3

[1007] At 0 °C under N 2 atmosphere, add dropwise TFA (3 mL) to a solution of C5 (1.1 g, 3.5 mmol) in DCM (12 mL). Stir the resulting mixture at room temperature under N 2 atmosphere for 5 h. Then concentrate the mixture under reduced pressure to dryness. Dissolve the residue in DCM (20 mL), basify with saturated NaHCO 3 solution until the pH is adjusted to pH = 8. Then dilute the mixture with water (50 mL) and extract with DCM (40 mL x 2). Wash the combined organic layers with brine (70 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 20 to 30% MeOH in DCM) to give L3 as a pale yellow oil (0.72 g, 96% yield). LC / MS (ESI) m / z: 211 (M+H) + .

[1008] Step 3: Synthesis of L4

[1009] At 0 °C under N 2 atmosphere, add dropwise 2,5-dioxopyrrolidin-1-ylmethyl carbamate (619 mg, 3.6 mmol) to a mixture of L3 (720 mg, 3.4 mmol) and TEA (1.0 g, 10.3 mmol) in dry DCM (30 mL). Stir the resulting mixture at room temperature for 12 h. Then dilute the mixture with water (60 mL) and extract with DCM (40 mL×2). Wash the combined organic layers with brine (50 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate under reduced pressure to dryness. Purify the residue by flash column chromatography (eluting with 10 to 15% MeOH in DCM) to give L4 as a colorless oil (670 mg, 73% yield). LC / MS (ESI) m / z: 268 (M+H) + . L4 (670 mg, 2.5 mmol) was purified via SFC ((R,R)-WHELK, 250×21.2 mm I.D., 5 μm A, A being CO 2And B was IPA (0.1% 7 mol / L NH3 in MeOH, 40 mL / min) for further separation to obtain L4-P1 (143 mg, 21% yield, 99% enantiomeric excess) and L4-P2 (164 mg, 25% yield, 99% enantiomeric excess) as colorless oils.

[1010] Step 4: Synthesis of L5

[1011] At 0 °C under N 2 atmosphere, 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (45 mg, 0.29 mmol) and Pd(PPh 3 ) 4 (23 mg, 0.02 mmol) were added to a solution of L4-P2 (50 mg, 0.19 mmol) in DCM (8 mL). The resulting mixture was stirred at room temperature for 30 min. Then the mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 25 to 30% MeOH in DCM) to obtain L5 (25 mg, 59% yield) as an orange oil. LC / MS (ESI) m / z: 228 (M+H) + .

[1012] Step 5: Synthesis of L6

[1013] At 0 °C, TEA (33 mg, 0.33 mmol) and L2 (28 mg, 0.11 mmol) were added to a solution of L5 (25 mg, 0.11 mmol) in anhydrous THF (6 mL). The resulting mixture was stirred at 50 °C under N 2 atmosphere for 18 h. Then the mixture was quenched with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 2 4 SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluting with 0 to 6% MeOH in DCM) to obtain L6 (29 mg, 64% yield) as a colorless oil. LC / MS (ESI) m / z: 413 (M+H) + .

[1014] Step 6: Synthesis of L7

[1015] To a solution of L6 (29 mg, 0.07 mmol) in anhydrous DCM (4 mL) at 0 °C was added TEA (21 mg, 0.21 mmol) and MsCl (9 mg, 0.08 mmol), and the resulting mixture was stirred at 0 °C under N 2 atmosphere for 15 min. Then the mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with and brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure to give crude L7 (30 mg, quantitative) as a pale yellow oil, which was used directly in the next step without further purification.

