Bcat2 inhibitors

Abstract

The disclosure is directed to compounds, and pharmaceutically acceptable salts thereof, that inhibit branched-chain amino acid aminotransferase 2 (BCAT2), pharmaceutical compositions comprising those compounds, and methods of using those compounds for treating branched chain amino acid (BCAA)-catabolism-related diseases. The disclosure is also directed to in vivo models for the study of disorders characterized by defects in the metabolism of BCAAs.

Description

128748-02920 (AGI-BCAT-03WO) BCAT2 INHIBITORS RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 467,125, filed May 17, 2023, the entire contents of which are incorporated herein by reference. REFERENCE TO ELECTRONIC SEQUENCE LISTING

[0002] The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on May 15, 2024, is named “128748-02920.xml” and is 56,094 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety. TECHNICAL FIELD

[0003] This application pertains to compounds that inhibit branched-chain amino acid aminotransferase 2 (BCAT2), pharmaceutical compositions comprising those compounds, and methods of using those compounds for treating branched chain amino acid (BCAA)-catabolism-related diseases. BACKGROUND

[0004] Leucine, isoleucine, and valine are essential branched chain amino acids (BCAAs). BCAAs are catabolized by enzymatic conversions that result in transformation of these amino acids into various metabolites. Fig. 1 shows the catabolism pathways for leucine, isoleucine, and valine.

[0005] When genetic mutations result in defects in the enzymes that facilitate the BCAA catabolic conversions (e.g., loss of function mutations), toxic levels of catabolic intermediates accumulate, resulting in organic acidemias. Propionic acidemia, for example, results from loss of function mutations in propionyl-CoA carboxylase. Methylmalonic acidemia results from deficiency of methylmalonyl CoA mutase, defective enzymes (MMADHC or MMAA / B) used in the synthesis of cofactor 5'-adenosylcobalamin, or deficient activity of methylmalonyl-CoA epimerase. Maple syrup urine disease (MSUD), - 1 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) isovaleric acidemia (IVA), propionic acidemia (PA), and methylmalonic acidemia (MMA) are some of the most common organic acidemias.

[0006] The accumulation of toxic levels of catabolic intermediates lead to a variety of pathologic disease phenotypes. For example, acute metabolic decompensations (AMDs) are induced as a result of a catabolic stressor which triggers protein catabolism and increases the production of these toxic metabolites, resulting in additional clinical distress. AMDs contribute to the neurological deficits in patients and put them at risk of stroke, coma, and death. Patients with MMA and PA, for example, experience frequent episodes of metabolic decompensations, especially in the first years of life. Those patients can suffer from a number of complications and impairments: potentially life-threatening episodes of acidosis, hyperammonemia, pancreatitis, metabolic stroke, cardiomyopathy, bone marrow suppression, seizures, and encephalopathy (which can accompany acutely deranged metabolism). The long-term cognitive outcome of patients with PA and MMA is negatively correlated to the number of metabolic decompensations they experience. Patients with PA also often experience significant cardiac issues. Intellectual impairment can be a major secondary presentation of both PA and MMA. Convulsions are a hallmark neurological alteration seen in children with MMA. Patients with MMA also often experience renal insufficiency.

[0007] There is currently no approved therapy on the market for either PA or MMA, except for CARBAGLU®, which is approved to treat hyperammonemia seen in MMA and PA. Liver transplantation may protect against metabolic instability but is not curative and patients remain at risk for long-term complications. Hepatic-specific gene therapy is the main treatment modality under development, but is not expected to be curative because it relies on the same mechanism of action as liver transplantation. Thus, a need exists for effective therapies for treating PA, MMA, and other BCAA-catabolism-related diseases.

[0008] The first step in BCAA catabolism is common to the catabolism of each of leucine, isoleucine, and valine (the BCAAs), i.e., an enzymatic conversion mediated by BCAA aminotransferase 2 (BCAT2). Subsequent catabolism of the metabolites follows distinct pathways. Inhibition of BCAT2 will lower BCAA pathway flux and should significantly reduce the level of toxic metabolites seen in patients with BCAA-catabolism- related diseases. Thus, a need exists for effective BCAT2 inhibitors for treating BCAA- catabolism-related diseases. SUMMARY - 2 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0009] The disclosure provides compounds that are BCAT2 inhibitors, pharmaceutical compositions comprising those BCAT2 inhibitors, and methods of treating BCAA-catabolism-related diseases using those BCAT2 inhibitors.

[0010] In some aspects, the disclosure is directed to compounds of Formula I or Formula II:or a pharmaceutically acceptable salt thereof, wherein: R1is optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted 4-, 5- or 6-membered heterocycloalkyl; R1ais hydrogen or fluoro; R1bis optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted 4-, 5- or 6-membered heterocycloalkyl; R1cis hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; X is CH or N; Cy is optionally substituted C5-C7 cycloalkyl or optionally substituted 6- or 7- membered heterocycloalkyl;L is a bond, -O-, -NRa-, or optionally substituted C1-C4alkylene; Rais hydrogen or C1-C4alkyl; R2is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted 5-membered heteroaryl, optionally substituted 4-, 5-, or 6- membered heterocycloalkyl, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6haloalkyl, optionally - 3 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) substituted C1-C6haloalkoxy, optionally substituted C3-C6cycloalkyl, or NRbRc; Rband Rcare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, OH, C1-C4alkoxy, C1-C6hydroxyalkyl, or C3-C6cycloalkyl; and Ar1is optionally substituted 6-membered heteroaryl, optionally substituted phenyl, orU is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl; V is an optionally substituted phenyl, optionally substituted 5- or 6-membered heterocycloalkyl, or optionally substituted 5- or 6-membered heteroaryl; and wherein the point of attachment to the carbonyl group of –NHC(O) for variable Z occurs at the optionally substituted phenyl or optionally substituted 6- membered heteroaryl of U; Y is O or NH; R3ais hydrogen, C1-C3alkyl, or oxo; R3bis hydrogen or C1-C3alkyl; or alternatively, R3aand R3bare taken together to form cyclopropyl; each R4is independently halo, cyano, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; and m is 0, 1, 2, 3, or 4.

[0011] Stereoisomers and mixtures of stereoisomers of the compounds of Formula I and Formula II, and the pharmaceutical salts thereof, are also described. Methods of using compounds of Formula I and Formula II are described, as well as pharmaceutical compositions including the compounds of Formula I and Formula II. - 4 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 illustrates the BCAA catabolism pathways, the point of BCAT2 involvement, and the points of catabolic impairment resulting in methylmalonic acidemia (MMA) and propionyl acidemia (PA).

[0013] FIG. 2A shows plasma methylmalonic acid (MMA) levels in mouse models of methylmalonic acidemia comprising mutations in the gene encoding MMA-CoA mutase. The mice are either homozygous for an M698K mutation in MMA-CoA mutase (M698K / M698K), comprise a gene encoding M698K MMA-CoA mutase at a first locus and a knockout of the MMA-CoA mutase gene at a second locus (M698K / KO), or comprise a gene encoding M698K MMA-CoA mutase at a first locus and a gene encoding wildtype MMA-CoA mutase at a second locus (M698K / WT).

[0014] FIG. 2B shows urine methylmalonic acid (MMA) levels in mouse models of methylmalonic acidemia comprising mutations in the gene encoding MMA-CoA mutase. The mice are either homozygous for an M698K mutation in MMA-CoA mutase (M698K / M698K), comprise a gene encoding M698K MMA-CoA mutase at a first locus and a knockout of the MMA-CoA mutase gene at a second locus (M698K / KO), or comprise a gene encoding M698K MMA-CoA mutase at a first locus and a gene encoding wildtype MMA-CoA mutase at a second locus (M698K / WT).

[0015] FIG. 3 shows the probability of survival in BCAT2 knockout (KO) mice fed a regular diet or a low branched-chain amino acid (BCAA) diet.

[0016] FIG. 4 shows plasma propionyl carnitine levels in a mouse model of propionic acidemia that is homozygous for an A134T mutation in propionyl-CoA carboxylase subunit α (PCCA).

[0017] FIG. 5 shows plasma isoleucine levels for mice that are either homozygous for BCAT2 knockout (MUTWT / WTBCAT2KO / KO), comprise a gene encoding M698K MMA- CoA mutase at a first locus and a knockout of the MMA-CoA mutase gene at a second locus (MUTM698K / KOBCAT2WT / WT), or both (MUTM698K / KOBCAT2KO / KO).

[0018] FIG. 6 shows plasma methylmalonic acid (MMA) levels for mice that are either homozygous for BCAT2 knockout (MUTWT / WTBCAT2KO / KO), comprise a gene encoding M698K MMA-CoA mutase at a first locus and a knockout of the MMA-CoA mutase gene at a second locus (MUTM698K / KOBCAT2WT / WT), or both (MUTM698K / KOBCAT2KO / KO). - 5 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0019] FIG. 7 shows plasma 3-OH-isobutyric acid (3-HIB) levels for mice that are either homozygous for BCAT2 knockout (MUTWT / WTBCAT2KO / KO), comprise a gene encoding M698K MMA-CoA mutase at a first locus and a knockout of the MMA-CoA mutase gene at a second locus (MUTM698K / KOBCAT2WT / WT), or both (MUTM698K / KOBCAT2KO / KO).

[0020] FIG. 8 shows plasma keto isoleucine (Keto-Ile) levels for mice that are either homozygous for BCAT2 knockout (MUTWT / WTBCAT2KO / KO), comprise a gene encoding M698K MMA-CoA mutase at a first locus and a knockout of the MMA-CoA mutase gene at a second locus (MUTM698K / KOBCAT2WT / WT), or both (MUTM698K / KOBCAT2KO / KO).

[0021] FIG. 9 shows BCAT2 protein expression levels in muscle of mice homozygous (Homo) or heterozygous (Het) for a knockout of the mouse BCAT2 gene. BCAT2 protein expression levels were determined by Western blot and normalized to GAPDH protein levels. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Definitions

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0023] As used in structures herein, “ ” indicates the point of attachment of the particular depicted structure or substituent group to the appropriate atom(s) in the remainder of the molecule.

[0024] The articles “a” and “an,” as used herein and in the appended claims, are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0025] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in a country other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans. - 6 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0026] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0027] A “pharmaceutically acceptable excipient” refers to a substance that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a compound of the disclosure and that is compatible therewith.

[0028] The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1- C12”), for example 1 to 6 carbons atoms (“C1-C6”), in the group. Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), hexyl (C6) (e.g., n-hexyl), heptyl (C7) (e.g., n-heptyl), - 7 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) octyl (C8) (e.g., n-octyl), and the like. In some embodiments, the alkyl group is a C1-C6alkyl; in some embodiments, it is a C1-C4alkyl; and in some embodiments, it is a C1-C3alkyl.

[0029] The term “alkylene,” when used alone or as part of a substituent group, refers to an alkyl diradical, i.e., a straight- or branched-chain hydrocarbon group that is attached to two other groups. For example, one embodiment of a C2alkylene is the diradical - CH2CH2-. In some embodiments, the alkylene group is C1-C4alkylene.

[0030] When a range of carbon atoms is used herein, for example, C1-C6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-C3” includes C1-C3, C1-C2, C2-C3, C1, C2, and C3.

[0031] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C3-C10”), for example from 3 to 7 carbon atoms (“C3-C7”). Examples of cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), and the like. In some embodiments, the cycloalkyl group is a C3- C4cycloalkyl; in some embodiments, it is a C3-C6cycloalkyl; and in some embodiments, it is C5-C7cycloalkyl.

[0032] The term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to twelve-membered monocyclic, saturated or partially unsaturated ring containing at least one heteroatom that is oxygen, nitrogen, or sulfur. The heterocycloalkyl group may be attached to another group or substituent through any heteroatom or carbon atom of the ring that results in a stable structure. In some embodiments, heterocycloalkyl rings are characterized by the number of ring atoms in the heterocycloalkyl group. For example, a 6-membered heterocycloalkyl group refers to a heterocycloalkyl group having 6 ring atoms in the group. Similarly, a 5-membered heterocycloalkyl group refers to a heterocycloalkyl group having 5 ring atoms in the group. Similarly, a 4-membered heterocycloalkyl group refers to a heterocycloalkyl group having 4 ring atoms in the group. The heterocycloalkyl moiety can be unsubstituted, or one or more of the carbon, nitrogen, or sulfur atoms in the ring can be substituted. Examples of heterocycloalkyl groups include azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, thianyl, thianyl sulfoxide, 1-oxo-1-imino-1thiacyclohexyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyranyl, and the like. In some embodiments, the heterocycloalkyl is a three to twelve-membered monocyclic, saturated ring containing at least one heteroatom that is oxygen, nitrogen, or sulfur. - 8 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0033] The terms “halo” or “halogen”, by itself or as part of a substituent group, means a fluorine, chlorine, bromine, or iodine atom.

[0034] The term “aryl” when used alone or as part of a substituent group also refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted. The term “aryl” also includes a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein two adjacent carbon atoms in the ring are optionally substituted such that said two adjacent carbon atoms and their respective substituents form a cycloalkyl or heterocycloalkyl ring. Examples of aryl groups include phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, and the like.

[0035] The term “heteroaryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms that are each independently nitrogen, oxygen, or sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. In some embodiments, heteroaryl rings are characterized by the number of ring atoms in the heteroaryl group. For example, a 6- membered heteroaryl group refers to a heteroaryl group having 6 ring atoms in the group. Similarly, a 5-membered heteroaryl group refers to a heteroaryl group having 5 ring atoms in the group. The heteroaryl moiety can be unsubstituted, or one or more of the carbon atoms or nitrogen atoms in the ring can be substituted. Examples of heteroaryls include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, isoindolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzoimidazolyl, indazolyl, quinoxalyl, quinazolinyl, triazolyl, tetrazolyl, isothiazolyl, pyranyl, purinyl, naphthyridinyl, phthalazinyl, cinnolinyl, pteridinyl, 1H-pyrrolo[2,3-b]pyridinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, furo[2,3- b]pyridinyl, thieno[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazol[1,5-a]pyridinyl, and pyrrolo[1,2]pyridazinyl and the like. The term “heteroaryl” also includes pyridine, pyrimidine, and pyrazines groups having a fused optionally substituted cycloalkyl or fused optionally substituted heterocycloalkyl group. A pyridine, pyrimidine, or pyrazine having a fused optionally substituted cycloalkyl or fused optionally substituted heterocycloalkyl group may be attached to the remainder of the molecule at any available carbon atom on the pyridine, pyrimidine, or pyrazine ring. Exemplary heteroaryls having a fused optionally - 9 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) substituted cycloalkyl or fused optionally substituted heterocycloalkyl group include but are

[0036] The term “optionally substituted,” as used herein to describe a chemical moiety defined herein, means that the moiety may, but is not required to be, substituted with one or more suitable functional groups or other substituents as provided herein. For example, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, or -I), cyano, -NO2, -N3, -OH, -SH, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, C1- C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylenethio, C1-C6alkyleneamino, -NH2, -NH(C1-C6alkyl), -N(C1-C-6alkyl)2, -NH(C1-C6alkoxy), -C(O)NH2, -C(O)NHC1-C6alkyl, - C(O)N(C1-C6alkyl)2, -COOH, -C1-C6alkyleneCOOH, -C3-C6cycloalkylCOOH, -C1- C6alkyleneC(O)NH2,-C3-C6cycloalkylC(O)NH2, -C1-C6alkyleneC(O)NHC1-C6alkyl,-C1- C6alkyleneC(O)N(C1-C6alkyl)2,-C(O)C1-C6alkyl, -C(O)OC1-C6alkyl, -NHC(O)(C1-C6alkyl), -N(C1-C6alkyl)C(O)(C1-C6alkyl), -S(O)C1-C6alkyl, -S(O)C3-C6cycloalkyl, -S(O)2C1-C6alkyl, -S(O)2C3-C6cycloalkyl, oxo (=O), 3-7-membered heterocycloalkyl, aryl, or heteroaryl groups. In some embodiments, the C1-C6alkyl group in any of the substituent groups in this paragraph is a C1-C4alkyl; in some embodiments it is C1-C3alkyl. In some embodiments, the C1- C6alkylene group in any of the substituent groups in this paragraph is a C1-C4alkylene. In some embodiments, the C1-C6haloalkyl substituent is a C1-C4haloalkyl; in some embodiments, it is C1-C3haloalkyl. In some embodiments, the C3-C6cycloalkyl substituent is a C3-C4cycloalkyl substituent. In some embodiments, the C1-C6alkoxy substituent is a C1- C3alkoxy; in some embodiments, it is C1-C4alkoxy. In some embodiments, the C1- C6haloalkoxy substituent is a C1-C3haloalkoxy; in some embodiments, it is C1-C4haloalkoxy.

[0037] In some embodiments, “optionally substituted,” refers to the following substituents: halo, CN, NO2, N3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, ORo1, SRs1, N(Rn1)2, C(=O)N(Rn1)2, N(Rn1)C(=O)Rc1, C(=O)Rc1, C(=O)ORo1,N(Rn1)S(=O)Rs1, N(Rn1)S(=O)2Rs1, N(Rn1)C(=O)ORo1, OC(=O)N(Rn1)2, N(Rn1)C(=O)N(Rn1)2, N(Rn1)S(=O)N(Rn1)2, N(Rn1)S(=O)2N(Rn1)2, N(Rn1)S(=O)ORo1, N(Rn1)S(=O)2ORo1, OS(=O)N(Rn1)2, or OS(=O)2N(Rn1)2; wherein each instance of Rn1is independently hydrogen, an optionally substituted C1-C6alkyl, or a nitrogen protecting group; each instance of Ro1is independently hydrogen, an optionally substituted C1-C6alkyl, or an - 10 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) oxygen protecting group; and each instance of Rc1is an optionally substituted C1-C6alkyl; and each instance of Rs1is independently an optionally substituted C1-C6alkyl or a sulfur protecting group.

[0038] As used herein, the term “alkenyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”) in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (- CH=CH2; C2alkenyl) allyl (-CH2-CH=CH2; C3alkenyl), propenyl (-CH=CHCH3; C3alkenyl); isopropenyl (-C(CH3)=CH2; C3alkenyl), butenyl (-CH=CHCH2CH3; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso-butenyl (-CH=C(CH3)2; C4alkenyl), 2-butenyl (- CH2CH=CHCH3; C4alkyl), pentenyl (CH=CHCH2CH2CH3; C5alkenyl), and the like. In some embodiments, the alkenyl group is a C2-C4 alkenyl group.

[0039] As used herein, the term “alkynyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”) in the group, and wherein the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH; C2alkynyl); propargyl (-CH2-C≡CH; C3alkynyl), propynyl (-C≡CCH3; C3alkynyl); butynyl (-C≡CCH2CH3; C4alkynyl), pentynyl (C≡CCH2CH2CH3; C5alkynyl), and the like. In some embodiments, the alkynyl group is a C2-C4alkynyl group.

[0040] As used herein, the term “alkoxy” refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxy groups include methoxy (-OCH3), ethoxy (-OCH2CH3), propoxy (e.g., -OnPr, -OiPr), butoxy (e.g., -OnBu, -OiBu, -OsBu, -OtBu) and the like. In some embodiments, the alkoxy group is a C1-C6alkoxy; in some embodiments, it is a C1-C4alkoxy; and in some embodiments, it is a C1-C3alkoxy.

[0041] As used herein, the term “deuterated alkoxy” refers to an alkoxy group as defined herein in which one or more hydrogen atoms has been replaced by deuterium. Examples of deuterated alkoxy groups include -OCD3, -OCH2CD3, and the like. In some embodiments, the deuterated alkoxy group is a deuterated C1-C6alkoxy; in some embodiments, it is a deuterated C1-C4alkoxy; and in some embodiments, it is a deuterated C1- C3alkoxy.

[0042] As used herein, the term “alkoxy(alkylene)” as used by itself or as part of a substituent group refers to an alkylene group as defined herein that is bound to an alkoxy group as defined herein. Examples of alkoxy(alkylene) groups include -CH2OCH3, - CH2CH2OCH3, and the like.

[0043] As used herein, the term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may - 11 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) be the same or different. In some embodiments, the alkyl is substituted by at least one halogen. In some embodiments, the alkyl is substituted by one, two, or three F and / or Cl. Examples of haloalkyl groups include fluoromethyl (CH2F), 1-fluoroethyl (CH(CH3)F), 2- fluoroethyl, difluoromethyl (CHF2), trifluoromethyl (CF3), pentafluoroethyl, 1,1- difluoroethyl (C(CH3)F2), 2,2-difluoroethyl (CH2CHF2), 2,2,2-trifluoroethyl (CH2CF3), 2- fluoropropan-2-yl (C(CH3)2F), 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, trichloromethyl and the like. In some embodiments, the haloalkyl group is a C1-C6haloalkyl; in some embodiments, it is a C1-C4haloalkyl; and in some embodiments, it is a C1-C3haloalkyl.

[0044] As used herein, the term “haloalkoxy” refers to an oxygen radical attached to a haloalkyl group by a single bond, wherein haloalkyl is defined above. Examples of haloalkoxy groups include fluoromethoxy (OCH2F), 2-fluoroethoxy, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3), pentafluoroethoxy, 1,1-difluoroethoxy (OC(CH3)F2), 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy (OCH2CF3), 3,3,3-trifluoropropoxy, (1,1,1,3,3,3- hexafluoropropan-2-yl)oxy (OCH(CF3)2), 4,4,4-trifluorobutoxy, trichloromethoxy groups, and the like. In some embodiments, the haloalkoxy group is C1-C6haloalkoxy; in some embodiments, it is C1-C4haloalkoxy; and in some embodiments, it is C1-C3haloalkoxy.

[0045] As used herein, the term “hydroxyalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more hydroxyl (i.e., -OH) groups. In some embodiments, the hydroxyalkyl contains one OH. In some embodiments, the hydroxyalkyl contains two OH. In further embodiments, the hydroxyalkyl contains three OH. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl (e.g., 1- hydroxyethyl, 2-hydroxyethyl), 1,2-dihydroxyethyl, hydroxypropyl (e.g., 2-hydroxypropyl, 3- hydroxypropyl), hydroxybutyl (e.g., 3-hydroxybutyl, 4-hydroxybutyl), 2-hydroxy-1- methylpropyl, 1,3 dihydroxyprop-2-yl, and the like. In some embodiments, the hydroxyalkyl group is C1-C6hydoxyalkyl; in some embodiments, it is C1-C4hydroxyalkyl; and in some embodiments, it is C1-C3hydroxyalkyl.

[0046] As used herein, the term “cyanoalkyl” as used by itself or as part of a substituent group refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced by one or cyano (i.e., -CN) groups. In some embodiments, the cyanoalkyl contains one cyano. In some embodiments, the cyanoalkyl contains two cyano. In further embodiments, the cyanoalkyl contains three cyano. Examples of cyanoalkyl groups include CH2CN, CH2CH2CN, CH(CN)CH3, CH2CH2CH2CN, C(CH3)2CN, CH2CH(CN)CH3, CH(CN)CH2CH3, and the like. In some embodiments, the cyanoalkyl group is a C1-- 12 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 6cyanoalkyl; in some embodiments, it is C1-4cyanoalkyl; and in some embodiments, it is C1- 3cyanoalkyl.

[0047] As used herein, the term “imidazolidinonyl” refers to a five-membered saturated ring radical containing two-nitrogen atoms and three-carbon atoms wherein one of the carbon atoms is oxo-substituted (=O). Non-limiting examples include:.

[0048] As used herein, the term “pyrrolidinonyl” refers to a five-membered saturated ring radical containing one nitrogen atom and four carbon atoms wherein one of the carbon atoms is oxo-substituted (=O). Non-limiting examples include:.

[0049] As used herein, the term “dihydropyrazolonyl” refers to a five-membered ring radical containing one unsaturation, two adjacent nitrogen atoms, and three carbon atoms wherein one of the carbon atoms is oxo-substituted (=O). Non-limiting examples include:.

[0050] As used herein, the term “dihydropyrrolonyl” refers to a five-membered ring radical containing one unsaturation, one nitrogen atom, and four carbon atoms wherein one of the carbon atoms is oxo-substituted (=O). Non-limiting examples include:.

[0051] As used herein, the term “dihydroimidazolonyl” refers to a five-membered ring radical containing one unsaturation, two non-adjacent nitrogen atoms, and three carbon atoms wherein one of the carbon atoms is oxo-substituted (=O). Non-limiting examples include: - 13 - ME148476702v.1128748-02920 (AGI-BCAT-03WO).

[0052] As used herein, the term “dihydrotriazolonyl” refers to a five-membered ring radical containing one unsaturation, three nitrogen atoms, and two carbon atoms wherein one of the carbon atoms is oxo-substituted (=O). Non-limiting examples include:.

[0053] The term “nitrogen protecting group” refers to a moiety that is attached to a nitrogen atom to prevent reaction at that nitrogen atom. Nitrogen protecting groups will be known by those skilled in the art and include those described in Wuts, P.G., Greene's Protective Groups in Organic Synthesis. Wiley; 5th edition (October 27, 2014), which is incorporated by reference herein.

[0054] The term “oxygen protecting group” refers to a moiety that is attached to an oxygen atom to prevent reaction at that oxygen atom. Oxygen protecting groups will be known by those skilled in the art and include those described in Wuts, P.G., Greene's Protective Groups in Organic Synthesis. Wiley; 5th edition (October 27, 2014), which is incorporated by reference herein.

[0055] The term “sulfur protecting group” refers to a moiety that is attached to a sulfur atom to prevent reaction at that sulfur atom. Sulfur protecting groups will be known by those skilled in the art and include those described in Wuts, P.G., Greene's Protective Groups in Organic Synthesis. Wiley; 5th edition (October 27, 2014), which is incorporated by reference herein.

[0056] Recitation of ranges of values herein are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure. - 14 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0057] The term “about” when used in combination with a numeric value or range of values means the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art.

[0058] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including supercritical fluid chromatography (SFC), chiral high pressure liquid chromatography (HPLC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0059] Exemplary compounds of the disclosure including a chiral center may be depicted herein as having particular stereochemistries, but for which absolute stereochemistry has not been obtained. Absolute configurations can be obtained using methods known in the art.

[0060] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution and connectivity but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers or diastereomers.

[0061] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by dashed or wedge bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0062] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of - 15 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0063] It will be understood that certain compounds disclosed herein may exist in tautomeric forms. Such forms are included as part of the present disclosure. Thus, when a compound herein is represented by a structural formula or designated by a chemical name herein, all tautomeric forms which may exist for the compound are encompassed by the structural formula.

[0064] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers.

[0065] In some embodiments, the compounds described herein are isotopically enriched compounds, e.g., an isotopologue. The term “isotopically enriched” refers to an atom having an isotopic composition other than the naturally abundant isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. In an isotopologue, “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope of a given atom in a molecule in the place of that atom’s natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.

[0066] Thus, as used herein, and unless otherwise indicated, the term “isotopic enrichment factor” refers to the ratio of the isotopic composition to the natural isotopic composition of a specified isotope.

[0067] With regard to the compounds provided herein, when a particular atom’s position is designated as having deuterium or “D” or “2H”, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 - 16 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium atom. The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0068] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compounds or compositions according to the present disclosure is provided. For treatment of those conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In general, in the present disclosure, the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.

[0069] In some embodiments, a subject is treated with compounds of the disclosure, or a pharmaceutical composition comprising compounds of the disclosure. In certain embodiments, the subject is a human subject, such as a human adult over 18 years old in need of treatment. In further embodiments, the human subject is a human child less than 18 years old in need of treatment.

[0070] The terms “therapeutically effective amount” or “effective amount” means an amount or dose of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) sufficient to generally bring about the desired therapeutic benefit in subjects in need of such treatment for the designated disease or disorder. Further, a therapeutically effective amount with respect to a compound of the disclosure means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease.

[0071] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (e.g., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder. - 17 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0072] The terms “prevent,” “preventing,” and “prevention” refer to the prevention of the onset, recurrence, or spread of the disease in a subject resulting from the administration of a prophylactic or therapeutic agent.

[0073] In some embodiments, the disclosure is directed to compounds of Formula I or Formula II:or a pharmaceutically acceptable salt thereof, wherein Z, Cy, L, R1, R2, X, R1a, R1b, and R1care defined herein.

[0074] In some embodiments, the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof,wherein Z, Cy, L, R1, R2, and X are defined herein.

[0075] In some embodiments, the compound is a compound of Formula I. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of Formula I.

[0076] In some embodiments, the compound of Formula I is a compound of Formula I-A:or a pharmaceutically acceptable salt thereof, wherein Ar1, Cy, L, R1, R2, and X are defined herein.

[0077] In some embodiments, the compound of Formula I is a compound of Formula I-B or Formula I-C: - 18 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)or a pharmaceutically acceptable salt thereof, wherein Cy, L, R1, R2, R3a, R3b, R4, m, and X are defined herein.

[0078] In some embodiments, the compound of Formula I is a compound of Formula I-B, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound of Formula I is a compound of Formula I-C, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound of Formula I is a compound of Formula I-D, Formula I-E, or Formula I-F:or a pharmaceutically acceptable salt thereof, wherein Cy, L, R1, R2, R4, m, X and Y are defined herein.

[0081] In some embodiments, the compound of Formula I is a compound of Formula I-D, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound of Formula I is a compound of Formula I-E, or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula I is a compound of Formula I-F, or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the compound is a compound of Formula II or a pharmaceutically acceptable salt thereof, - 19 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)wherein Z, Cy, L, R1a, R1b, R1c, and R2are defined herein.

[0085] In some embodiments, the compound is a compound of Formula II. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of Formula II.

[0086] In some embodiments, the compound of Formula II is a compound of Formula II-A:or a pharmaceutically acceptable salt thereof, wherein Ar1, Cy, L, R1a, R1b, R1c, and R2are defined herein.

[0087] In some embodiments, the compound of Formula II is a compound of Formula II-B or Formula II-C:or a pharmaceutically acceptable salt thereof, wherein Cy, L, R1a, R1b, R1c, R2, R3a, R3b, R4, and m are defined herein.

[0088] In some embodiments, the compound of Formula II is a compound of Formula II-B, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound of Formula II is a compound of Formula II-C, or a pharmaceutically acceptable salt thereof. - 20 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0090] In some embodiments, the compound of Formula II is a compound of Formula II-D, Formula II-E, or Formula II-F:or a pharmaceutically acceptable salt thereof, wherein Cy, L, R1a, R1b, R1c, R2, R4, m, and Y are defined herein.

[0091] In some embodiments, the compound of Formula II is a compound of Formula II-D, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound of Formula II is a compound of Formula II-E, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compound of Formula II is a compound of Formula II-F, or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, X in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, or Formula I-F is CH.

[0095] In some embodiments, X in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, or Formula I-F is N.

[0096] In some embodiments, Y in the compounds of Formula I, Formula I-D, Formula I-F, Formula II, Formula II-D, or Formula II-F is O.

[0097] In some embodiments, Y in the compounds of Formula I, Formula I-D, Formula I-F, Formula II, Formula II-D, or Formula II-F is N.

[0098] In some embodiments, R3aand R3bin the compounds of Formula I, Formula I-B, Formula I-C, Formula II, Formula II-B, or Formula II-C are hydrogen.

[0099] In some embodiments, R3ain the compounds of Formula I, Formula I-B, Formula I-C, Formula II, Formula II-B, or Formula II-C is oxo and R3bin the compounds of Formula I, Formula I-B, Formula I-C, Formula II, Formula II-B, or Formula II-C is hydrogen.

[0100] In some embodiments, each R4in the compounds of Formula I, Formula I- B, Formula I-C, Formula I-D, Formula I-E, or Formula I-F, Formula II, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is independently halo. - 21 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0101] In some embodiments, each R4in the compounds of Formula I, Formula I- B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is independently F or Cl.

[0102] In some embodiments, m in the compounds of Formula I, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-B, Formula II- C, Formula II-D, Formula II-E, or Formula II-F is 1 or 2.

[0103] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is optionally substituted C5-C7cycloalkyl.

[0104] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted C5-C7 cycloalkyl.

[0105] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is C5-C7cycloalkyl substituted with one or more of OH, deuterium, halo, cyano, C1-C4alkyl, C1- C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3-C4cycloalkyl), N3, or NRdRe, wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)(C1-C4alkyl), SO2(C1-C4alkyl), or SO2(C3- C4cycloalkyl).

[0106] In some embodiments, the optionally substituted C5-C7cycloalkyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is an optionally substituted cyclohexyl or an optionally substituted cycloheptyl.

[0107] In some embodiments, the optionally substituted cyclohexyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, - 22 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula

[0108] In some embodiments, the optionally substituted cyclohexyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula

[0109] In some embodiments, the optionally substituted cyclohexyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is substituted with one of OH, C1-C3alkoxy, C1-C3haloalkoxy or NRdRe, wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen or C1-C4alkyl.

[0110] In some embodiments, the optionally substituted cyclohexyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula

[0111] In some embodiments, the optionally substituted cyclohexyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula

[0112] In some embodiments, the optionally substituted cycloheptyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula- 23 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0113] In some embodiments, the optionally substituted cycloheptyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula

[0114] In some embodiments, the optionally substituted cycloheptyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is substituted with one of OH or C1-C3alkoxy.

[0115] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is optionally substituted 6-membered heterocycloalkyl.

[0116] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, optionally substituted thianyl, optionally substituted thianyl sulfone, optionally substituted thianyl sulfoxide, or optionally substituted 1-oxo-1-imino-1-thiacyclohexyl.

[0117] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is optionally substituted piperidinyl.

[0118] In some embodiments, the nitrogen in the piperidinyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is substituted with C1-C6alkyl, C(O)(C1-C6alkyl), oxo, OH, C1-C6alkoxy, CO2(C1-C6alkyl), SO2(C1-C6alkyl), or SO2(C3-C6cycloalkyl).

[0119] In some embodiments, the nitrogen in the piperidinyl in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is substituted with C1-C4alkyl or C(O)(C1-C4alkyl). - 24 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0120] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is optionally substituted 7-membered heterocycloalkyl, such as optionally substituted oxazepanyl, optionally substituted thiepanyl, optionally substituted thiepanyl-1-oxide, optionally substituted thiepanyl-1,1-dioxide, optionally substituted azepanyl, or optionally substituted 1- imino-1-oxide-thiepanyl.

[0121] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is optionally substituted C5-C7 cycloalkyl or optionally substituted 6- or 7-membered heterocycloalkyl. In other embodiments, Cy is optionally substituted C6-C7 cycloalkyl or optionally substituted 6- membered heterocycloalkyl. In yet other embodiments, Cy is optionally substituted C6cycloalkyl or optionally substituted piperidinyl.

[0122] It will be understood that the Cy group in the compounds of the disclosure, when unsubstituted, is a diradical with two attachments to other parts of the molecule. As such, the potential exists for Cy to have multiple stereochemical configurations. When no stereochemistry is indicated, such as, for example:, the structure is meant to represent all stereoisomeric configurations (e.g., cis and trans) including any mixture of stereoisomers in any proportions. Where a specific stereochemistry is indicated in the structure, then the structure is meant to encompass the stereoisomer with the indicated absolute configuration, but that structure may also contain a mixture of the other enantiomer of the indicated absolute configuration in any ratio. Thus, for example, unless otherwise indicated, the structuremeant to representinclude the enantiomerany ratio. - 25 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0123] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted cyclopentyl, such as, for example,.

[0124] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted cyclohexyl, such as, for example,.

[0125] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is substituted cyclohexyl.

[0126] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0127] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0128] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- - 26 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0129] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0130] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0131] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0132] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0133] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- - 27 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0134] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0135] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0136] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0137] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted cycloheptyl, such as, for example,.

[0138] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- - 28 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is.

[0139] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted piperidinyl, such as, for example,.

[0140] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl substituted with methyl, such as, for example,.

[0141] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl substituted with ethyl, such as, for example,.

[0142] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl substituted with acetyl, such as, for example,.

[0143] In a some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl - 29 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) substituted with C1-C6hydroxyalkyl, such as, for example,.

[0144] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl substituted with C(O)NRfRg, wherein each Rfand Rgis independently hydrogen or C1- C4alkyl, such as, for example,.

[0145] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl substituted with SO2C1-C6alkyl, such as, for example,.

[0146] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is piperidinyl substituted with C(O)OC1-C6alkyl, such as, for example,.

[0147] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted tetrahydropyranyl, such as, for example,. - 30 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0148] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted thianyl, such as, for example,.

[0149] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted thianyl sulfone, such as, for example,.

[0150] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted thianyl sulfoxide, such as, for example,.

[0151] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted 1-oxo-1-imino-1-thiacyclohexyl, such as, for example,.

[0152] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted oxazepanyl, such as, for example,.

[0153] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- - 31 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted oxepanyl, such as, for example,.

[0154] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted dioxepanyl, such as, for example,.

[0155] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted azepanyl, such as, for example,.

[0156] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted diazepanyl, such as, for example,.

[0157] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted thiepanyl, such as, for example,.

[0158] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted thiepanyl-1-oxide, such as,. - 32 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0159] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted thiepanyl-1,1-dioxide, such as, for example,.

[0160] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is unsubstituted 1-imino-1-oxide-thiepanyl, such as, for example,.