[1016] Step 7: Synthesis of Example 11 / L8

[1017] To a solution of L7 (30 mg, 0.06 mmol) in DMF (4 mL) was added NaCN (4 mg, 0.09 mmol). The resulting mixture was stirred at 60 °C under N 2 atmosphere for 16 h. Then the mixture was quenched with saturated NH 4 Cl solution (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give Example 11 / L8 (11 mg, 42% yield) as a white solid. LC / MS (ESI) m / z: 422 (M+H) + . 1 H NMR (400 MHz, MeOD) δ 7.32 (t, J = 8.3 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.94 (t, J = 5.8 Hz, 1H), 4.40 (d, J = 5.5 Hz, 2H), 4.14 - 4.06 (m, 1H), 3.89 - 3.79 (m, 1H), 3.73 - 3.60 (m, 1H), 3.18 - 3.08 (m, 1H), 2.70 (s, 3H), 2.58 - 2.52 (m, 1H), 2.52 - 2.39 (m, 3H), 2.07 - 1.85 (m, 3H), 1.00 - 0.88 (m, 2H), 0.80 - 0.69 (m, 2H).1 9 F NMR (376 MHz, MeOD) δ -118.40 (s).

[1018] Table 2: Compounds prepared according to the above method.

[1019]

[1020]

[1021]

[1022]

[1023]

[1024] Table 3: Compounds prepared according to the adjustments of the method used to prepare Examples 1 - 11 in Table 1.

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108] Incorporation by reference

[1109] All U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference.

[1110] Equivalent schemes

[1111] Those skilled in the art will recognize or be able to determine using only routine experimentation many equivalent schemes of the specific embodiments of the invention described herein. Such equivalent schemes are intended to be covered by the appended claims.

Claims

1. A compound of formula (I): Wherein: n is 0, 1 or 2; L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -; L 2 Absent or -CH 2 -; L 3 is absent or is -C(O)-; X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H; Y 1 selected from aryl and heteroaryl; Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, -O-hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ; Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, and cycloalkyl; Each Y 2 ″is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocyclic or cycloalkyl group; and Y 3 and Y 4 together with the carbon to which they are bonded form a 4-, 5- or 6-membered cycloalkyl, cycloheteroalkyl or heterocyclic group, or Y 3 and Y 4 each independently selected from -OH, -CN, -CO 2 H, -CO 2 (alkyl), alkyl, hydroxyalkyl, cyanoalkyl and halogen; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ; Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; Each Y 2 is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; and Y 3 and Y 4 together with the carbon to which they are bonded form a 4-, 5- or 6-membered cycloalkyl, cycloheteroalkyl or heterocyclic group.

3. The compound according to claim 1 or 2, wherein Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted 4-, 5- or 6-membered heterocyclic group.

4. The compound according to any one of claims 1 to 3, wherein Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted 4-, 5- or 6-membered cyclic urea, cyclic carbamate, cyclic sulfone, cyclic sulfonamide, lactam, azalactam or lactone.

5. The compound according to claim 3 or 4, wherein Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures: Wherein Z 1 selected from O, NH, and CH 2 ; Z 2 selected from O, NH, and CH 2 ; Z 3 selected from O and NH; Z 4 selected from NH and CH 2 ; and Z 5 selected from NH and CH 2 ; Provided that Z 1 and Z 2 one of which is not CH 2 .

6. The compound according to claim 3 or 4, wherein Y 3 and Y 4 together with the carbon to which they are attached form the following structure: Wherein Z 1 selected from O, NH, and CH 2 ; and Z 2 selected from O, NH, and CH 2 ; Provided that Z 1 and Z 2 one of which is not CH 2 .

7. The compound according to claim 3 or 4, wherein Y 3 and Y 4 together with the carbon to which they are bonded form any of the following structures: Wherein Z 3 selected from O and NH; and Z 5 Selected from NH and CH 2 .

8. A compound according to any one of claims 1 to 3, wherein Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted 4-, 5- or 6-membered cycloheteroalkyl group.

9. The compound according to claim 8, wherein Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted piperidinyl, tetrahydrofuranyl, azetidinyl or morpholinyl group.

10. The compound according to any one of claims 1 to 9, wherein Y 3 and Y 4 together with the carbon to which they are attached form any one of the following structures:

11. The compound according to claim 1 or 2, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5- or 6-membered heterocyclic group.