[0161] In some embodiments, Cy in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula II, Formula II- A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, or Formula II-F is a substituted 1-imino-1-oxide-thiepanyl.

[0162] In some embodiments, the compound of Formula I is a compound of Formula I-G:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl), and L, R1, R2, and Z are defined herein. - 33 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0163] In some embodiments, the compound of Formula I-G is a compound of Formula I-G-1:or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound of Formula II is a compound of Formula II-G:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl), and L, R1a, R1b, R1c, R2, and Z are defined herein.

[0165] In some embodiments, the compound of Formula II-G is a compound of Formula II-G-1:or a pharmaceutically acceptable salt thereof. - 34 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0166] In some embodiments, R5in the compounds of Formula I-G, Formula I-G- 1, Formula II-G, or Formula II-G-1 is OH, C1-C3alkoxy, C1-C3haloalkoxy, or NH2, and R6is hydrogen.

[0167] In some embodiments, R5in the compounds of Formula I-G, Formula I-G- 1, Formula II-G, or Formula II-G-1 is hydrogen and R6is OH, C1-C3alkoxy, C1- C3haloalkoxy, or NH2.

[0168] In some embodiments, C1-C3alkoxy in the compounds of Formula I-G, Formula I-G-1, Formula II-G, or Formula II-G-1 is OCH3 and the C1-C3haloalkoxy is OCF3 or OCHF2.

[0169] In some embodiments, the compound of Formula I is a compound of Formula I-H or Formula I-J:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl), and L, R1, R2, and Z are defined herein.

[0170] In some embodiments, the compound of Formula I-H is a compound of Formula I-H-1, or a pharmaceutically acceptable salt thereof, and the compound of Formula I-J is a compound of Formula I-J-1, or a pharmaceutically acceptable salt thereof: - 35 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0171] In some embodiments, the compound of Formula II is a compound of Formula II-H or Formula II-J:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl), and L, R1a, R1b, R1c, R2, and Z are defined herein.

[0172] In some embodiments, the compound of Formula II-H is a compound of Formula II-H-1, or a pharmaceutically acceptable salt thereof, and the compound of Formula II-J is a compound of Formula II-J-1, or a pharmaceutically acceptable salt thereof:- 36 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0173] In some embodiments, R5in the compounds of Formula I-H, Formula I-H- 1, Formula I-J, Formula I-J-1, Formula II-H, Formula II-H-1, Formula II-J, or Formula II-J-1 is OH or C1-C3alkoxy and R6is hydrogen.

[0174] In some embodiments, R5in the compounds of Formula I-H, Formula I-H- 1, Formula I-J, Formula I-J-1, Formula II-H, Formula II-H-1, Formula II-J, or Formula II-J-1 is hydrogen and R6is OH or C1-C3alkoxy.

[0175] In some embodiments, the C1-C3alkoxy in the compounds of Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula II-H, Formula II-H-1, Formula II-J, or Formula II-J-1 is OCH3.

[0176] In some embodiments, the compound of Formula I is a compound of Formula I-K:or a pharmaceutically acceptable salt thereof, wherein: R7is hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, oxo, OH, C1-C6alkoxy, C(O)NRfRg, C1- C6hydroxyalkyl, CO2(C1-C6alkyl), SO2(C1-C6alkyl), or SO2(C3-C6cycloalkyl); and each Rfand Rgis independently hydrogen or C1-C4alkyl, and L, R1, R2, and Z are defined herein.

[0177] In some embodiments, the compound of Formula I-K is a compound of Formula I-K-1:or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the compound of Formula II is a compound of Formula II-K: - 37 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)or a pharmaceutically acceptable salt thereof, wherein: R7is hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, oxo, OH, C1-C6alkoxy, C(O)NRfRg, C1- C6hydroxyalkyl, CO2(C1-C6alkyl), SO2(C1-C6alkyl), or SO2(C3-C6cycloalkyl); and each Rfand Rgis independently hydrogen or C1-C4alkyl, and L, R1a, R1b, R1c, R2, and Z are defined herein.

[0179] In some embodiments, the compound of Formula II-K is a compound of Formula II-K-1:or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, R7in the compounds of Formula I-K, Formula I-K- 1, Formula II-K, or Formula II-K-1 is C1-C4alkyl or C(O)C1-C4alkyl.

[0181] In some embodiments, R7in the compounds of Formula I-K, Formula I-K- 1, Formula II-K, or Formula II-K-1 is CH3, CH2CH3, or C(O)CH3.

[0182] In some embodiments, Z in the compounds of Formula I, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is –NHC(O)Ar1, and Ar1is defined herein.

[0183] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is optionally substituted 6-membered heteroaryl or optionally substituted phenyl. - 38 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0184] In some embodiments, the optionally substituted 6-membered heteroaryl is pyridinyl, pyrimidinyl, or pyridazinyl, each optionally substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1- C6hydroxyalkyl, cyano, OH, oxo, or NRjRk; wherein each Rjand Rkis independently hydrogen or C1-C4alkyl.

[0185] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1

[0186] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1wherein R8, R9, R10, and R11are each independently hydrogen, halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, or C1-C4haloalkoxy. In some embodiments, at least two of R8, R9, R10, and R11are hydrogen.

[0187] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is phenyl, optionally substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1- C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, OH, NRjRk, C(O)NRfRg, CO2(C1- C6alkyl), SO2(C1-C4alkyl), SO2(C3-C4cycloalkyl), C1-C4alkylene-R12, or O-R13; wherein R12- 39 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) is cyano, NRjRk, OH, or C1-C4alkoxy; R13is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, (C1-C4alkylene)C1-C4alkoxy, (C1- C4alkylene)NRjRk, or (C1-C4alkylene)-(optionally substituted 4-, 5-, or 6-membered heterocycloalkyl), and each Rf, Rg, Rj, and Rkis independently hydrogen or C1-C4alkyl.

[0188] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1

[0189] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, - 40 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1wherein: R14is hydrogen, halo, cyano, or C1-C6haloalkyl; R15is halo, C1-C6alkoxy, C1-C6haloalkoxy, OH, NRjRk, C1-C4alkylene-R16, or O-R17; R16is NRjRkor OH; R17is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6- membered heterocycloalkyl, (C1-C4alkylene)C1-C4alkoxy, (C1-C4alkylene)NRjRk, or (C1-C4alkylene)-(optionally substituted 4-, 5-, or 6-membered heterocycloalkyl); and each Rjand Rkis independently hydrogen or C1-C4alkyl.

[0190] In some embodiments, Ar1in the compounds of Formula I, Formula I-A, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is, wherein the point of attachment to the carbonyl group of –NHC(O) for variable Z occurs at the phenyl or optionally substituted 6-membered heteroaryl of U, and U and V are defined herein.

[0191] In some embodiments, U is optionally substituted 6-membered heteroaryl. In some embodiments, the optionally substituted 6-membered heteroaryl is optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl.

[0192] In some embodiments, U is 6-membered heteroaryl, optionally substituted with one or more of halo, cyano, or C1-C6haloalkyl.

[0193] In some embodiments, U is phenyl substituted with one or more of halo, cyano, or C1-C6haloalkyl.

[0194] In some embodiments, U is optionally substituted phenyl or optionally substituted 6-membered heteroaryl, and V is optionally substituted 5-membered heterocycloalkyl or optionally substituted 5-membered heteroaryl. In other embodiments, U - 41 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) is optionally substituted phenyl, and V is optionally substituted 5-membered heterocycloalkyl or optionally substituted 5-membered heteroaryl.

[0195] In some embodiments, V is optionally substituted furanyl, optionally substituted isofuranyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted thiophenyl. In other embodiments, V is unsubstituted furanyl, unsubstituted isofuranyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted thiazolyl, unsubstituted isothiazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, or unsubstituted thiophenyl.

[0196] In some embodiments, U is phenyl substituted with one or more halo and V is unsubstituted furanyl.

[0197] In some embodiments, Z in the compounds of Formula I, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or FormulaR3ais hydrogen or oxo, and Y, R4, and m are defined herein.

[0198] In some embodiments, each R4in the compounds of Formula I, Formula I- G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is independently halo and m is 1 or 2.

[0199] In some embodiments, each R4in the compounds of Formula I, Formula I- G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, - 42 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Formula I-K-1, Formula II, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is independently F or Cl.

[0200] In some embodiments, Z in the compounds of Formula I, Formula I-G, Formula I-G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1,

[0201] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 is optionally substituted heteroaryl.

[0202] In some embodiments, R1is in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 optionally substituted 5- or 6-membered heteroaryl.

[0203] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 is optionally substituted 5-membered heteroaryl. In some embodiments, the optionally substituted 5-membered heteroaryl is optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl. - 43 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0204] In some embodiments, the 5-membered heteroaryl is substituted with one or more of oxo, NRhRi, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, C1- C6alkoxy, C1-C6haloalkoxy, CO2(C1-C6alkyl), or C(O)NRfRg; and wherein each Rf, Rg, Rhand Riis independently hydrogen or C1-C4alkyl.

[0205] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 is optionally substituted 6-membered heteroaryl. In some embodiments, the optionally substituted 6-membered heteroaryl is optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl.

[0206] In some embodiments, the 6-membered heteroaryl is substituted with one or more of oxo, NRhRi, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, C1- C6alkoxy, C1-C6haloalkoxy, CO2(C1-C6alkyl), or C(O)NRfRg; and wherein each Rf, Rg, Rhand Riis independently hydrogen or C1-C4alkyl.

[0207] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K-, wherein: R18is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; R19is hydrogen or C1-C6alkyl; R20and R21are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, or CO2(C1-C6alkyl); W is O or S; R22is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C1-C6hydroxyalkyl, or NRhRi; R23is hydrogen or C1-C6alkyl; R24, R25, and R26are each independently hydrogen, halo, cyano, C1-C6alkyl, C1- C6haloalkyl, or C3-C6cycloalkyl; and each Rhand Riis independently hydrogen or C1-C4alkyl.

[0208] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- - 44 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 1 is optionally substituted 9-membered heteroaryl, such as optionally substituted benzofuranyl, optionally substituted isobenzofuranyl, optionally substituted benzoxazolyl, optionally substituted benzoisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoisothiazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, or optionally substituted benzothiophenyl.

[0209] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 is optionally substituted aryl. In some embodiments, the optionally substituted aryl is phenyl, optionally substituted with one or more of C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, halo, cyano, or C1-C6cyanoalkyl.

[0210] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 is optionally substituted 4-, 5- or 6-membered heterocycloalkyl, such as optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted dioxanyl.

[0211] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 is pyrrolidinyl, optionally substituted with one or more of oxo, C1-C6hydroxyalkyl, C1- C6alkyl, C1-C6alkoxy(alkylene), C1-C6cyanoalkyl, OH, cyano, C(O)NRfRg, and wherein each Rfand Rgis independently hydrogen or C1-C4alkyl.

[0212] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is optionally substituted heteroaryl.

[0213] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is optionally substituted 5- or 6-membered heteroaryl. In some embodiments, the optionally substituted 5- or 6-membered heteroaryl is optionally substituted - 45 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted tetrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl.

[0214] In some embodiments, the optionally substituted 5- or 6-membered heteroaryl is substituted with one or more of oxo, NRhRi, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, halo, cyano, C1-C6alkoxy, C1-C6haloalkoxy, CO2(C1-C6alkyl), or C(O)NRfRg; and wherein each Rf, Rg, Rhand Riis independently hydrogen or C1-C4alkyl.

[0215] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K,wherein: R18is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; R19is hydrogen or C1-C6alkyl; R20and R21are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, or CO2(C1-C6alkyl); W is O or S; R22is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C1-C6hydroxyalkyl, or NRhRi; R23is hydrogen or C1-C6alkyl; R24, R25, and R26are each independently hydrogen, halo, cyano, C1-C6alkyl, C1- C6haloalkyl, or C3-C6cycloalkyl; and each Rhand Riis independently hydrogen or C1-C4alkyl.

[0216] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is optionally substituted 9-membered heteroaryl, such as optionally substituted benzofuranyl, optionally substituted isobenzofuranyl, optionally substituted benzoxazolyl, optionally substituted benzoisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoisothiazolyl, optionally substituted indolyl, optionally substituted - 46 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, or optionally substituted benzothiophenyl.

[0217] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is optionally substituted aryl. In some embodiments, the optionally substituted aryl is phenyl, optionally substituted with one or more of C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, or C1-C6cyanoalkyl.

[0218] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is optionally substituted 4-, 5- or 6-membered heterocycloalkyl, such as optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl.

[0219] In some embodiments, R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is pyrrolidinyl, optionally substituted with one or more of oxo, C1- C6hydroxyalkyl, C1-C6alkyl, C1-C6alkoxy(alkylene), C1-C6cyanoalkyl, OH, cyano, C(O)NRfRg, and wherein each Rfand Rgis independently hydrogen or C1-C4alkyl.

[0220] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are - 47 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)wherein: each instance of Rd1is independently hydrogen, optionally substituted C1-C6alkyl, or a nitrogen protecting group; each instance of E is independently halo, CN, NO2, N3, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, ORo1, SRs1, N(Rn1)2, C(=O)N(Rn1)2, N(Rn1)C(=O)Rc1, C(=O)Rc1, C(=O)ORo1, OC(=O)Rc1, S(=O)Rs1, S(=O)2Rs1, S(=O)ORo1, OS(=O)Rc1, S(=O)2ORo1, OS(=O)2Rc1, S(=O)N(Rn1)2, S(=O)2N(Rn1)2, S(=O)(C3- C6cycloalkyl), S(=O)2(C3-C6cycloalkyl), N(Rn1)S(=O)Rs1, N(Rn1)S(=O)2Rs1, - 48 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) N(Rn1)C(=O)ORo1, OC(=O)N(Rn1)2, N(Rn1)C(=O)N(Rn1)2, N(Rn1)S(=O)N(Rn1)2, N(Rn1)S(=O)2N(Rn1)2, N(Rn1)S(=O)ORo1, N(Rn1)S(=O)2ORo1, OS(=O)N(Rn1)2, or OS(=O)2N(Rn1)2;or alternatively two instances of (E)pattached to adjacent carbon atoms, can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted cycloalkyl or a heterocycloalkyl; wherein: each instance of Rn1is independently hydrogen, an optionally substituted C1-C6alkyl, or a nitrogen protecting group; each instance of Ro1is independently hydrogen, an optionally substituted C1-C6alkyl, or an oxygen protecting group; and each instance of Rc1is independently an optionally substituted C1- C6alkyl; and each instance of Rs1is independently an optionally substituted C1- C6alkyl or a sulfur protecting group; and p is 0, 1, 2, 3, or 4, as valency permits. Where a particular atom is not substituted with E, it should be understood as having the required number of hydrogens as valency permits so as to form a stable ring.

[0221] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are - 49 - ME148476702v.1128748-02920 (AGI-BCAT-03WO).

[0222] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H,- 50 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0223] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 arewherein: each instance of E is independently halo, CN, NO2, N3, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, ORo1, SRs1, N(Rn1)2, C(=O)N(Rn1)2, N(Rn1)C(=O)Rc1, C(=O)Rc1, C(=O)ORo1, OC(=O)Rc1, S(=O)Rs1, S(=O)2Rs1, S(=O)(C3-OC(=O)N(Rn1)2, N(Rn1)C(=O)N(Rn1)2, N(Rn1)S(=O)N(Rn1)2, N(Rn1)S(=O)2N(Rn1)2, - 51 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) N(Rn1)S(=O)ORo1, N(Rn1)S(=O)2ORo1, OS(=O)N(Rn1)2, or OS(=O)2N(Rn1)2; or alternatively two instances of (E)p attached to adjacent carbon atoms, can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted cycloalkyl or a heterocycloalkyl; wherein: each instance of Rn1is independently hydrogen, an optionally substituted C1-C6alkyl, or a nitrogen protecting group; each instance of Ro1is independently hydrogen, an optionally substituted C1-C6alkyl, or an oxygen protecting group; and each instance of Rc1is independently an optionally substituted C1- C6alkyl; and each instance of Rs1is independently an optionally substituted C1- C6alkyl or a sulfur protecting group; and p is 0, 1, 2, 3, or 4, as valency permits. Where a particular atom is not substituted with E, it should be understood as having the required number of hydrogens as valency permits so as to form a stable ring.

[0224] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are,

[0225] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- - 52 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are,

[0226] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are

[0227] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 arewherein: each instance of E is independently halo, CN, NO2, N3, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, ORo1, SRs1, N(Rn1)2, C(=O)N(Rn1)2, N(Rn1)C(=O)Rc1, C(=O)Rc1, C(=O)ORo1, OC(=O)Rc1, S(=O)Rs1, S(=O)2Rs1, S(=O)(C3-OC(=O)N(Rn1)2, N(Rn1)C(=O)N(Rn1)2, N(Rn1)S(=O)N(Rn1)2, N(Rn1)S(=O)2N(Rn1)2, N(Rn1)S(=O)ORo1, N(Rn1)S(=O)2ORo1, OS(=O)N(Rn1)2, or OS(=O)2N(Rn1)2;or alternatively - 53 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) two instances of (E)p attached to adjacent carbon atoms, can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted cycloalkyl or a heterocycloalkyl; wherein: each instance of Rn1is independently hydrogen, an optionally substituted C1-C6alkyl, or a nitrogen protecting group; each instance of Ro1is independently hydrogen, an optionally substituted C1-C6alkyl, or an oxygen protecting group; and each instance of Rc1is independently an optionally substituted C1-C6alkyl; and each instance of Rs1is independently an optionally substituted C1-C6alkyl or a sulfur protecting group; and p is 0, 1, 2, 3, 4, or 5, as valency permits. Where a particular atom is not substituted with E, it should be understood as having the required number of hydrogens as valency permits so as to form a stable ring.

[0228] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are

[0229] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are - 54 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)wherein: each instance of Rdand Reis independently hydrogen, optionally substituted C1- C6alkyl, or a nitrogen protecting group; each instance of E is independently halo, CN, NO2, N3, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, ORo1, SRs1, N(Rn1)2, C(=O)N(Rn1)2, N(Rn1)C(=O)Rc1, C(=O)Rc1, C(=O)ORo1, OC(=O)Rc1, S(=O)Rs1, S(=O)2Rs1, S(=O)(C3-OC(=O)N(Rn1)2, N(Rn1)C(=O)N(Rn1)2, N(Rn1)S(=O)N(Rn1)2, N(Rn1)S(=O)2N(Rn1)2, N(Rn1)S(=O)ORo1, N(Rn1)S(=O)2ORo1, OS(=O)N(Rn1)2, or OS(=O)2N(Rn1)2;or alternatively two instances of (E)p attached to the same or adjacent carbon atoms, can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted cycloalkyl or a heterocycloalkyl; wherein: each instance of Rn1is independently hydrogen, an optionally substituted C1- C6alkyl, or a nitrogen protecting group; each instance of Ro1is independently hydrogen, an optionally substituted C1- C6alkyl, or an oxygen protecting group; and each instance of Rc1is independently an optionally substituted C1-C6alkyl; and each instance of Rs1is independently an optionally substituted C1-C6alkyl or a sulfur protecting group; and - 55 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) p is 0, 1, 2, 3, or 4, as valency permits. Where a particular atom is not substituted with E, it should be understood as having the required number of hydrogens as valency permits so as to form a stable ring.

[0230] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, such as, for example, optionally substituted: azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, thianyl, thianyl sulfoxide, 1-oxo-1-imino- 1thiacyclohexyl, dithianyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl.

[0231] In some embodiments, R1and R1bare an unsubstituted 4-, 5-, or 6- membered heterocycloalkyl, such as, for example, unsubstituted: azetidinyl, oxetanyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, thianyl, dithianyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl.

[0232] In some embodiments, R1and R1bare an optionally substituted 4- membered heterocycloalkyl, such as, for example, optionally substituted: azetidinyl or oxetanyl.

[0233] In some embodiments, R1and R1bare an optionally substituted 5- membered heterocycloalkyl, such as, for example, optionally substituted: pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, or tetrahydrothiophenyl.

[0234] In some embodiments, R1and R1bare an optionally substituted 6- membered heterocycloalkyl, such as, for example, optionally substituted: piperazinyl, piperidinyl, dioxanyl, morpholinyl, thianyl, dithianyl, thiomorpholinyl, or tetrahydropyranyl.

[0235] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are optionally - 56 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) substituted imidazolidinonyl, optionally substituted pyrrolidinonyl, optionally substituted dihydropyrazolonyl, optionally substituted dihydropyrrolonyl, optionally substituted dihydroimidazolonyl, or optionally substituted dihydrotriazolonyl.

[0236] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are optionally substituted pyrrolidinyl.

[0237] In some embodiments, R1and R1bare unsubstituted pyrrolidinyl, such as,

[0238] In some embodiments, R1and R1bare pyrrolidinyl substituted with one or more of oxo, C1-C6hydroxyalkyl, C1-C6alkyl, C1-C6alkoxy(alkylene), C1-C6cyanoalkyl, OH, cyano, C(O)NRbRc, wherein each Rband Rcis independently hydrogen or C1-C4alkyl. In other embodiments, R1and R1bare pyrrolidinyl substituted with one or more of oxo, C(CH3)2OH, methyl, CH2OH, CH2OCH3, OH, C(O)NH2, cyano, or CH2CN. In yet other

[0239] In some embodiments, R1in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, or Formula I-K- 1 and R1bin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 are optionally substituted tetrahydrofuranyl. In other embodiments, R1and R1bare an unsubstituted tetrahydrofuranyl, such as, for example,. - 57 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0240] In some embodiments, R1ain the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is hydrogen.

[0241] In some embodiments, R1ain the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is fluoro.

[0242] In some embodiments, R1cin the compounds of Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-J-1, Formula II-K, or Formula II-K-1 is hydrogen.

[0243] In some embodiments, L in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is a bond.

[0244] In some embodiments, L in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is –O–.

[0245] In some embodiments, L in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is -NRa-, wherein Rais hydrogen or C1-C4alkyl.

[0246] In some embodiments, L in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula - 58 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted C1-C4alkylene.

[0247] In some embodiments, L is C1-C4alkylene substituted with deuterium, oxo, halo, NH2, NH(C1-C4alkyl), N(C1-C4alkyl)2, OH, C1-C3alkoxy, NRlC(O)(C1-C4alkyl), NRlCO2(C1-C4alkyl), or an optionally substituted 4-, 5-, or 6-membered heterocycloalkyl containing a nitrogen wherein the nitrogen is connected to the alkylene carbon and each Rlis independently hydrogen or C1-C4alkyl.

[0248] In some embodiments, L is unsubstituted C1-C4alkylene.

[0249] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or NRbRc, wherein Rband Rcare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, OH, C1- C4alkoxy, C1-C6hydroxyalkyl, or C3-C6cycloalkyl.

[0250] In some embodiments, R2is phenyl or pyridinyl, each optionally substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, cyano, OH, NRmRn, C(O)NRfRg, CO2(C1-C6alkyl), COOH, C1-C4alkylene-R27, or O-R28, wherein: R27is cyano, NRmRn, or COOH; R28is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, or (C1-C4alkylene)C1-C4alkoxy; and each Rf, Rg, Rm, and Rnis independently hydrogen or C1-C4alkyl.

[0251] In some embodiments, L in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- - 59 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) J-1, Formula II-K, or Formula II-K-1 is a bond;wherein: R29, R30, R31, R32, R33, R34, and R35are each independently hydrogen, halo, OH, cyano, C1-C4alkoxy, C1-C4haloalkoxy, C(O)NRfRg, or O-R28; R28is C1-C6hydroxyalkyl or (C1-C4alkylene)C1-C4alkoxy; and wherein each Rfand Rgis independently hydrogen or C1-C4alkyl.

[0252] In some embodiments, L in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is a bond, -O-, -NRa-, or optionally substituted C1- C4alkylene, wherein Rais hydrogen or C1-C4alkyl.

[0253] In some embodiments, L is -NRa-, wherein Rais hydrogen or C1-C4alkyl. In embodiments in which L is -NRa- and Rais hydrogen, L is -NH-. In embodiments in which L is -NRa- and Rais C1-C6alkyl, L is -N(C1-C6alkyl)-, such as, for example, - N(C6alkyl)-, -N(C5alkyl)-, -N(C4alkyl)-, -N(C3alkyl)-, -N(C2alkyl)- (e.g., -N(CH2CH3)-), - N(C1alkyl)- (e.g., -N(CH3)-).

[0254] In some embodiments, L is optionally substituted C1-C4alkylene, such as, for example, optionally substituted: C4alkylene, C3alkylene, C2alkylene (e.g., -CH2CH2-), C1alkylene (e.g., -CH2-), and the like.

[0255] In some embodiments, L is substituted C1-C4alkylene, wherein the C1- C4alkylene is substituted with deuterium, oxo, halo, NH2, NH(C1-C4alkyl), N(C1-C4alkyl)2, OH, C1-C3alkoxy, NRlC(O)(C1-C4alkyl), NRlCO2(C1-C4alkyl), or an optionally substituted 4-, 5-, or 6-membered heterocycloalkyl containing a nitrogen wherein the nitrogen is connected to the alkylene carbon and each Rlis independently hydrogen or C1-C4alkyl.

[0256] In some embodiments, L is substituted C1-C4alkylene, wherein the C1- C4alkylene is substituted with OH, NH2, oxo, F, OCH3, NHC(O)CH3, or NHCO2CH3.

[0257] In some embodiments, L is -CHOH-, -CHNH2-, -C(O)-, -CHF-, -CF2-, - CH(OCH3)-, -CH(NHC(O)CH3)-, or -CHNH(CO2CH3)-. - 60 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0258] In some embodiments, L is substituted C1-C4alkylene, wherein the C1- C4alkylene is substituted with deuterium.

[0259] In some embodiments, L is -CHD- or -CD2-.

[0260] In some embodiments, L is substituted C1-C4alkylene, wherein the C1-

[0261] In some embodiments, L is unsubstituted C1-C4alkylene, such as, for example, unsubstituted: C4alkylene, C3alkylene, C2alkylene (e.g., -CH2CH2-), C1alkylene (e.g., -CH2-), and the like.

[0262] In some embodiments, L is -CH2-.

[0263] In some embodiments, L is -CH2CH2-.

[0264] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula, wherein R34and R35are each hydrogen, and R33is hydrogen, halo, or C1-C4haloalkoxy. In other embodiments, R33is hydrogen, F, or OCHF2.

[0265] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formulawherein at least two of R29, R30, R31, and R32are hydrogen and R29, R30, R31, and R32are defined herein. In other embodiments, one of R29and R32is halo, OH, C1-C4alkoxy, or C1-C4haloalkoxy and the other of R29and R32is - 61 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) halo; and R30and R31are hydrogen. In yet other embodiments, R29is halo, cyano, OH, C1- C4haloalkoxy, C1-C4alkoxy, C(O)NRfRg, or O-R28, and R30, R31, and R32are each hydrogen.

[0266] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II-

[0267] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is C1-C6alkyl, optionally substituted with cyano, OH, or C(O)NRiRj, and wherein each Riand Rjis independently hydrogen or C1-C4alkyl. In other embodiments, R2is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, CH2C(CH3)3, C(CH3)2OH, CH(OH)(CH3), C(CH3)2CN, C(CH3)2C(O)NH2, or C(CH3)(CH2CH2OH).

[0268] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is C1-C6alkoxy, optionally substituted with OH. In other embodiments, R2is OCH3, OCH(CH3)2, or OCH2CH2OH.

[0269] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- - 62 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is C1-C6haloalkyl or C1-C6haloalkoxy. In other embodiments, R2is CF3, CH(CH3)(CF3), CH2CF3, C(CH3)2F, CH2C(CH3)2F, C(CH3)F2, CH2C(CH3)F2, CHFCH(CH3)2, CF2CH(CH3)2, OCF3, OCH2CF3, OCHF2, OCH2F, or OCH(CH3)(CF3).

[0270] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is C3-C6cycloalkyl, optionally substituted with one or more of C1-C4alkyl or C1-C4haloalkyl.

[0271] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is NRbRc, wherein Rband Rcare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, OH, C1-C4alkoxy, C1-C6hydroxyalkyl, or C3- C6cycloalkyl. In other embodiments, R2is NRbRc, wherein Rband Rcare each independently hydrogen or C1-C4alkyl. In yet other embodiments, R2is NH(CH3), N(CH3)2, N(CH3)(CH2CH3), or NH(CH2CH3).

[0272] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted 5-membered heteroaryl, such as optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl.

[0273] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- - 63 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted 4-, 5- or 6-membered heterocycloalkyl, such as optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted dioxanyl.

[0274] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted 5-membered heteroaryl, optionally substituted 4-, 5-, or 6- membered heterocycloalkyl, optionally substituted C1-C6alkyl, optionally substituted C1- C6alkoxy, optionally substituted C1-C6hydroxyalkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6haloalkoxy, optionally substituted C3-C6cycloalkyl, or NRbRc, wherein Rband Rcare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, OH, C1- C4alkoxy, C1-C6hydroxyalkyl, or C3-C6cycloalkyl.

[0275] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted phenyl or optionally substituted pyridinyl.

[0276] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted phenyl.

[0277] In some embodiments, R2is an unsubstituted phenyl. - 64 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0278] In some embodiments, R2is a substituted phenyl. In some embodiments, the phenyl may be substituted with 1, 2, or 3, independently selected substituents.

[0279] In some embodiments, R2is a phenyl substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, OH, NRmRn, C(O)NRfRg, CO2(C1-C6alkyl), COOH, C1-C4alkylene-R27, or O-R28wherein R27is cyano, NRmRn, or COOH; R28is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, or (C1-C4alkylene)C1-C4alkoxy; and each Rf, Rg, Rm, and Rnis independently hydrogen or C1-C4alkyl.

[0281] In some embodiments, R2is phenyl substituted with 1, 2, 3, 4, or 5 deuterium atoms. In some embodiments, the phenyl with 1, 2,3, or 4 deuterium atoms may be - 65 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) additionally substituted with one or more of halo, C1-C6alkyl, cyano, or C1-C6haloalkyl. In some embodiments,

[0282] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted pyridinyl. In some embodiments, the optionally substituted pyridinyl may attach to L at any carbon atom in the pyridinyl ring, i.e.,, and the like, whereinindicates the point of attachment to L.

[0283] In some embodiments, R2is an unsubstituted pyridinyl.

[0284] In some embodiments,

[0285] In some embodiments, R2is a substituted pyridinyl. In some embodiments, the pyridinyl may be substituted with 1, 2, or 3, independently selected substituents.

[0286] In some embodiments, R2is a pyridinyl substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, OH, NRmRn, C(O)NRfRg, CO2(C1-C6alkyl), COOH, C1-C4alkylene-R27, or O-R28wherein R27is cyano, NRmRn, or COOH; R28is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, or (C1-C4alkylene)C1-C4alkoxy; and each Rf, Rg, Rm, and Rnis independently hydrogen or C1-C4alkyl.

[0287] In some embodiments, R2is a pyridinyl, where the pyridinyl nitrogen atomis substituted by an oxide (=O) to form an N-oxide, such as, for example,. - 66 - ME148476702v.1128748-02920 (AGI-BCAT-03WO).

[0289] In some embodiments, R2is pyridinyl substituted with 1, 2, 3, or 4 deuterium atoms. In further embodiments, the pyridinyl with 1, 2, or 3 deuterium atoms may be additionally substituted with one or more of halo, C1-C6alkyl, or C1-C6haloalkyl. In yet some embodiments,

[0290] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted 5-membered heteroaryl, such as, for example, optionally substituted: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, or thiadiazolyl. In some embodiments, the optionally substituted 5-membered heteroaryl may attach to L at a carbon atom or a nitrogen atom in the 5-membered heteroaryl ring.

[0291] In some embodiments, R2is optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl.

[0292] In some embodiments, R2is an unsubstituted 5-membered heteroaryl.

[0293] In some embodiments, R2is an unsubstituted pyrazolyl. In some embodiments,

[0294] In some embodiments, R2is an unsubstituted triazolyl. In some- 67 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0295] In some embodiments, R2is a substituted 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl may be substituted with 1, 2, or 3, independently selected substituents. In some embodiments, R2is a 5-membered heteroaryl substituted with one or more of halo, C1-C6alkyl, or C1-C6haloalkyl. In other embodiments, R2is a 5- membered heteroaryl substituted with one or more C1-C6alkyl. In yet other embodiments, R2is a 5-membered heteroaryl substituted with one or more CH3. In some embodiments, R2is

[0297] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, such as, for example, optionally substituted: azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, dioxanyl, tetrahydropyranyl, thianyl, thianyl sulfone, thianyl sulfoxide, or 1-oxo-1-imino-1-thiacyclohexyl. In some embodiments, the optionally substituted heterocycloalkyl may attach to L at a carbon atom or a nitrogen atom in the heterocycloalkyl ring.

[0298] In some embodiments, R2is optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted dioxanyl.

[0299] In some embodiments, R2is optionally substituted tetrahydrofuranyl, optionally substituted optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted dioxanyl, or optionally substituted tetrahydropyranyl. - 68 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0300] In some embodiments, R2is an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl.

[0301] In some embodiments,

[0302] In some embodiments, R2is a substituted 4-, 5-, or 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl may be substituted with 1, 2, or 3, independently selected substituents.

[0303] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted C1-C6alkyl, such as, for example, optionally substituted: C6alkyl, C5alkyl, C4alkyl such as CH2CH(CH3)2, C3alkyl such as CH(CH3)2, C2alkyl, or C1alkyl (e.g., CH3).

[0304] In some embodiments, R2is unsubstituted C1-C6alkyl.

[0305] In some embodiments, R2is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, or CH2C(CH3)3.

[0306] In some embodiments, R2is CH3.

[0307] In some embodiments, R2is CH2CH3.

[0308] In some embodiments, R2is CH2CH(CH3)2.

[0309] In some embodiments, R2is CH(CH3)2.

[0310] In some embodiments, R2is C(CH3)3.

[0311] In some embodiments, R2is CH2C(CH3)3.

[0312] In some embodiments, R2is C1-C6alkyl, substituted with cyano, OH, or C(O)NRiRj, wherein each Riand Rjis independently hydrogen or C1-C4alkyl.

[0313] In some embodiments, R2is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, CH2C(CH3)3, C(CH3)2OH, CH(OH)(CH3), C(CH3)2CN, C(CH3)2C(O)NH2, or C(CH3)(CH2CH2OH).

[0314] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- - 69 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted C1-C6alkoxy, such as, for example, optionally substituted: C6alkoxy, C5alkoxy, C4alkoxy, C3alkoxy such as OCH(CH3)2, C2alkoxy, or C1alkoxy (e.g., OCH3).

[0315] In some embodiments, R2is unsubstituted C1-C6alkoxy.

[0316] In some embodiments, R2is OCH3 or OCH(CH3)2.

[0317] In some embodiments, R2is C1-C6alkoxy, optionally substituted with OH.

[0318] In some embodiments, R2is OCH3, OCH(CH3)2, or OCH2CH2OH.

[0319] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted C1-C6haloalkyl, such as, for example, optionally substituted: C6haloalkyl, C5haloalkyl, C4haloalkyl, C3haloalkyl such as CH(CH3)(CF3), C2haloalkyl such as CH2CF3, or C1haloalkyl such as CF3, CHF2 or CH2F.

[0320] In some embodiments, R2is unsubstituted C1-C6haloalkyl.

[0321] In some embodiments, R2is CF3, CH(CH3)(CF3), CH2CF3, C(CH3)2F, CH2C(CH3)2F, C(CH3)F2, CH2C(CH3)F2, CHFCH(CH3)2, or CF2CH(CH3)2.

[0322] In some embodiments, R2is CF3.

[0323] In some embodiments, R2is CH2CF3.

[0324] In some embodiments, R2is CH(CH3)(CF3).

[0325] In some embodiments, R2is C(CH3)2F.

[0326] In some embodiments, R2is CH2C(CH3)2F.

[0327] In some embodiments, R2is C(CH3)F2.

[0328] In some embodiments, R2is CH2C(CH3)F2.

[0329] In some embodiments, R2is CHFCH(CH3)2.

[0330] In some embodiments, R2is CF2CH(CH3)2.

[0331] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula - 70 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted C1-C6haloalkoxy, such as, for example, optionally substituted: C6haloalkoxy, C5haloalkoxy, C4haloalkoxy, C3haloalkoxy such as OCH(CH3)(CF3), C2haloalkoxy such as OCH2CF3, or C1haloalkoxy such as OCF3, OCHF2, or OCH2F.

[0332] In some embodiments, R2is unsubstituted C1-C6haloalkoxy.

[0333] In some embodiments, R2is OCF3, OCH2CF3, OCHF2, OCH2F, or OCH(CH3)(CF3).

[0334] In some embodiments, R2is OCF3.

[0335] In some embodiments, R2is OCH2CF3.

[0336] In some embodiments, R2is OCHF2.

[0337] In some embodiments, R2is OCH2F.

[0338] In some embodiments, R2is OCH(CH3)(CF3).

[0339] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is optionally substituted C3-C6cycloalkyl.

[0340] In some embodiments, R2is unsubstituted C3-C6cycloalkyl.

[0341] In some embodiments, R2is C3-C6cycloalkyl, optionally substituted with one or more of C1-C4alkyl or C1-C4haloalkyl.