12. The compound according to any one of claims 1 to 3, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5- or 6-membered cyclic urea, cyclic carbamate, cyclic sulfone, cyclic sulfonamide, lactam, azalactam or lactone.

13. The compound according to claim 12, wherein the cyclic urea, cyclic carbamate, cyclic sulfonamide, lactam or azalactam is N-substituted.

14. The compound according to claim 13, wherein the cyclic urea, cyclic carbamate, cyclic sulfonamide, lactam or azalactam is N-alkyl substituted.

15. The compound according to any one of claims 11 to 14, wherein Y 3 and Y 4 together with the carbon to which they are attached form the following structure: Wherein Z 6 selected from -H and alkyl; and Z 7 selected from -H and alkyl; Provided that Z 6 and Z 7 are not both -H.

16. The compound according to any one of claims 11 to 14, wherein Y 3 and Y 4 together with the carbon to which they are attached form any one of the following structures: Wherein Each Z 8 is independently an alkyl group; Z 9 selected from -H and alkyl; and Z 10 Selected from -H and alkyl; Provided that Z 9 and Z 10 are not both -H.

17. The compound according to any one of claims 11 to 14, wherein Y 3 and Y 4 together with the carbon to which they are attached form any one of the following structures: Wherein Z 11 is an alkyl group; Z 12 selected from -H and alkyl; and Z 13 selected from -H and alkyl; Provided that Z 12 and Z 13 are not both -H.

18. The compound according to any one of claims 11 to 14, wherein Y 3 and Y 4 together with the carbon to which they are attached form the following structure: where Z 14 is an alkyl group.

19. A compound according to any one of claims 1 to 32, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5- or 6-membered cycloheteroalkyl group.

20. The compound according to claim 19, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted piperidinyl, tetrahydrofuranyl, azetidinyl or morpholinyl group.

21. The compound according to claim 19 or 20, wherein Y 3 and Y 4 together with the carbon to which they are attached form an N-alkyl or N-acetyl-substituted piperidinyl, azetidinyl or morpholinyl.

22. The compound according to any one of claims 1 to 3, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted 4-, 5- or 6-membered cycloalkyl group.

23. The compound according to claim 22, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted cyclopropyl or cyclobutyl group.

24. The compound according to any one of claims 11 to 23, wherein Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures:

25. The compound according to claim 1, wherein Y 3 and Y 4 together with the carbon to which they are attached form an unsubstituted 4-, 5- or 6-membered cycloheteroalkyl group.

26. The compound according to claim 25, wherein Y 3 and Y 4 together with the carbon to which they are attached form a substituted tetrahydrofuranyl or tetrahydropyranyl group.

27. The compound according to claim 25 or 26, wherein Y 3 and Y 4 together with the carbon to which they are attached form any of the following structures:

28. The compound according to claim 1, wherein Y 3 and Y 4 are each independently selected from -OH, -CN, -CO 2 H, -CO 2 (alkyl), alkyl, hydroxyalkyl, cyanoalkyl, and halogen.

29. The compound according to claim 27, wherein Y 3 and Y 4 are each independently selected from -F, -OH, -CN, -CO 2 H, -CO 2 Et, -CH 3 、-CH 2 CH 3 、-CH 2 CN, -CH 2 OH and -CH 2 OSO 2 Me.

30. The compound according to claim 28, wherein Y 3 is selected from -F, CH 3 , -CH 2 CH 3 ; and Y 4 is selected from -OH, -CN, -CO 2 H, -CO 2 Et, -CH 2 CN, -CH 2 OH and -CH 2 OSO 2 Me.