[0342] In some embodiments, R2is cyclopropyl, cyclobutyl,.

[0343] In some embodiments, R2in the compounds of Formula I, Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, Formula I-G, Formula I- G-1, Formula I-H, Formula I-H-1, Formula I-J, Formula I-J-1, Formula I-K, Formula I-K-1, Formula II, Formula II-A, Formula II-B, Formula II-C, Formula II-D, Formula II-E, Formula II-F, Formula II-G, Formula II-G-1, Formula II-H, Formula II-H-1, Formula II-J, Formula II- J-1, Formula II-K, or Formula II-K-1 is NRbRc, wherein Rband Rcare each independently - 71 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) hydrogen, C1-C6alkyl, C1-C6haloalkyl, OH, C1-C4alkoxy, C1-C6hydroxyalkyl, or C3- C6cycloalkyl.

[0344] In some embodiments, R2is NH2, NH(CH3), N(CH3)2, NH(CH(CH3)2), N(CH3)(CH2CH3), N(CH3)(cyclopropyl), NH(CH2CH3), or N(CH3)(CH2CH3).

[0345] In some embodiments, the compound is a compound of Formula I selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of Formula I selected from Table 1, or a pharmaceutically acceptable salt thereof. In yet other embodiments, the compound is a compound of Formula I selected from Table 2, or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the compound is a compound of Formula II selected from Table 3 or Table 4, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of Formula II selected from Table 3, or a pharmaceutically acceptable salt thereof. In yet other embodiments, the compound is a compound of Formula II selected from Table 4, or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, compounds of the disclosure are any one or more of the compounds of Tables 1, 2, 3, and 4, and their pharmaceutically acceptable salts and / or isotopologues. Compounds having the Formulas I and II are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included.

[0348] In another embodiment, the compounds of the disclosure may be enantiomerically enriched, e.g., the enantiomeric excess or “ee” of the compound is greater than about 5% as measured by chiral HPLC. In some embodiments, the ee is greater than about 10%. In some embodiments, the ee is greater than about 20%. In further embodiments, the ee is greater than about 30%. In yet some embodiments, the ee is greater than about 40%. In still further embodiments, the ee is greater than about 50%. In some embodiments, the ee is greater than about 60%. In further embodiments, the ee is greater than about 70%. In still some embodiments, the ee is greater than about 80%. In yet further embodiments, the ee is greater than about 85%. In some embodiments, the ee is greater than about 90%. In further embodiments, the ee is greater than about 91%. In yet some embodiments, the ee is greater than about 92%. In still further embodiments, the ee is greater than about 93%. In some embodiments, the ee is greater than about 94%. In further embodiments, the ee is greater than about 95%. In still some embodiments, the ee is greater than about 96%. In yet further embodiments, the ee is greater than about 97%. In some embodiments, the ee is greater than about 98%. In further embodiments, the ee is greater than about 99%. - 72 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0349] The present disclosure encompasses the preparation and use of salts of compounds of the disclosure. Salts of compounds of the disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid or base as appropriate. Examples

[0350] In some embodiments, the disclosure provides specific examples of Formula I, and their pharmaceutically acceptable salts and / or isotopologues, as set forth in Table 1 below.- 73 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 74 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 75 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 76 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 77 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 78 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 79 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 80 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 81 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 82 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 83 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 84 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 85 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 86 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 87 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 88 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 89 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 90 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 91 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 92 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 93 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 94 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 95 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 96 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 97 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 98 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 99 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 100 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 101 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 102 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 103 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 104 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 105 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 106 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 107 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 108 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 109 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 110 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 111 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 112 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 113 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 114 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 115 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0351] In some embodiments, the disclosure provides additional prophetic examples of Formula I, and their pharmaceutically acceptable salts and / or isotopologues, as set forth in Table 2 below. The prophetic compounds in Table 2 may be made in accordance with the procedures described in the General Schemes, Intermediate Schemes, and Examples herein alone or in combination with knowledge of a person of ordinary skill in the art.- 116 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 117 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 118 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 119 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 120 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 121 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0352] In some embodiments, the disclosure provides specific examples of Formula II, and their pharmaceutically acceptable salts and / or isotopologues, as set forth in Table 3 below.- 122 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 123 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Table 3- 124 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Table 3- 125 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Table 3- 126 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Table 3- 127 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Table 3

[0353] In some embodiments, the disclosure provides additional prophetic examples of Formula II, and their pharmaceutically acceptable salts and / or isotopologues, as set forth in Table 4 below. The prophetic compounds in Table 4 may be made in accordance with the procedures described in the General Schemes, Intermediate Schemes, and Examples herein alone or in combination with knowledge of a person of ordinary skill in the art. - 128 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 129 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 130 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)- 131 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)Pharmaceutical Compositions

[0354] The disclosure also provides pharmaceutical compositions comprising compounds of the disclosure and a pharmaceutically acceptable carrier or excipient.

[0355] The methods of the present disclosure can be accomplished by administering compounds of the disclosure as the neat compound or as a pharmaceutical composition. Administration of a pharmaceutical composition, or neat compound of the disclosure, can be performed at any time period as determined by the attending physician. Typically, the pharmaceutical compositions contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.

[0356] Pharmaceutical compositions include those wherein compounds of the disclosure are administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician.

[0357] Compounds of the disclosure can be administered by any suitable route, e.g., by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high-pressure technique.

[0358] Compounds of the disclosure may be administered in admixture with pharmaceutical carriers selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more - 132 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) physiologically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of compounds of the disclosure.

[0359] Administration of the compounds or pharmaceutical compositions of the disclosure can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

[0360] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. The desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, e.g., as one, two, three, four or more subdoses per day. In some embodiments, the compounds disclosed herein are effective over a wide dosage range. For example, in the treatment of adult humans, dosage forms containing from about 0.01 to 1000 mg of a compound disclosed herein per day are examples of dosage forms that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.

[0361] In some embodiments, a compound of the disclosure is administered in a single dose.

[0362] Typically, such administration will be by a solid oral dosage form such as tablet or capsule. However, other routes may be used as appropriate. A single dose of a compound may also be used for treatment of an acute condition.

[0363] In some embodiments, a compound of the disclosure may be administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. In another embodiment, a compound described herein and another therapeutic agent are administered together about once per day to about 6 times per day. Administration of the compounds disclosed herein may continue as long as - 133 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) necessary. In some embodiments, a compound is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0364] An effective amount of a compound of the disclosure may be administered in either single or multiple doses by any of the accepted modes of administration of therapeutic agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0365] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include one or more conventional pharmaceutical carriers or excipients and a compound disclosed herein as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0366] Exemplary parenteral administration forms include solutions or suspensions of the compound of the disclosure in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0367] Unless otherwise noted, the amounts of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent or counterions (such as in pharmaceutically acceptable salts).

[0368] Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same. Pharmaceutical compositions for oral administration.

[0369] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing a compound of the disclosure and pharmaceutical excipients suitable for oral administration.

[0370] In some embodiments, the disclosure provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the disclosure; optionally (ii) an effective amount of a second therapeutic agent; and (iii) a - 134 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) pharmaceutical excipient suitable for oral administration. In some embodiments, the pharmaceutical composition further contains: (iv) an effective amount of a third therapeutic agent.

[0371] In some embodiments, the pharmaceutical composition may be a pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions containing a compound of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, tablets, liquids, or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the compound of the disclosure into association with the carrier, which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately admixing the compound of the disclosure with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surfactant or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0372] This disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising a compound of the disclosure, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms containing a compound of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms containing a compound of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. - 135 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0373] The compound of the disclosure can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the pharmaceutical compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0374] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, and mixtures thereof.

[0375] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0376] Disintegrates may be used in the pharmaceutical compositions and dosage forms disclosed herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrate may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrate that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrate used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. - 136 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) About 0.5 to about 15 weight percent of disintegrate, or about 1 to about 5 weight percent of disintegrate, may be used in the pharmaceutical composition. Disintegrates that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0377] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, and mixtures thereof. A lubricant can optionally be added, in an amount of less than about 2 weight percent of the pharmaceutical composition.

[0378] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0379] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0380] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. - 137 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0381] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0382] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[0383] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof.

[0384] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0385] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated - 138 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0386] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0387] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG1000 succinate, PEG-24 cholesterol, polyglyceryl-10-oleate, Tween 40, - 139 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[0388] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0389] In one embodiment, the pharmaceutical composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the disclosure and to minimize precipitation of the compound of the disclosure. This can be important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion.

[0390] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; polyethylene glycol 66012-hydroxystearate, amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone - 140 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0391] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG having a molecular weight between 100 and 8000 g / mole, glycofurol and propylene glycol.

[0392] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the pharmaceutical composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of less than about 10%, less than about 25%, less than about 50%, about 100%, or up to less than about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer may also be used, such as less than about 5%, less than about 2%, less than about 1% or even less. Typically, the solubilizer may be present in an amount of less than about 1% to about 100%, more typically less than about 5% to less than about 25% by weight.

[0393] The pharmaceutical composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. Pharmaceutical compositions for injection.

[0394] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound described herein and pharmaceutical - 141 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) excipients suitable for injection. Components and amounts of agents in the pharmaceutical compositions are as described herein.

[0395] The forms in which the pharmaceutical compositions of the disclosure may be incorporated for administration by injection include aqueous or oil suspensions or emulsions. Such compositions may comprise sesame oil, corn oil, cottonseed oil, peanut oil, elixirs containing mannitol or dextrose, sterile water, and similar pharmaceutical vehicles.

[0396] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0397] Sterile injectable solutions are prepared by incorporating the compound of the disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Other pharmaceutical compositions.

[0398] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for topical, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2004; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s - 142 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. Methods of Use

[0399] The methods disclosed herein typically comprise administering to a subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. The therapeutically effective amount of a compound of the disclosure may vary depending upon the intended application (in vitro or in vivo), the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like. In some embodiments, a therapeutically effective amount refers to a dose that will induce a particular response in target cells. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0400] In treatment methods of the disclosure, a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) is administered to a subject suffering from or diagnosed as having such a disease or disorder. An example of a dose is in the range of from about 0.001 to about 100 mg of compound per kg of subject's body weight per day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, a suitable dosage amount is from about 0.05 to about 7 g / day.

[0401] In addition, the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the diseases or disorders disclosed herein. The additional active ingredients may be coadministered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure.

[0402] In some embodiments, the disclosure is directed to a method of treating a BCAA-catabolism-related disease comprising administering a compound or pharmaceutical composition of the disclosure. - 143 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0403] In some embodiments, the BCAA-catabolism-related disease is methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), maple syrup urine disease, methylmalonic semialdehyde (MMSDH) deficiency, 3- hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, isobutyryl-CoA (IBD) deficiency, acetyl-CoA carboxylase 1 (ACC) deficiency, mitochondrial short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency, methylbutyryl CoA dehydrogenase (SBCAD) deficiency (also known as short / branched chain acyl-CoA dehydrogenase deficiency), beta-ketothiolase deficiency (BKT), hydroxy-3- methylglutaconyl-CoA lysase (HMGCL) deficiency, 3-methylglutaconyl-CoA-hydratase deficiency (MGA), 3-methylcrotonyl-CoA (3-MCC) deficiency, glutaric aciduria type 1 (GA1), 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MGA), 3-methylglutaconic acidemia, D-2 hydroxyglutaric aciduria (D2-HGA), isobutyryl-CoA dehydrogenase deficiency, 3-hydroxyisobutyric aciduria (ICBD), L-2-hydroxy-glutaricaciduria (L2HGA), malonyl-CoA decarboxylase deficiency aka malonic acidemia (MA), multiple carboxylase deficiency (MCD, holocarboxylase synthetase), or 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency.

[0404] In some embodiments, the BCAA-catabolism-related disease is an organic acidemia.

[0405] In some embodiments, the BCAA-catabolism-related disease is methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), or maple syrup urine disease.

[0406] In some embodiments, the BCAA-catabolism-related disease is methylmalonic acidemia (MMA).

[0407] In some embodiments, the BCAA-catabolism-related disease is propionic acidemia (PA).

[0408] In some embodiments, the BCAA-catabolism-related disease is isovaleric acidemia (IVA).

[0409] In some embodiments, the BCAA-catabolism-related disease is maple syrup urine disease.

[0410] In some embodiments, the methods of the disclosure reduce and / or ameliorate the symptoms of the BCAA-catabolism-related disease in the subject.

[0411] In some embodiments, the disclosure provides methods of reducing toxic BCAA metabolites in one or more bodily fluids of the subject such as the blood or urine of a subject, comprising administering a therapeutically effective amount of a BCAT2 inhibitor of - 144 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) the disclosure. As used here, the term “reducing” means that the BCAA metabolite levels in the subject’s bodily fluids are lower after being administered a therapeutically effective amount of a BCAT2 inhibitor of the disclosure than the level prior to administration. Methods of measuring the levels of BCAA metabolites in blood and urine and normal ranges of those metabolites in such bodily fluids are known in the art.

[0412] In some embodiments, the methods cause a decrease in toxic branched chain amino acid (BCAA) metabolite levels.

[0413] In some embodiments, the toxic metabolite is ammonia, propionic acid, 2- methylcitric acid, 3-hydroxypropionic acid, propionyl-CoA, methylmalonic acid, methylmalonyl-CoA or isovaleric acid. In some embodiments, the toxic metabolite is propionic acid, 2-methylcitric acid, 3-hydroxypropionic acid, propionyl-CoA, methylmalonic acid, methylmalonyl-CoA or isovaleric acid.

[0414] In some embodiments, the toxic metabolites are allosteric enzyme inhibitors.

[0415] In some embodiments, the methods of the disclosure cause an increase in BCAA levels in the blood of a subject. As used here, the term “increase” means that the BCAA level in the subject’s blood is greater after being administered a therapeutically effective amount of a BCAT2 inhibitor of the disclosure than the level prior to the administration. Methods of measuring the blood levels of BCAAs are known in the art.

[0416] In some embodiments, the BCAA is one or more of leucine, isoleucine, or valine.

[0417] In some embodiments, the methods of the disclosure modulate metabolic flux through a BCAA-catabolism pathway. As used herein, “metabolic flux” refers to the rate of passage of molecules through a metabolic pathway. The term modulate means to change, i.e., to increase or decrease. Methods of measuring metabolic flux are known in the art. Thus, in such embodiments, the metabolic flux through a BCAA-catabolism pathway is different before and after administering a BCAT2 inhibitor of the disclosure.

[0418] ln some embodiments, the methods of the disclosure decrease metabolic flux through a BCAA-catabolism pathway.

[0419] In some embodiments, the methods of the disclosure decrease BCAT2- mediated metabolic flux through a BCAA-catabolism pathway.

[0420] In some embodiments, the reduction of BCAT2-mediated flux occurs by reduction or inhibition of leucine catabolism. In some embodiments, leucine catabolism is reduced or inhibited at one or more enzymes in the BCAA-catabolism pathway, wherein the - 145 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) enzyme is branched chain α-ketoacid dehydrogenase complex (BCKDH complex), isovaleryl CoA dehydrogenase (IVD), 3-methylcrotonyl-CoA carboxylase (3MCC), 3- methylglutaconyl-CoA hydratase (3MGA), 3-hydroxy-3-methylglutaryl-CoA lyase (HMGL), acetyl-CoA carboxylase (AC), or malonyl-CoA decarboxylase (MA).

[0421] In some embodiments, the reduction of BCAT2-mediated flux occurs by reduction or inhibition of isoleucine catabolism. In some embodiments, isoleucine catabolism is reduced or inhibited at one or more enzymes in the BCAA-catabolism pathway, wherein the enzyme is BCKDH complex, methylbutyryl CoA dehydrogenase (SBCAD), mitochondrial short-chain enoyl-CoA hydratase, 2-methyl-3-hydroxyisobutyryl-CoA dehydrogenase (MHBD), acetoacetyl-CoA thiolase / beta-ketothiolase (T2 / ACAT1), AC, MA, propionyl-CoA carboxylase (PCC), or methylmalonyl-CoA mutase (MUT), or succinyl-CoA ligase (SUCLA).

[0422] In some embodiments, the reduction of BCAT2-mediated flux occurs by reduction or inhibition of valine catabolism. In some embodiments, valine catabolism is reduced or inhibited at one or more enzymes in the BCAA-catabolism pathway, wherein the enzyme is BCKDH complex, isobutyryl-CoA dehydrogenase (IBDH), mitochondrial short- chain enoyl-CoA hydratase, 3-hydroxyisobutyryl-CoA deacylase (hydrolase) (HIBDA), 3- hydroxyisobutyrate dehydrogenase (HIBDH), methylmalonic semialdehyde dehydrogenase (MMSDH), PCC, MUT, or SUCLA.

[0423] In some embodiments, the disclosure provides methods of reducing a toxic load burden in cells of a subject having a BCAA-catabolism-related disease, comprising administering a therapeutically effective amount of a BCAT2 inhibitor of the disclosure.

[0424] The present disclosure provides compounds of the disclosure as BCAT2 inhibitors for the treatment of diseases and conditions wherein inhibition of BCAT2 has a beneficial effect. Compounds of the disclosure typically inhibit BCAT2 (IC50) in a concentration less than 20 μM, e.g., less than 10 μM, less than 5 μM, less than 3 μM, and less than 2 μM, less than about 1 µM, less than about 0.5 µM, less than about 0.1 µM, less than about 0.05 µM, or less than about 0.01 µM. In some embodiments, the present disclosure relates to a method of treating a subject suffering from a disease or condition wherein inhibition of BCAT2 provides a benefit comprising administering a therapeutically effective amount of a compound of the disclosure to a subject in need thereof.

[0425] In some embodiments, the disclosure is directed to methods of reducing plasma methylmalonic acid in a subject having an elevated methylmalonic acid level comprising administering to the subject a therapeutically effective amount of a compound of - 146 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) the disclosure. As used herein, “reducing” means that the plasma methylmalonic acid level in the subject is lower after administering the compound of the disclosure than before administering the compound of the disclosure. Methods of measuring plasma methylmalonic acid levels in plasma are known in the art. See, e.g., Manoli I, et al. Isolated Methylmalonic Acidemia. 2005 Aug 16 [Updated 2016 Dec 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. As used herein, “elevated methylmalonic acid level” refers to a plasma methylmalonic acid level that is higher than the normal level expected for a given subject. See Anna-Kaisa Niemi, et al., Treatment of Methylmalonic Acidemia by Liver or Combined Liver-Kidney Transplantation, The Journal of Pediatrics, Volume 166, Issue 6, 2015, 1455- 1461.e1. Normal blood level of methylmalonic acid in humans is <0.27 µmol / L. Elevated blood levels of methylmalonic acid levels in humans range from 5-1000 µmol / L, depending in part on the enzyme deficiency that is causing the patient’s MMA.

[0426] In some embodiments, the disclosure is directed to methods of reducing blood ammonia in a subject having an elevated ammonia level (hyperammonemia) comprising administering to the subject a therapeutically effective amount of a compound of the disclosure. As used here, “reducing” means that the blood ammonia level in the subject is lower after administering the compound of the disclosure than before administering the compound of the disclosure. Normal blood level of ammonia in humans generally range from 11-32 µmol / L. A blood ammonia level above 75 µmol / L is associated with symptomatic decompensation and a blood ammonia level above 200 µmol / L is associated with impaired vigilance. See Nicola Longo et al., Hyperammonaemia in classic organic acid: a review of the literature and two case histories, Orphanet Journal of Rare Diseases, Volume 13, Issue 1, 2018, 219.

[0427] In some embodiments, the disclosure is directed to methods of reducing blood 2-methylcitrate in a subject having an elevated 2-methylcitrate level comprising administering to the subject a therapeutically effective amount of a compound of the disclosure. As used here, “reducing” means that the blood 2-methylcitrate level in the subject is lower after administering the compound of the disclosure than before administering the compound of the disclosure. Normal blood level of 2-methylcitrate in humans is ≤ 0.63 µmol / L, whereas blood 2-methylcitrate in MMA and PA patients range between 1.0-12.0 µmol / L according to one report. Osama Y. Al-Dirbashi et al., Assessment of methylcitrate and methylcitrate to citrate ratio in dried blood spots as biomarkers for inborn errors of propionate metabolism, Volume 9, 2019, 123666. - 147 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0428] In some embodiments, the methods of the disclosure are performed in combination with other treatment strategies.

[0429] In some embodiments, the other treatment strategies are aimed at reducing the levels of toxic metabolites.

[0430] In some embodiments, the treatment strategies aimed at reducing the levels of toxic metabolites are directed to reducing the supply of BCAAs. Such strategies include isoleucine, valine, threonine and methionine restriction as part of a protein-restricted diet (with or without amino acid supplementation), eating a high caloric diet during illness, administering antibiotics, administering laxatives, or reducing odd-chain fatty acids and cholesterol.

[0431] In some embodiments, the treatment strategies aimed at reducing the levels of toxic metabolites are directed to increasing enzyme activity. Such embodiments include administering hydroxycobalamin, solid organ transplantation (liver or combined liver-kidney transplantation), gene therapy, promotion of premature stop codon read-through, messenger RNA therapy, pharmacological stabilization of enzyme activity, enzyme replacement therapy, or hepatocyte transplantation.

[0432] In some embodiments, the treatment strategies aimed at reducing the levels of toxic metabolites are directed to increasing disposal of toxic metabolites. Such embodiments include administering a carbamoyl phosphate synthetase 1 (CPS 1) activator, administering N-carbamylglutamate (CARBAGLU®), administering sodium benzoate, extracorporeal detoxification, administering L-carnitine, or administering sodium bicarbonate.

[0433] In some embodiments, the other treatment strategies are aimed at preventing or treating mitochondrial energetic failure and increase of reactive oxygen species (ROS) formation.

[0434] In some embodiments, other treatment strategies aimed at preventing or treating mitochondrial energetic failure and increase of reactive oxygen species (ROS) formation are directed to effecting energetic supply. Such embodiments include administering succinate, citric acid, or creatine.

[0435] In some embodiments, other treatment strategies aimed at preventing or treating mitochondrial energetic failure and increase of reactive oxygen species (ROS) formation are directed to cofactor supplementation. Such embodiments include administering pyridoxine (vitamin B6) or administering thiamine (vitamin B1). - 148 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0436] In some embodiments, other treatment strategies aimed at preventing or treating mitochondrial energetic failure and increase of reactive oxygen species (ROS) formation are directed to anti-oxidant supplementation. Such embodiments include administering coenzyme Q10, ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), CB agonist WIN, S-allylcysteine, gluthathione, GM1 ganglioside, melatonin, mitoQ, resveratrol, tiron, or trolox.

[0437] In some embodiments, the other treatment strategies that are aimed at preventing or treating mitochondrial energetic failure and increase of reactive oxygen species (ROS) formation are directed to electron transfer mediator supplementation. Such embodiments include administering methylene blue.

[0438] In some embodiments, the other treatment strategies that are aimed at preventing or treating mitochondrial energetic failure and increase of reactive oxygen species (ROS) formation are directed to administering NMDA receptor antagonists. Such embodiments include administering celecoxib, fish oil, kynurenic acid, or MK-801.

[0439] In some embodiments, the other treatment strategies include administering an inhibitor of an ammo acid transporter, optionally with a SLC6A19 inhibitor. In further embodiments, the amino acid transporter is B0AT1 (also referred to as SLC6A19), and the inhibitor is a SLC6A19 inhibitor. Examples of SLC6A19 inhibitors include nimesulide, benztropine, NSC63912, NSC22789, cinromide, CB3, E62, JNT-517, and the like.

[0440] In some embodiments, performing the methods of the disclosure in combination with the other treatment strategies results in levels of branched chain amino acids that are reduced compared to treatment without performance of the other treatment strategy. Animal Models

[0441] The present disclosure also provides in vivo models for the study of disorders characterized by defects in the metabolism of branched-chain amino acids (BCAAs), e.g., leucine, isoleucine and valine. These disorders include BCAT2 deficiency, methylmalonic acidemia, and propionic acidemia.

[0442] The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. BCAT2 deficiency is an inborn error of BCAA catabolism. BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs, low-normal branched-chain keto acids (BCKAs), and undetectable L-allo- - 149 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) isoleucine. The biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet, and early treatment may improve outcome in affected individuals. See Knerr et al., J Inherit Metab Dis. 42(5): 809-817 (2019).

[0443] Methylmalonic acidemia refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix. Two main forms of the disease have been identified, isolated methylmalonic acidemia and combined methylmalonic acidemia and homocystinuria. Isolated methylmalonic acidemia is due to defects of methylmalonyl-CoA mutase or the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl), while combined methylmalonic acidemia and homocystinuria is characterized by elevated plasma homocysteine and decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Methylmalonic acidemia is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase, a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Methylmalonic acidemia has a wide clinical spectrum, ranging from a benign condition to fetal neonatal disease. Affected children usually exhibit anorexia, failure to thrive, hypotonia, developmental delay, progressive renal failure, functional immune impairment, optic nerve atrophy, and hematologic abnormalities. See Zhou et al., Intractable Rare Dis Res. 7(2): 73– 78 (2018).

[0444] Propionic acidemia (PA) is caused by deficiency of the mitochondrial multimeric enzyme propionyl-CoA carboxylase (PCC) that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. The enzyme is composed of α- and β-subunits encoded by their respective genes, PCCA and PCCB. PA is caused by deficiency in either the α or β subunits of propionyl-CoA carboxylase. Deficient activity of propionyl-CoA carboxylase results in accumulation of propionic acid and propionyl-CoA related metabolites, which can be detected biochemically. This disease causes metabolic acidosis, ketosis, vomiting, lethargy, cognitive reductions, and death. See Barry, Expert Review of Precision Medicine and Drug Development, 4:4, 229-237 (2019).

[0445] Transgenic mice for use as animal models of these disorders are described below. - 150 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) BCAT2 knockout mice as an animal model of BCAT2 deficiency

[0446] BCAT2 catalyzes the first step in BCAA metabolism, which is transfer of the α-amino group of a BCAA to α-ketoglutarate to form glutamate and the three respective branched chain α-keto acids.

[0447] In certain aspects, the disclosure relates to a mouse (Mus musculus) comprising one or more genomic mutations in an endogenous BCAT2 gene that results in a knockout of the endogenous BCAT2 gene. In some embodiments, the mouse is an animal model for Branched Chain Amino Acid Transaminase 2 (BCAT2) deficiency.

[0448] In some embodiments, the one or more mutations are in exon 3 of the BCAT2 gene. In some embodiments, the one or more mutations comprise or consist of a deletion in exon 3 of the BCAT2 gene. In some embodiments, the one or more mutations comprise or consist of a deletion of only one nucleotide in exon 3 of the BCAT2 gene. Exon 3 of the BCAT2 gene corresponds to positions 127-330 of SEQ ID NO: 1. In some embodiments, the one or more mutations in exon 3 of the BCAT2 gene comprise or consist of a deletion of adenine (A) at position 245 of SEQ ID NO: 1.

[0449] In some embodiments, the one or more mutations result in a premature stop codon in the BCAT2 gene. In some embodiments, the premature stop codon is in exon 4 of the BCAT2 gene. Exon 4 of the BCAT2 gene corresponds to positions 331-441 of SEQ ID NO: 1. In some embodiments, the premature stop codon in exon 4 of the BCAT2 gene is a TGA stop codon at positions 344-346 of SEQ ID NO: 1.

[0450] In some embodiments, the mouse is homozygous for the knockout of the endogenous BCAT2 gene. These mice are designated as BCAT2KO / KOmice herein. In some embodiments, the mouse is heterozygous for the knockout of the endogenous BCAT2 gene. These mice are designated as BCAT2KO / WTherein.

[0451] In some embodiments, the mouse is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous BCAT2 gene. In some embodiments, a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 8 and an sgRNA encoded by the polynucleotide sequence of SEQ ID NO: 9 are used for the CRISPR / Cas9-mediated HDR.

[0452] In some embodiments, the mouse comprising a knockout of one or more BCAT2 genes has increased plasma isoleucine levels relative to a mouse that does not comprise a knockout of an endogenous BCAT2 gene. In some embodiments, BCAT2KO / KOmice have at least a 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold - 151 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) increase in plasma isoleucine levels relative to a mouse that does not comprise a knockout of an endogenous BCAT2 gene. The term “2-fold increase” as used herein refers to a doubling of a value relative to a standard, e.g., an increase in plasma isoleucine levels from 10 µM to 20 µM. The term “3-fold increase” as used herein refers to a tripling of a value relative to a standard, etc. In some embodiments, BCAT2KO / KOmice have at least a 10-fold increase in plasma isoleucine levels relative to a mouse that does not comprise a knockout of an endogenous BCAT2 gene.

[0453] In some embodiments, the mouse comprising a knockout of one or more BCAT2 genes has reduced plasma levels of 3-HIB (a downstream metabolite of valine breakdown) relative to a mouse that does not comprise a knockout of an endogenous BCAT2 gene. In some embodiments, BCAT2KO / KOmice have at least a 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% reduction in plasma 3-HIB levels relative to a mouse that does not comprise a knockout of an endogenous BCAT2 gene. In some embodiments, BCAT2KO / KOmice have at least a 50% reduction in plasma 3-HIB levels relative to a mouse that does not comprise a knockout of an endogenous BCAT2 gene. MMA-CoA Mutase M698K / M698K, M698K / KO, and combination with BCAT2 KO

[0454] Methylmalonyl-CoA mutase is a nuclear-encoded mitochondrial enzyme that catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA, which then enters the citric acid cycle. L-Methylmalonyl-CoA is predominantly derived from the catabolism of branched chain amino acids in the diet, odd chain fatty acids via propionyl-CoA, and propionate synthesized from gut flora. See Peters, et al., J Biol. Chem. 278(52): 52909–52913 (2003).

[0455] In certain aspects, the disclosure relates to a mouse (Mus musculus) comprising one or more genomic mutations in at least one endogenous methylmalonyl Coenzyme A (MMA-CoA) mutase gene that results in an M698K substitution relative to the amino acid sequence of SEQ ID NO: 4 in a MMA-CoA protein encoded by the gene. In some embodiments, the mouse is an animal model for methylmalonic academia. Any one or more genomic mutations that result in an M698K mutation in MMA-CoA mutase may be used. In some embodiments, the one or more genomic mutations consist of or comprise a T2228A substitution relative to the nucleic acid sequence of SEQ ID NO: 3. Other genomic mutations that result in an M698K substitution in MMA-CoA mutase may also be used. For example, in some embodiments, the T2228A substitution relative to the nucleic acid sequence - 152 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) of SEQ ID NO: 3 may be combined with a G2229A substitution relative to the nucleic acid sequence of SEQ ID NO: 3. The combination of the T2228A and G2229 substitutions converts the ATG codon (encoding methionine) at positions 2227-2229 of SEQ ID NO: 3 to an AAA codon (encoding lysine).

[0456] In some embodiments, the mouse is homozygous for the one or more genomic mutations in the endogenous MMA-CoA mutase gene that results in the M698K substitution. These homozygous mice are designated as MUTM698K / M698Kmice herein. In some embodiments, the mouse is heterozygous for the one or more genomic mutations in the endogenous MMA-CoA mutase gene that results in the M698K substitution. These heterozygous mice are designated as MutM698K / WTherein. In some embodiments, the mouse comprises the one or more genomic mutations that results in the M698K substitution at a first locus of an endogenous MMA-CoA mutase gene, and further comprises one or more genomic mutations that result in a knockout of an endogenous MMA-CoA mutase gene at a second locus of an endogenous MMA-CoA mutase gene. These mice are designated as MUTM698K / KOmice herein.

[0457] In some embodiments, the mice comprising the M698K substitution in the MMA-CoA mutase gene are generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous MMA-CoA mutase gene that results in the M698K substitution. In some embodiments, a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 19 and an sgRNA encoded by the polynucleotide sequence of SEQ ID NO: 20 are used for the CRISPR / Cas9- mediated HDR to generate the M698K substitution. In some embodiments, the CRISPR / Cas9-mediated HDR utilizes a donor DNA having the polynucleotide sequence of SEQ ID NO: 21 to generate the M698K substitution.

[0458] In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene is in exon 2 of the endogenous MMA- CoA mutase gene. Exon 2 of the MMA-CoA mutase gene corresponds to positions 96 to 514 of SEQ ID NO: 3. In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene introduce a premature stop codon into the endogenous MMA-CoA mutase gene. For example, in some embodiments, in the MMA- CoA mutase knockout mice the guanine (g) at position 311 of SEQ ID NO: 3 is changed to adenine (A), resulting in the codon encoding tryptophan (TGG) at positions 310-312 of SEQ ID NO: 3 being converted to a stop codon (TAG). Accordingly, in some embodiments, the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA - 153 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) mutase gene comprise or consist of a G311A substitution relative to the nucleic acid sequence of SEQ ID NO: 3. Any one or more genomic mutations that result in a stop codon being introduced into the MMA-CoA mutase gene may be used. For example, in some embodiments, the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene comprise or consist of G311A and G312A substitutions relative to SEQ ID NO: 3, resulting in the stop codon TAA at positions 310-312 of SEQ ID NO: 3. In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene comprise or consist of a G312A substitution relative to SEQ ID NO: 3, resulting in the stop codon TGA at positions 310-312 of SEQ ID NO: 3. In some embodiments, the mouse is homozygous for the knockout of the endogenous MMA-CoA mutase gene. These mice are designated MUTKO / KOmice herein.

[0459] In some embodiments, CRISPR / Cas9-mediated homology-directed repair (HDR) is used to introduce the one or more genomic mutations into the endogenous MMA- CoA mutase gene that results in a knockout of an endogenous MMA-CoA mutase gene. In some embodiments, a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 14 is used for the CRISPR / Cas9-mediated HDR.

[0460] In some embodiments, the MUTKO / KOmice, the MUTM698K / KOmice, or the MUTM698K / M698Kmice further comprises one or more genomic mutations in an endogenous BCAT2 gene that results in a knockout of the endogenous BCAT2 gene. In some embodiments, the mouse is homozygous for the knockout of the endogenous BCAT2 gene (BCAT2KO / KO).

[0461] In some embodiments, the mouse comprising the M698K substitution in MMA-CoA mutase and / or knockout of the MMA-CoA mutase gene has increased plasma and / or urine levels of a compound selected from the group consisting of 3-OH-isobutyric acid (3-HIB) and methylmalonic acid (MMA) relative to a syngeneic wildtype mouse.

[0462] In some embodiments, the homozygous MutM698K / M698Kmice have increased plasma and urine MMA levels relative to heterozygous MutM698K / WTmice, or relative to MutWT / WTmice. In some embodiments, the MutM698K / M698Kmice have at least a 2- fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold increase in plasma and / or urine MMA levels relative to heterozygous MutM698K / WTmice, or relative to MutWT / WTmice. In some embodiments, the homozygous MutM698K / M698Kmice have at least a 10-fold increase in plasma MMA levels relative to heterozygous MutM698K / WTmice. In some embodiments, the homozygous MutM698K / M698Kmice have at least a 100-fold increase in plasma MMA levels relative to heterozygous MutM698K / WTmice. In some embodiments, the homozygous - 154 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) MutM698K / M698Kmice have at least a 10-fold increase in urine MMA levels relative to heterozygous MutM698K / WTmice. In some embodiments, the homozygous MutM698K / M698Kmice have at least a 50-fold increase in urine MMA levels relative to heterozygous MutM698K / WTmice.

[0463] In some embodiments, heterozygous MutM698K / KOmice have at least a 2- fold, 3-fold, 4-fold, 5-fold, 10-fold, or 20-fold increase in plasma and / or urine MMA levels relative to homozygous MutM698K / M698Kmice. In some embodiments, heterozygous MutM698K / KOmice have at least a 2-fold increase in plasma MMA levels relative to homozygous MutM698K / M698Kmice. In some embodiments, heterozygous MutM698K / KOmice have at least a 10-fold increase in urine MMA levels relative to homozygous MutM698K / M698Kmice. PCCA A134T / A134T and A134T / KO

[0464] Propionyl-CoA carboxylase (PCC) is a ubiquitously expressed, heteropolymeric mitochondrial enzyme involved primarily in the catabolism of branched- chain amino acids and fatty acids, which harbor odd-numbered chain lengths. PCC contains two subunits, an α subunit (PCCA) and a β subunit (PCCB).

[0465] In certain aspects, the disclosure relates to a mouse (Mus musculus) comprising one or more genomic mutations in at least one endogenous propionyl-Coenzyme A carboxylase (PCCA) gene that results in an A134T substitution relative to the amino acid sequence of SEQ ID NO: 6 in a PCCA protein encoded by the gene. In some embodiments, the mouse is an animal model for propionic academia. The A134T substitution may be introduced into PCCA by changing the guanine (G) at position 439 of the nucleic acid sequence of SEQ ID NO: 5 to an adenine (A). This substitution changes the alanine (A) codon GCT at positions 439 to 441 of SEQ ID NO: 5 to the threonine (T) codon ACT. Accordingly, in some embodiments, the one or more genomic mutations comprise or consist of a G439A substitution relative to the nucleic acid sequence of SEQ ID NO: 5. Any substitution in the PCCA gene that results in the A134T substitution in the PCCA protein may be used. For example, in some embodiments, the G439A substitution may be combined with a T441C, T441A or T441G substitution relative to the nucleic acid sequence of SEQ ID NO: 5 to produce the A134T substitution in the PCCA protein.