31. A compound of formula (II): Wherein: m is 0, 1 or 2; L 1 absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -; L 2 is absent or is -CH 2 -; L 3 is absent or is -C(O)-; X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H; Y 1 selected from aryl and heteroaryl; Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl, -O-hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ; Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cycloalkyl; Each Y 2 ″is independently an alkyl group, or two instances together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-membered heterocyclic group or cycloalkyl group; Y 5 Selected from cycloalkyl, heteroaryl, heterocyclic group, C 0 -C 6 alkyl - Y 5 ′ and C 2 -C 6 alkenyl - Y 5 ′; Y 5 ′ is selected from -CN, -OH, -NH 2 , -OSO 2 -alkyl, -NH(Y 5 ″), -C(O)N(Y 5 ″′) 2 , -SO 2 N(Y 5 ″′) 2 , -O(CO)-Y 5 ″′, -(CO)O-Y 5 ″′, alkoxy, benzyloxy, -C=N-O(alkyl) and formamide moieties; Y 5 ″selected from alkyl, -C(O)-alkyl, and -SO 2 -alkyl; and Y 5 ″′ is independently selected from -H, alkyl, aminoalkyl, and aryl each time it appears; or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 31, wherein Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ; Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; Each Y 2 ″is independently alkyl, or two instances together with the nitrogen atom to which they are bonded form a 5- or 6-membered heterocyclic group; Y 5 selected from cyano, cycloalkyl, heteroaryl, heterocyclic, alkyl-Y 5 ′ and the squaramide moiety; Y 5 ′ is selected from -CN, -OH, -NH 2 , -NH(Y 5 ″), -C(O)N(Y 5 ″′) 2 , -SO 2 N(Y 5 ″′) 2 , - and formamide moieties; Y 5 ″selected from alkyl, -C(O)-alkyl, and -SO 2 -alkyl; and Y 5 ″′ is independently selected from -H and alkyl each time it appears.

33. The compound according to claim 31 or 32, which has the following structure:

34. A compound according to any one of claims 31 to 33, wherein Y 5 is an unsubstituted 5-membered heteroaryl group.

35. The compound according to claim 34, wherein Y 5 is selected from unsubstituted pyrazolyl, unsubstituted diazolyl, unsubstituted oxazolyl, and unsubstituted isoxazolyl.

36. The compound according to claim 35, wherein Y 5 is selected from 37. The compound according to any one of claims 31 to 33, wherein Y 5 is a substituted 6-membered heteroaryl.

38. The compound according to claim 37, wherein Y 5 is selected from substituted pyridyl and substituted pyrimidinyl.

39. The compound according to claim 38, wherein Y 5 is selected from 40. A compound according to any one of claims 31 to 33, wherein Y 5 is C 0 -C 6 alkyl-Y 5 '.

41. The compound according to claim 40, wherein Y 5 is C 1 -C 4 alkyl-Y 5 '; and said alkyl is unbranched.

42. The compound according to claim 40, wherein Y 5 is C 1 -C 4 alkyl-Y 5 '; and the alkyl is branched.

43. The compound according to claim 40, wherein Y 5 is C 1 -C 4 alkyl - Y 5 '; and the alkyl is substituted by cycloalkyl.

44. The compound according to any one of claims 40 to 43, wherein Y 5 ′ is selected from -NH(Y 5 ″), -C(O)N(Y 5 ″′) 2 and -SO 2 N(Y 5 ″′) 2 ; Y 5 ″selected from -C(O)-CH 3 and -SO 2 -CH 3 ; and Y 5 ″′each occurrence is independently selected from -H and -CH 3 。 45. A compound according to any one of claims 40 to 43, wherein Y 5 ′ is -OH, -CN or an alkoxy group.

46. The compound according to claim 31 or 33, wherein Y 5 ′ is -O(CO)-Y 5 ″′ or -(CO)O-Y 5 ″′.

47. The compound according to claim 46, wherein Y 5 ″′ is alkyl, aminoalkyl or aryl.

48. A compound according to any one of claims 40 to 43, wherein Y 5 ′ is a squaramide moiety.

49. The compound according to claim 48, wherein Y 5 ′ is wherein Z 15 is independently selected from -H and alkyl each time it appears.