[0466] In some embodiments, the mouse is homozygous for the one or more genomic mutations in the endogenous PCCA gene that results in the A134T substitution. - 155 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) These mice are designated as PCCAA134T / A134Tmice herein. In some embodiments, the mouse is heterozygous for the one or more genomic mutations in the endogenous PCCA gene that results in the A134T substitution. These mice are designated as PCCAA134T / WTmice herein.

[0467] In some embodiments, the mouse comprises the one or more genomic mutations that results in the A134T substitution at a first locus of an endogenous PCCA gene, and further comprises one or more genomic mutations that result in a knockout of an endogenous PCCA gene at a second locus of an endogenous PCCA gene. In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous PCCA gene are in exon 5 of the endogenous PCCA gene. Exon 5 is nucleotides 328-441 of SEQ ID NO: 5. In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous PCCA gene introduce a premature stop codon into the endogenous PCCA mutase gene. In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous PCCA gene comprise the addition of one or more nucleotides to exon 5 of the endogenous PCCA gene. For example, the knockout in exon 5 may be introduced by adding an additional adenine (A) after the adenine (A) at position 379 of SEQ ID NO: 5. This addition creates a premature stop codon at positions 381-383 of SEQ ID NO: 5. Any mutation that results in a premature stop codon in exon 5 may be used. For example, in some embodiments, addition of a single nucleotide upstream of position 381 of SEQ ID NO: 5 may be used to create the premature stop codon in exon 5. In some embodiments, the one or more genomic mutations that result in a knock out of the endogenous PCCA gene comprise the addition of a nucleotide at position 379 of SEQ ID NO: 5. In some embodiments, the nucleotide is adenine.

[0468] In some embodiments, the mouse containing an A134T substitution in PCCA is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous PCCA gene that results in an A134T substitution. In some embodiments, a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 31 is used for the CRISPR / Cas9-mediated HDR. In some embodiments, the CRISPR / Cas9-mediated HDR utilizes a donor DNA having the polynucleotide sequence of SEQ ID NO: 32. In some embodiments the mouse containing an A134T substitution in PCCA is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous PCCA gene that results in a knockout of an endogenous PCCA gene. In some embodiments, a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 26 is used for the CRISPR / Cas9-mediated HDR. - 156 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0469] In some embodiments, the mouse having an A134T substitution in PCCA and / or a knockout of an endogenous PCCA gene has increased plasma propionyl carnitine (PPC) levels relative to a mouse that does not comprise the A134T substitution and / or a knockout in an endogenous PCCA gene. For example, in some embodiments, PCCA134T / A134Tmice have increased PPC levels relative to wildtype mice. In some embodiments, the mouse having an A134T substitution in PCCA and / or a knockout of an endogenous PCCA gene has at least a 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or 20-fold increase in plasma PPC levels relative to a wildtype mouse. For example, in some embodiments, homozygous PCCAA134T / A134Tmice have at least a 5-fold increase in plasma PPC levels relative to a wildtype mouse.

[0470] In some embodiments, the mice described herein are male. In some embodiments, the mice described herein are female. In some embodiments, the mice described herein are C57BL / 6 mice. Synthesis of Compounds of the Disclosure

[0471] Compounds of the disclosure can be prepared by methods described in the General Schemes, Intermediate Schemes, procedures, and Examples set forth within, and by related methods known in the art.

[0472] General Scheme 1A: Preparation of Compounds of Formula I-A and Formula II-A- 157 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0473] Compounds of formulas I-A and II-A were obtained through General Scheme 1A. Starting with an intermediate of formula A1 or A2, Ar1groups were then installed by reacting an Ar1carboxylic acid of formula 1.1 or a basic salt (i.e., Li, K, or Na) thereof with the amine of formula A1 or A2 using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base) or TEA, to afford compounds of Formula I-A or II-A. If the compounds still contain any protecting groups on the Cy or R2groups, they may be removed under acidic conditions such as hydrochloric acid to afford compounds of Formula I-A or II-A.

[0474] General Scheme 1B: Preparation of Formulas I-B and II-B

[0475] Compounds of formulas I-B and II-B wherein R3aand R3bare each hydrogen were obtained through General Scheme 1B. Starting with an intermediate of formula A1 or A2, the amine in a compound of formula A1 or A2 was condensed with a methyl 2- (bromomethyl)benzoate of formula 1.2 in the presence of a base, such as TEA, and heat, followed by cyclization to afford compounds of formulas 1.3 and 1.4. - 158 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0476] General Scheme 1C: Preparation of Formulas I-C and II-C

[0477] Compounds of formulas I-C and II-C wherein R3aand R3bare each hydrogen were obtained through General Scheme 1C. Starting with an intermediate of formula A1 or A2, the amine in a compound of formula A1 or A2 was condensed with a methyl 2-(2-bromoethyl)benzoate of formula 1.5 (Method A) or an isochroman-1-one of formula 1.6 (Method B) in the presence of a base, such as TEA, and heat, followed by cyclization to afford compounds of formulas 1.7 and 1.8.

[0478] Alternatively, in method B, the isochroman-1-one of formula 1.6 may be activated first by reacting it with thionyl chloride and heat to afford a 2-(2- chloroethyl)benzoyl chloride of formula 1.9,, which is then condensed with the amine of formula A1 or A2 in the presence of a base and heat. - 159 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0479] General Scheme 1D: Preparation of Compounds of Formulas I-D and II-D

[0480] Compounds of formulas I-D and II-D wherein Y is O were obtained through General Scheme 1D. Starting with an intermediate of formula A1 or A2, the amine in a compound of formulas A1 or A2 was reacted with a 2-hydroxybenzoic acid of formula 1.10 using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base) or TEA, to afford compounds of formulas 1.11 and 1.13. A compound of formula 1.11 or 1.13 was treated with 1,3,5- trioxlane, sodium metabisulfite, and sulfuric acid to afford compounds of formulas 1.12 and 1.14.

[0481] General Scheme 1E: Couplings to Afford Compounds of Formulas I-D and I-E and Formulas II-D and II-E - 160 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0482] Compounds of formulas I-D and I-E and formulas II-D and II-E, wherein Y is N were obtained through General Scheme 1E. In Step 1, starting with an intermediate of formula A1 or A2, the amine in a compound of formulas A1 or A2 was reacted with a Boc- protected 2-(amino)benzoic acid of formula 1.15 using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base) or TEA, followed by removal of the boc protecting group under acidic conditions to afford compounds of formulas 1.16 and 1.19. In Step 2, a compound of formula 1.16 or 1.19 is then cyclized using the reagents in Methods A or B to afford compounds of formulas 1.17 and 1.20. In Method A, a compound of formula 1.16 or 1.19 is reacted with 1,3,5-trioxlane, - 161 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) sodium metabisulfite, and sulfuric acid. In Method B, a compound of formula 1.16 or 1.19 is reacted with formaldehyde and a base such as sodium hydroxide in an alcoholic solvent with heat. In Step 3, a compound of formula 1.16 or 1.19 is reacted with trimethoxymethane to afford a compound of formula 1.18 and 1.21.

[0483] General Scheme 1F: Couplings to Afford Compounds of Formulas I-F and II-F

[0484] Compounds of formula I-F and formula II-F, wherein Y is N were obtained through General Scheme 1F. Starting with a compound of formula 1.16 or formula 1.19 (prepared in accordance with General Scheme 1E), a compound of formula 1.16 or 1.19 is reacted with 1,3-dibromopropane and a base such as potassium carbonate to affordcompounds of formulas 1.22 and 1.23.- 162 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0485] General Scheme 1G: Preparation of Formulas I-B and II-B

[0486] Compounds of formulas I-B and II-B wherein R3ais oxo (=O) and R3bis hydrogen were obtained through General Scheme 1G. Starting with an intermediate of formula A1 or A2, the amine in a compound of formula A1 or A2 was condensed with an isobenzofuran- 1,3-dione of formula 1.24 with heat to afford compounds of formulas 1.25 and 1.26. - 163 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0487] General Scheme 1H: Preparation of Formulas I-C and II-C

[0488] Compounds of formulas I-C and II-C wherein R3ais oxo (=O) and R3bis hydrogen may be obtained through General Scheme 1H. Starting with an intermediate of formula A1 or A2, the amine in a compound of formula A1 or A2 is condensed with a 3,4- dihydro-1H-2-benzopyran-1,3-dione of formula 1.27 with heat to afford compounds of formulas 1.28 and 1.29. - 164 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0489] General Scheme 2A: Preparation of Intermediates of Formula A1

[0490] Intermediates of formula A1 were obtained through General Scheme 2A. Beginning with the 2,4-di-halo-5-nitropyridine of formula 2.1, a nucleophilic aromatic substitution reaction conducted under basic conditions was used to couple a N-Boc-1,3-Cy- diamine compound of formula 2.2 (Method A) to afford compounds of formula 2.4. Alternatively, reagent 2.1 underwent selective nucleophilic aromatic substitution by 1,3-Cy- diamine of formula 2.3 (Method B), and the intermediate amine group was protected with a Boc-protecting group (or other suitable nitrogen protecting group) to afford compounds of formula 2.4. The chloride / bromide moiety of a compound of formula 2.4 can be used as a functional handle to install various R1aryls, R1heteroaryls, and R1heterocycloalkyls. Under Method C, R1heteroaryls such as unsubstituted and substituted 1,2,4-triazoles, thiazoles, oxazoles, and imidazoles can be installed via a C-H functionalization reaction. Under Method D, the chloride / bromide moiety of a compound of formula 2.4 was converted to a R1heteroaryl or aryl using a Stille coupling (R1-SnBu3), Suzuki coupling (R1-BPin or R1- - 165 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) B(OH)2), or a cross-coupling with a substituted sulfone (R1-SO2(CH2)2-CO2CH3) to afford compounds of formula 2.6. In some cases, the chloride / bromide moiety needed to be converted to the more reactive iodide moiety using the reaction conditions in Method E prior to the Stille or Suzuki coupling. Under Method F, a heteroaryl or heterocycloalkyl containing at least one nitrogen (formula 2.5) was installed by displacing the bromide or chloride in a compound of formula 2.4 with the NH of the heteroaryl or heterocycloalkyl reagent of formula 2.5 in the presence of a suitable base such as cesium carbonate and / or a metal catalyst such as CuI to form compounds of formula 2.6. The nitro group in a compound of formula 2.6 was reduced with a reducing agent, such as iron in the presence of ammonium chloride or Pd / C, to afford the pyridine-diamine compound of formula 2.7. Subsequently, various L and R2groups were installed by coupling the pyridine-diamine compound of formula 2.7 with an acid of formula 2.8 to form an amide intermediate (Method G), which was then cyclized under either basic or acidic conditions to form compounds of formula 2.11. Alternatively, the pyridine-diamine compound of formula 2.7 was condensed with an aldehyde of formula 2.9 (Method H), followed by cyclization and in situ oxidation to afford compounds of formula 2.11. Alternatively, as shown in Method I, the pyridine-diamine compound of formula 2.7 was condensed with a carbothioyl chloride to form an amide intermediate, which was then cyclized under basic or acidic conditions to form a compound of formula 2.11. The Boc protecting group of a compound of formula 2.11 was then removed under acidic conditions such as TFA or HCl to form intermediates of formula A1. Intermediates of formula A1 may then be converted to compounds of Formula I as set forth in General Schemes 1A through 1H. - 166 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0491] General Scheme 2B: Preparation of Intermediates of Formula A1

[0492] Intermediates of formula A1 were also obtained through General Scheme 2B. The nitro group of intermediate of formula 2.4 (prepared via General Scheme 2A) was reduced with a reducing agent such as iron in the presence of ammonium chloride to afford 2- bromopyridine-diamine compounds of formula 2.12. Subsequently, various L and R2groups were installed by coupling the pyridine-diamine compound of formula 2.12 with an acid of formula 2.8 to form the amide intermediate (Method A), which was subsequently cyclized under either basic or acidic conditions to form compounds of formula 2.13. Alternatively, the pyridine-diamine compound of formula 2.12 was condensed with an aldehyde of formula 2.9 (Method B), followed by cyclization and in situ oxidation to form compounds of formula 2.13. R1groups were installed by reacting the bromide in compounds of formula 2.13 with the reagents specified in Methods A, B, C, D, E, F, G, and H to afford compounds of formula 2.11. Under Methods A and B, R1heteroaryls such as 1,2,4-triazole, 4-methyloxazole, 4- methylthiazole, imidazole, and benzoxazole were installed via a C-H functionalization reaction of the heteroaryl. Under Method C, the bromide of formula 2.13 was displaced by the NH of heterocyclic amines (saturated or aromatic) (reagent of formula 2.14) in the - 167 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) presence of a suitable base such as cesium carbonate and / or metal catalysts such as CuI. Under Method D, the bromide of formula 2.13 was converted to a R1heteroaryl or aryl using a Stille coupling (R1-SnBu3) or Suzuki coupling (R1-BPin or R1-B(OH)2) to afford compounds of formula 2.11. In some cases, the bromide moiety needed to be converted to the more reactive iodide moiety using the reaction conditions in Method E prior to the Stille or Suzuki coupling. Under Method F, a 1,2,3-triazole was installed by (1) converting the bromide of formula 2.13 to an ethynyltrimethylsilane moiety, (2) removing the trimethylsilane group under basic conditions such as potassium carbonate, and (3) reacting the intermediate with TMSN3 in the presence of a metal catalyst such as CuI. Under Method G, an 1,3,4-oxadiazol-2-one was installed by converting the bromide moiety to a methyl ester, followed by reacting the methyl ester with hydrazine hydrate and cyclizing with CDI. Under Method H, an 1,2,4-oxadiazol-one was installed by converting the bromide moiety of formula 2.13 to an iodide moiety, which was then subsequently converted to a cyano moiety via reaction with Zn(CN)2 and Pd(PPh3)4. The cyano moiety was then reacted hydroxylamine and cyclized with CDI. The Boc protecting group in compounds of formula 2.11 was removed under acidic conditions such as TFA or HCl to afford intermediates of formula A1. Intermediates of formula A1 may then be converted to compounds of Formula I as set forth in General Schemes 1A through 1H.

[0493] General Scheme 2C: Preparation of Intermediates of Formula A1

[0494] Intermediates of formula A1 were obtained through General Scheme 2C. The pyridine-diamine compound of formula 2.7 (made in accordance with General Scheme 2A) was reacted with trimethyl orthoformate to form the imidazole of azabenzimidazole compound of formula 2.17. An iodide or bromide was installed at the 2-position of the azabenzimidazole compound of formula 2.17 using a bromination or iodination reagent to - 168 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) afford compounds of formula 2.18. Subsequently, various L and R2groups were installed by displacing the halide in compounds of formula 2.18 with an R2-alcohol or R2-primary amine or heterocyclic amine of formula 2.19 (Method A), wherein the heterocyclic ring can be saturated or aromatic, to afford compounds of formula 2.11. Alternatively, using Method B, the halide in compound of formula 2.18 was converted to an aryl or R1heteroaryl group using a Stille coupling (R1-SnBu3) or a Suzuki coupling (R1-BPin or R1-B(OH)2) to afford compounds of formula 2.11. The amino Boc protecting group in compounds of formula 2.11 was removed under acidic conditions to afford intermediates of formula A1. Intermediates of formula A1 may then be converted to compounds of Formula I as set forth in General Schemes 1A through 1H.

[0495] General Scheme 2D: Preparation of Intermediates of Formula 2.11

[0496] Compounds of formula 2.11 wherein L is -O- or -NH- may also be obtained through General Scheme 2D. In step A, the pyridine-diamine compound of formula 2.7 (made in accordance with General Scheme 2A) was first reacted with thiocarbonyliimidazole, and then methyl iodide to afford compounds of formula 2.20. In step B, the 2-methylthio moiety of formula 2.20 was oxidized with mCPBA to afford compounds of formula 2.21. In step C, the methylsulfonyl moiety of formula 2.21 was then displaced by an R2-alcohol or R2- primary amine (wherein R2is a heteroaryl or heterocycloalkyl) in the presence of a base such as cesium carbonate to afford compounds of formula 2.11. Compounds of formula 2.11 may then be converted to compounds of Formula I wherein L is -O- or -NH- as set forth in General Schemes 1A through 1H.

[0497] Alternatively, Steps A, B, and C of General Scheme 2D can be carried out starting from compounds of formula 2.12, prepared in accordance with General Scheme 2B, and then the R1group is installed using Methods A, B, C, D, E, F, G, and H from General Scheme 2B, before the additional steps of General Scheme 2C are carried out. - 169 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0498] General Scheme 3: Preparation of Intermediates of Formula 3.4

[0499] Intermediates of formula A1 wherein R1is a 1,2,4-oxadiazole may be obtained through General Scheme 3. The bromide in the 2-bromopyridine-diamine compounds of formula 2.13 (prepared via General Scheme 2B) can be converted to a cyano group either directly (Method A) or by first converting the bromide to an iodide, followed by cyanation (Method B) to afford compounds of formula 3.1. The cyano moiety of a compound of formula 3.1 can be converted to a 1,2,4-oxadiazole using hydroxylamine hydrochloride followed by triethyl orthoformate to afford compounds of formula 3.3. The Boc protecting group of compounds of formula 3.3 can be removed under acidic conditions such as TFA or HCl to afford compounds of formula 3.4. Compounds of formula 3.4 may then be converted to compounds of Formula I as set forth in General Schemes 1A through 1H.

[0500] General Scheme 4: Preparation of Intermediate of Formula 4.2

[0501] Compounds of formula 4.2 can be obtained through General Scheme 4 (relative stereochemistry is indicated in General Scheme 4). A compound of formula 8.1 (see General Scheme 8) is fluorinated with a suitable fluorination agent to afford compounds of formula 4.1. The Boc protecting group of a compound of formula 4.1 is then removed under acidic conditions such as TFA or HCl to form a compound of formula 4.2. Compounds of formula 4.2 may then be converted to compounds of Formula I as set forth in General Schemes 1A through 1H. - 170 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0502] General Scheme 5: Preparation of Compounds of Formula I-A

[0503] Compounds of Formula I-A may also be obtained through General Scheme 5. In step 1, the Boc protecting group of a compound of formula 2.6 (prepared according to General Scheme 2A) is removed under acidic conditions such as TFA or HCl to generate compounds of formula 5.1. In step 2, Ar1groups are then installed by reacting an Ar1carboxylic acid of formula 1.1 or a basic salt (i.e., Li, K, or Na) thereof with the amine of formula 5.1 using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base) or TEA to afford compounds of formula 5.2. In step 3, the nitro group in compounds of formula 5.2 is reduced with a reducing reagent such as iron in the presence of ammonium chloride or Pd / C to generate the pyridine-diamine compound of formula 5.3. In step 4, various L and R2groups are installed by coupling the pyridine-diamine compound of formula 5.3 with an acid of formula 2.8 to form an amide intermediate (Method A), which is subsequently cyclized under either basic or acidic conditions to form compounds of Formula I-A. Alternatively, the pyridine-diamine compound of formula 5.3 is condensed with an aldehyde of formula 2.9 (Method B), followed by cyclization and in situ oxidation to afford compounds of Formula I-A. Alternatively, the pyridine-diamine of formula 5.3 could be condensed with 2-chloro-1,1,1- trimethoxyethane to afford the 2-chloromethyl imidazole intermediate (Method C), followed by displacement of the chloride with an R2-alcohol or R2-primary amine or heterocyclic - 171 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) amine of formula 2.19 wherein the heterocyclic ring is either saturated or aromatic, to afford compounds of Formula I-A.