50. The compound according to claim 49, wherein each Z 15 is -H, each Z 15 is -CH 3 , or one Z 15 is -H and the other is -CH 3 .

51. A compound according to any one of claims 31 to 33, wherein Y 5 is a squaramide moiety.

52. The compound according to claim 51, wherein Y 5 is wherein Z 15 is independently selected from -H and alkyl each time it appears.

53. The compound according to claim 52, wherein each Z 15 is -H, each Z 15 is -CH 3 , or one Z 15 is -H and the other is -CH 3 .

54. A compound according to any one of claims 31 to 53, wherein Y 5 is selected from 55. A compound according to any one of claims 31 to 47, wherein Y 5 is selected from -OH, -OAc, 56. A compound according to any one of claims 1 to 55, wherein X 1 and X 2 one of which is -H; and the other of X 1 and X 2 is selected from -CH 3 -, -CH 2 CH 3 -, -CH 2 CF 3 -, -CH 2 CH 2 CH 3 , 57. The compound according to any one of claims 1 to 55, wherein X 1 is -H; and X 2 is 58. The compound according to any one of claims 1 to 57, wherein L 1 is absent.

59. The compound according to any one of claims 1 to 58, wherein L 1 is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -.

60. The compound according to claim 59, wherein L 1 is selected from -CH 2 -, -C(H)(CH 3 )-, -CH 2 CH 2 -, and -C(H)(OH)CH 2 -.

61. The compound according to claim 59, wherein L 1 is selected from 62. The compound according to claim 59, wherein L 1 is selected from 63. The compound according to any one of claims 1 to 62, wherein Y 1 is a substituted aryl group.

64. The compound according to claim 63, wherein Y 1 is and 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 one of R 1 , R 2 , R 3 , R 4 and R 5 is not -H.

65. The compound according to claim 64, wherein 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 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCF 3 , and 66. A compound according to any one of claims 64 to 65, wherein two of R 1 , R 2 , R 3 , R 4 , and R 5 are not -H, or three of R 1 , R 2 , R 3 , R 4 , and R 5 are not -H.

67. A compound according to any one of claims 64 to 66, wherein Y 1 is selected from 68. A compound according to any one of claims 1 to 62, wherein Y 1 is an unsubstituted heteroaryl.

69. The compound according to claim 56, wherein Y 1 is selected from 70. The compound according to any one of claims 1 to 62, wherein Y 1 is a substituted heteroaryl.

71. The compound according to claim 70, wherein Y 1 is selected from And R 6 、R 7 、R 8 and R 9 Each occurrence of is independently selected from -H, halogen, -CN, -OCF 3 、-OCHF 2 、alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl and heteroaryl; provided that at least one of R 6 、R 7 、R 8 and R 9 is not -H.

72. The compound according to any one of claims 1 to 71, wherein L 2 is absent.

73. A compound according to any one of claims 1 to 71, wherein L 2 is -CH 2 -.

74. The compound according to any one of claims 1 to 73, wherein L 3 is absent.

75. The compound according to claim 74, wherein Y 2 is an unsubstituted heteroaryl group.

76. The compound according to claim 75, wherein Y 2 is selected from 77. The compound according to claim 76, wherein Y 2 is 78. The compound according to claim 75, wherein Y 2 is a substituted heteroaryl.

79. The compound according to claim 78, wherein Y 2 is R 10 , R 11 and R 12 independently selected from -H, halogen, -CN, -OH, -NH 2 、-OCF 3 、-OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 , -CO 2 R 15 and -C(O)NHSO 2 R 15 ; The premise is R 10 , R 11 and R 12 At least one of is not -H; and R 13 , R 14 and R 15 Each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

80. The compound according to claim 79, wherein R 10 、R 11 and R 12 are independently selected from -H, -F, -Cl, -Br, -CN, -CH 3 、-CH 2 CH 3 、-CF 3 、-CHF 2 、-CF 2 CH 3 、-OCH 3 、-OCF 3 、-OCHF 2 、-OAc, -NH 2 、-NHCH 3 、-NHAc, -C(O)NH 2 、-C(O)NHCH 3 、-C(O)NHCH 2 CH 3 、-C(O)NHSO 2 CH 3 、-C(O)NHSO 2 CH 2 CH 3 、-CH 2 OH, -CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

81. The compound according to claim 78, wherein Y 2 is selected from 82. The compound according to claim 78, wherein Y 2 is and R 26 and R 27 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or Y 2 For And R 27 and R 28 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or Y 2 For And R 26 and R 29 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 Y 2 For And R 30 selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl; or Y 2 For And R 31 selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl.

83. The compound as described in 82, wherein Y 2 is selected from 84. A compound according to any one of claims 1 to 73, wherein L 3 is -C(O)-.

85. The compound according to claim 84, wherein Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl and cyanoalkyl.

86. The compound according to claim 85, wherein Y 2 is selected from -CH 3 , -CH 2 CH 3 , -CF 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 , -OCH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CH 2 F, -CH 2 CH 2 CN and -CH 2 OCH 3 .

87. The compound according to claim 86, wherein Y 2 is selected from -CH 2 OH and -CH 2 CH 2 OH.

88. The compound according to claim 84, wherein Y 2 is an unsubstituted heteroaryl.

89. The compound according to claim 88, wherein Y 2 is 90. The compound according to claim 84, wherein Y 2 is a substituted heteroaryl.

91. The compound according to claim 90, wherein Y 2 is R 10 , R 11 and R 12 independently selected from -H, halogen, -CN, -OH, -NH 2 、-OCF 3 、-OCHF 2 , -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, aryl, heteroaryl, -C(O)NR 13 R 14 and -CO 2 R 15 ; The premise is R 10 , R 11 and R 12 At least one of is not -H; and R 13 、R 14 and R 15 Each occurrence of is independently selected from -H, alkyl, aryl, and heteroaryl.

92. The compound according to claim 91, wherein R 10 , R 11 and R 12 are independently selected from -H, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , -CF 2 CH 3 , -OCH 3 , -OCF 3 , -OCHF 2 , -OAc, -NH 2 , -NHCH 3 , -NHAc, -C(O)NH 2 , -C(O)NHCH 3 , -C(O)NHCH 2 CH 3 , -C(O)NHSO 2 CH 3 , -C(O)NHSO 2 CH 2 CH 3 , -CH 2 OH, -CO 2 H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

93. The compound according to claim 90, wherein Y 2 is 94. The compound according to claim 90, wherein Y 2 is And R 26 and R 27 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or Y 2 For And R 27 and R 28 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 atom to which they are attached form an unsubstituted or substituted fused C 5 -C 7 cycloalkyl; or Y 2 For And R 26 and R 29 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 Y 2 For And R 30 selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl; or Y 2 For And R 31 selected from halogen, -CN, -OH, -OCF 3 , -OCHF 2 , -NH 2 , alkyl, alkoxy, alkylamino and cycloalkyl.

95. The compound as described in 94, wherein Y 2 is selected from 96. The compound according to claim 84, wherein Y 2 is -NH(Y 2 ′).

97. The compound according to claim 96, wherein Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, and cycloalkyl.

98. The compound according to claim 97, wherein Y 2 ′ is selected from -H, -OH, -OCH 3 , -CH 3 , -CH 2 CH 2 OCH 3 and 99. The compound according to claim 96, wherein Y 2 ′ is selected from -H, alkyl, alkoxy, haloalkyl, and hydroxyalkyl.

100. The compound according to claim 99, wherein Y 2 ′ is selected from -H, -OCH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 F, and -CH 2 CH 2 CH 2 F.

101. The compound according to claim 84, wherein Y 2 is -N(Y 2 ″) 2 .

102. The compound according to claim 101, wherein each Y 2 ″ is -CH 3 .

103. The compound according to claim 101, wherein Y 2 ″ Two instances of which, together with the nitrogen atom to which they are bonded, form a morpholinyl group or an azetidinyl group.

104. The compound according to claim 84, wherein Y 2 ′ is selected from cyanoalkyl, -O-alkoxyalkyl, -O-haloalkyl and -O-hydroxyalkyl.

105. The compound according to claim 84, wherein Y 2 ′ is selected from -CH 2 CH 2 CN, -OCH 2 CH 2 CH 2 CN, -OCH 2 CHF 2 , -OCH 2 CH 2 CHF 2 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 and -OCH 2 CH 2 CH 2 OH.

106. The compound according to claim 1, which has a structure selected from the following:

107. The compound according to claim 31, which has the following structure:

108. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

109. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

110. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

111. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

112. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

113. A compound of formula (III): Wherein: L 1 absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH 2 -; L 3 absent or -C(O)-; X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H; Y 1 selected from aryl and heteroaryl; Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ; Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; Each Y 2 is independently alkyl, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; and Y 6 and Y 7 form, together with the carbon atoms to which they are bonded, a 4-, 5- or 6-membered cycloalkyl or heterocyclic group; or a pharmaceutically acceptable salt thereof.

114. A compound of formula (IV): Wherein: L 1 is absent or selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, -heteroaryl- and -heteroaryl-CH 2 -; L 2 is absent or is -CH 2 -; L 3 is absent or is -C(O)-; X 1 and X 2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclic group; provided that X 1 and X 2 are not both -H; Y 1 selected from aryl and heteroaryl; Y 2 selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NH(Y 2 ′) and -N(Y 2 ″) 2 ; Y 2 ′ is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; Each Y 2 is independently an alkyl group, or two instances together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; Y 8 selected from cyano, cycloalkyl, heteroaryl, heterocyclic, alkyl-Y 8 ′ and the squaramide moiety; Y 8 ′ is selected from -CN, -OH, -NH 2 , -NH(Y 8 ″), -C(O)N(Y 8 ″′) 2 , -SO 2 N(Y 8 ″′) 2 and a squaramide moiety; Y 8 ″selected from alkyl, -C(O)-alkyl, and -SO 2 -alkyl; and Y 8 each occurrence is independently selected from -H and alkyl; or a pharmaceutically acceptable salt thereof.

115. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

116. A compound or a pharmaceutically acceptable salt thereof, which has the structure of any one of the following compounds:

117. A pharmaceutical composition, which comprises a compound according to any one of claims 1 to 116 and a pharmaceutically acceptable excipient.

118. A method for treating or preventing a disease or disorder associated with a genetic defect of phenylalanine hydroxylase, which comprises administering to a subject in need an effective amount of a compound according to any one of claims 1 to 116.

119. A method for treating or preventing phenylketonuria, which comprises administering to a subject in need an effective amount of a compound according to any one of claims 1 to 116.

120. A method for treating or preventing hyperphenylalaninemia, which comprises administering to a subject in need an effective amount of a compound according to any one of claims 1 to 116.

121. The method according to any one of claims 118 to 120, wherein the compound reduces the systemic phenylalanine level in the subject.

122. A method for treating or preventing tyrosinemia (type I, II or III), which comprises administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 116.

123. The method according to claim 122, wherein the compound reduces the systemic tyrosine level in the subject.

124. A method for treating or preventing non-ketotic hyperglycinemia, which comprises administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 116.

125. The method according to claim 124, wherein the compound reduces the systemic glycine level in the subject.

126. A method for treating or preventing isovaleric academia, methylmalonic academia, propionic academia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder or hyperammonemia, which comprises administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 116.

127. A method for treating or preventing diabetes, chronic kidney disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome, obesity-related disorders, or neurodevelopmental and autism spectrum disorders, which comprises administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 116.

128. The method according to any one of claims 118 to 127, wherein the compound inhibits SLC6A19 in the subject.

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