[0504] General Scheme 6: Preparation of Compounds of Formula I-A

[0505] Compounds of formula 6.6 were obtained through General Scheme 6 (relative stereochemistry is indicated in General Scheme 6). Beginning with a compound of formula 6.1, the Boc protecting group was removed under acidic conditions such as TFA to form a compound of formula 6.2. Ar1groups were then installed by reacting an Ar1carboxylic acid of formula 1.1 or a basic salt (i.e., Li, K, or Na) thereof with the amine of formula 6.2 using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base), pyridine, or TEA to afford compounds of formula 6.3. The TBS protecting group of a compound of formula 6.3 was removed with TBAF to afford compounds of formula 6.4. The hydroxyl moiety of a compound of formula 6.4 was oxidized to a ketone moiety via reaction with the Dess-Martin reagent or other suitable oxidation agent to afford a compound of formula 6.5. A compound of formula 6.5 then underwent a reductive animation reaction with ammonium chloride and a reducing agent such as NaBH3CN to afford compounds of formula 6.6.

[0506] Compounds of formula 6.2 may also be coupled with the methyl 2- (bromomethyl)benzoate of formula 1.2 (Scheme 1B), the methyl 2-(2-bromoethyl)benzoate of formula 1.5 (Scheme 1C), the isochroman-1-one of formula 1.6 (Scheme 1C), the 2- hydroxybenzoic acid of formula 1.10 (Scheme 1D), the reagents in Schemes 1E and 1F, the isobenzofuran-1,3-dione of formula 1.24 (Scheme 1G), the 3,4-dihydro-1H-2-benzopyran- - 172 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 1,3-dione of formula 1.27 (Scheme 1H) under the conditions described in Schemes 1B to 1H to afford compounds of formulas 1.3, 1.7, 1.12, 1.17, 1.18, 1.22, 1.25, and 1.28.

[0507] General Scheme 7: Preparation of Compounds of Formula I

[0508] Compounds of formula 7.4, 7.7, and 7.9 were obtained through General Scheme 7. Under Routes A and B, the hydroxyl moiety of a compound of formula 7.1 was converted to a tosylate or mesylate moiety by reacting a compound of formula 7.1 with mesyl chloride or tosyl chloride in the presence of base such as TEA or NaH, to afford compounds of formula 7.2. Under Route A, a compound of formula 7.2 is reacted with sodium cyanide in a SN2 reaction to afford a compound of formula 7.3. Under Route B, a compound of formula 7.2 is reacted with sodium azide in a SN2 reaction to afford a compound of formula 7.5. Under Route C, a compound of formula 7.1 is reacted with an alkyl carbonochloride to afford a compound of formula 7.8. The Boc protecting groups in compounds of formulas 7.3, 7.5, and 7.8 were removed under acidic conditions, and then Ar1groups were then installed by reacting an Ar1carboxylic acid of formula 1.1 or a basic salt (i.e., Li, K, or Na) thereof with the unprotected amine using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base) or TEA to afford compounds of formula 7.4, 7.6, and 7.9. The azido moiety in compounds of formula 7.6 can be reduced to an amino moiety under reduction conditions such as triphenylphosphine in THF / water or Pd / C in the presence of H2 gas to afford compounds of formula 7.7. - 173 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0509] Alternatively, once the Boc protecting groups in compounds of formulas 7.3, 7.5, and 7.8 are removed under acidic conditions, the resulting unprotected amine may be coupled with the methyl 2-(bromomethyl)benzoate of formula 1.2 (Scheme 1B), the methyl 2-(2-bromoethyl)benzoate of formula 1.5 (Scheme 1C), the isochroman-1-one of formula 1.6 (Scheme 1C), the 2-hydroxybenzoic acid of formula 1.10 (Scheme 1D), the reagents in Schemes 1E and 1F, the isobenzofuran-1,3-dione of formula 1.24 (Scheme 1G), the 3,4- dihydro-1H-2-benzopyran-1,3-dione of formula 1.27 (Scheme 1H) under the conditions described in Schemes 1B to 1H to afford compounds of formulas 1.3, 1.7, 1.12, 1.17, 1.18, 1.22, 1.25, and 1.28.

[0510] General Scheme 8: Preparation of Compounds of Formula I-A

[0511] Compounds of formula 8.5, 8.7, and 8.8 were obtained through General Scheme 8. The stereochemistry of the hydroxyl moiety of a compound of formula 7.1 was inverted by first using a Dess-Martin oxidization reaction to afford a compound of formula 8.1, followed by a reduction reaction using L-selectride to afford compounds of formula 8.2. The hydroxyl moiety of compounds of formula 8.2 was converted to a mesylate moiety by reacting a compound of formula 8.2 with mesyl chloride in the presence of base to afford compounds of formula 8.3. Under Route A, a compound of formula 8.3 is reacted with sodium cyanide in a SN2reaction to afford a compound of formula 8.4. Under Route B, a - 174 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) compound of formula 8.3 is reacted with sodium azide in a SN2 reaction to afford a compound of formula 8.6. The Boc protecting groups in compounds of formulas 8.4 and 8.6 were removed under acidic conditions, and then Ar1groups were then installed by reacting an Ar1carboxylic acid of formula 1.1 or a basic salt (i.e., Li, K, or Na) thereof with the unprotected amine using acid coupling conditions known in the art, such as using HATU or EDCI and HOBt along with a base, such as DIPEA (Hunig’s base) or TEA to afford compounds of formula 8.5 and 8.7. The azido moiety in compounds of formula 8.7 can be reduced to an amino moiety under reduction conditions such as triphenylphosphine in THF / water or Pd / C in the presence of H2 gas to afford compounds of formula 8.8.

[0512] Alternatively, once the Boc protecting groups in compounds of formulas 8.4 and 8.6 are removed under acidic conditions, the resulting unprotected amine may be coupled with the methyl 2-(bromomethyl)benzoate of formula 1.2 (Scheme 1B), the methyl 2-(2-bromoethyl)benzoate of formula 1.5 (Scheme 1C), the isochroman-1-one of formula 1.6 (Scheme 1C), the 2-hydroxybenzoic acid of formula 1.10 (Scheme 1D), the reagents in Schemes 1E and 1F, the isobenzofuran-1,3-dione of formula 1.24 (Scheme 1G), the 3,4- dihydro-1H-2-benzopyran-1,3-dione of formula 1.27 (Scheme 1H) under the conditions described in Schemes 1B to 1H to afford compounds of formulas 1.3, 1.7, 1.12, 1.17, 1.18, 1.22, 1.25, and 1.28. - 175 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0513] General Scheme 9: Preparation of Intermediates of Formula A2

[0514] Intermediates of formula A2 were obtained through General Scheme 9. The chloride / bromide moiety of a compound of formula 9.1 can be used as a functional handle to install various R1aryls, R1heteroaryls, and R1heterocycloalkyls. Under Method A, unsubstituted and substituted 1,2,4-triazoles, thiazoles, and oxazoles can be installed via a C- H functionalization reaction of the heteroaryl. Under Method B, the chloride / bromide moiety of a compound of formula 9.1 was converted to a R1heteroaryl or aryl using a Stille coupling (R1-SnBu3), Suzuki coupling (R1-BPin or R1-B(OH)2), or a cross-coupling with a substituted sulfone (R1-SO2(CH2)2-CO2CH3) to afford compounds of formula 9.2. In some cases, the chloride / bromide moiety needed to be converted to the more reactive iodide moiety using the reaction conditions in Method C prior to the Stille or Suzuki coupling. The nitro group in a compound of formula 9.2 was reduced using a reducing reagent such as iron in the presence of ammonium chloride or Pd / C to afford the pyridine-diamine compounds of formula 9.3. Subsequently, various L and R2groups were installed by coupling the pyridine-diamine compound of formula 9.3 with a L-R2carboxylic acid of formula 2.8 to form an amide intermediate (Method D), which was then cyclized under either basic or acidic conditions to form a compound of formula 9.4. Alternatively, the pyridine-diamine compound of formula 9.3 was condensed with an aldehyde of formula 2.9 (Method E), followed by cyclization and in situ oxidation to afford a compound of formula 9.4. Alternatively, as shown in Method F, the pyridine-diamine compound of formula 9.3 was condensed with a carbothioyl chloride of - 176 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) formula 2.10 to form an amide intermediate, which was then cyclized under basic or acidic conditions to form a compound of formula 9.4. The Boc protecting group of a compound of formula 9.4 was then removed under acidic conditions such as TFA or HCl to form intermediates of formula A2. Intermediates of formula A2 may then be converted to compounds of Formula II as set forth in General Schemes 1A through 1H.

[0515] The present disclosure will be more fully understood by reference to the Examples described herein. The examples should not, however, be construed as limiting the scope of the present disclosure.

[0516] Units and terms list anhy. anhydrous aq. aqueous atm atmosphere min minute(s) hrs hours mL milliliter µL microliter mmol millimole(s) µmol micromole(s) mol mole(s) MS mass spectrometry LC-MS Liquid chromatography–mass spectrometry NMR nuclear magnetic resonance TLC thin layer chromatography HPLC high-performance liquid chromatography sat. saturated ºC degrees Celsius rt room temperature wt weight N2 nitrogen gas H2hydrogen gas

[0517] NMR Spectra Hz hertz δ chemical shift - 177 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) s singlet d doublet t triplet q quartet m multiplet br broad dd doublet of doublets CDCl3 chloroform-d CD3OD methanol-d4 DMSO-d6dimethylsulfoxide-d6CD3CN acetonitrile-d3

[0518] Solvents and Reagents: CHCl3 chloroform DCM dichloromethane DCE 1,2-dichloroethane DMF dimethylformamide EtOH ethyl alcohol EtOAc ethyl acetate MeOH methyl alcohol MeCN or ACN acetonitrile PE petroleum ether THF tetrahydrofuran DMSO dimethyl sulfoxide t-BuOH tert-butanol AcOH acetic acid HCl hydrochloric acid H2SO4 sulfuric acid FA formic acid NH4C1 ammonium chloride NaOH sodium hydroxide LiOH lithium hydroxide K2CO3potassium carbonate Na2CO3 sodium carbonate - 178 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Cs2CO3 cesium carbonate TFA trifluoroacetic acid Na2SO4sodium sulfate Na2CO3 sodium carbonate NaHCO3 sodium bicarbonate K3PO4potassium phosphate NaH sodium hydride MeONa sodium methoxide MeMgBr methylmagnesium bromide CH3I or MeI methyl iodide NH4OH ammonium hydroxide Et3N or TEA triethylamine DIEA N,N-diisopropylethylamine DIPA diisopropylamine DMEDA N,N′-Dimethylethylenediamine Py pyridine EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt 1-hydroxybenzotriazole HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate CDI carbonyldiimidazole DBU 1,8-diazabicyclo[5.4.0]undec-7-ene Boc2O di-tert-butyl dicarbonate H2O water K2OsO4.2H2O potassium osmate(VI) dihydrate Fe iron PPh3triphenyl phosphine Pd / C palladium on carbon Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2Cl2bis(triphenylphosphine)palladium(II) dichloride Pd(OAc)2 palladium (II) acetate Pd(dppf)Cl2 (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride - 179 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) t-BuXphos-Pd-G3 [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate Cu(OAc)2 copper (II) acetate CuI copper iodine CuCl copper chloride NaN3sodium azide Na2O5S2 sodium metabisulfite SOCl2 thionyl chloride NaI sodium iodide Zn(CN)2 zinc cyanide TBDPSCl tert-butyldiphenylsilyl chloride TsCl p-toluenesulfonyl chloride DEAD diethyl azodicarboxylate TBAF tetra-n-butylammonium fluoride TMSN3trimethylsilyl azide

[0519] General Experimental

[0520] In the following examples, the reagents and solvents were purchased from commercial sources (such as Alfa, Acros, AstaTech, CombiBlocks, Enamine, Sigma Aldrich, TCI, PharmaBock, Bide Pharmatech Ltd., Accela ChemBio, Aladdin, Shanghai Haohong Pharmaceutical Co., Ltd, Amkchem, Beijing Ouhe Technology Co., Ltd, Haoyuan Chemexpress Co., Ltd, Hualun, Coolpharm, Scochem, Titan and WuXi LabNetwork), and used without further purification unless otherwise specified. Flash chromatography was performed on a CombiFlashRf 150 (ISCO), CombiFlash Rf+, or CombiFlash Rf+Lumen via columns with silica gel particles of 200-300 mesh. HPLC was performed on an Agilent 1100 Liquid Chromatography (Agilent, USA), a Shimadzu LC 20 / 20A (Shimadzu, Japan), and a Waters Acquity UPLC (Waters, USA). Supercritical fluid chromatography was performed on a Waters Prep SFC 150 AP / 80Q / 200 / 350 system (Waters, USA) or a SHIMADZU Prep- UC (Shimadzu, Japan). Analytical and preparative thin layer chromatography plates (TLC) were HSGF 254 (0.15-0.2mm thickness, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AV-400 NMR (Bruker, Switzerland). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA). LC-MS was performed on an Agilent Prime- - 180 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 6125B / Agilent LC1260-MS6150 / Agilent LC1260-MS6125B / Agilent LC1200-MS6110 (Agilent, USA), a Shimadzu LC20-MS2020, and a Waters Acquity UPLC-H Class. Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden). Lyophilizations were done on EYELA Freeze Dryer FDU-2100 (TOKYO RIKAKIKAI, Japan) or FreeZone 6 Liter Freeze Dryer (LABCONCO, USA).

[0521] Preparation of intermediates of formula 2.2 and formula 2.3:. The following Intermediate Schemes 1 to 16 describe the syntheses of intermediates of formula 2.2 or formula 2.3. Additional intermediates of formulas 2.2 and 2.3 are commercially available such as, for example, tert-butyl ((1S,3R)-3- aminocyclohexyl)carbamate, tert-butyl (3-aminocyclohexyl)carbamate, and tert-butyl (5- aminotetrahydro-2H-pyran-3-yl)carbamate.

[0522] Intermediate Scheme 1. Preparation of intermediate tert-butyl (3-amino-2- hydroxycyclohexyl)carbamate (relative stereochemistry is indicated in Intermediate Scheme 1)

[0523] Step 1A. Synthesis of N,N-dibenzylcyclohex-2-en-1-amine (B2)

[0524] A mixture of N-benzyl-1-phenyl-methanamine (3.0 g, 15.2 mmol, 2.91 mL) and 3-bromocyclohexene (B1) (2.45 g, 15.2 mmol, 1.75 mL) in DMF (12 mL) was degassed and purged with N2 gas 3 times, and then NaH (639 mg, 16.0 mmol, 60% purity) was added to the reaction mixture at 0°C. The reaction mixture was stirred at rt for 12 hrs under N2atmosphere, then quenched by the addition of H2O (15 mL) at 0°C, followed by the addition of additional H2O (200 mL), and the aqueous portion extracted with EtOAc (200 mL×3). The - 181 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) combined organic layers were washed with brine (300 mL×3), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to give B2 (5.3 g, 62.8% yield). LC-MS: m / z 278.2 [M+H]+.

[0525] Step 1B. Synthesis of 3-(dibenzylamino)cyclohexane-1,2-diol (B3)

[0526] To a mixture of N,N-dibenzylcyclohex-2-en-1-amine (B2) (1.93 g, 6.96 mmol) in t-BuOH (40 mL) and H2O (8 mL) were added K2OsO4.2H2O (28.2 mg, 76.5 µmol) and 4-methyl-4-oxido-morpholin-4-ium (897 mg, 7.65 mmol). The reaction mixture was stirred at rt for 14 hrs. The reaction mixture was treated with sat. aq. sodium hydrosulfite solution (5 mL) and stirred for 1 hr, and then concentrated under reduced pressure. The aqueous portion was extracted with DCM (100 mL×3). The combined organic layers were concentrated to dryness, and the residue was purified by silica gel column chromatography to give B3 (1.63 g, 75.2% yield). LC-MS: m / z 312.2 [M+H]+.

[0527] Step 1C. Synthesis of 4-(dibenzylamino)hexahydrobenzo[d][1,3,2] dioxathiole 2-oxide (B4)

[0528] To a solution of 3-(dibenzylamino)cyclohexane-1,2-diol (B3) (1.63 g, 5.23 mmol) in DCM (10 mL) was added Et3N (4.24 g, 41.9 mmol). SOCl2(1.87 g, 15.7 mmol) was then added slowly to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C to rt for 2 hrs, then poured into H2O (80 mL) at 5°C. Additional water (20 mL) was added, and the aqueous portion extracted with DCM (80 mL×3). The combined organic layers were washed with brine (80 mL×3), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give B4 (940 mg, 50.2% yield). LC-MS: m / z 358.2 [M+H]+.

[0529] Step 1D. Synthesis of 2-azido-6-(dibenzylamino)cyclohexan-1-ol (B5)

[0530] To a solution of 4-(dibenzylamino)hexahydrobenzo[d][1,3,2] dioxathiole 2- oxide (B4) (100 mg, 280 µmol) in DMF (2 mL) was added NaN3 (54.6 mg, 839 µmol) at rt. The reaction mixture was heated at 100°C for 30 hrs. The reaction mixture was cooled to rt, quenched by the addition of brine (10 mL) at 15°C, then H2O (10 mL) was added, and the aqueous portion extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give B5 (55 mg, 58.4% yield). LC-MS: m / z 337.2 [M+H]+.

[0531] Step 1E. Synthesis of 2-amino-6-(dibenzylamino)cyclohexan-1-ol (B6)

[0532] To a solution of 2-azido-6-(dibenzylamino)cyclohexan-1-ol (B5) (342 mg, 1.02 mmol) in THF (1 mL) was added Pd / C (50 mg, 1.02 mmol, 10% purity) under N2 - 182 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2 (15 psi) at rt for 1.2 hrs. The reaction mixture was filtered, and the filter cake washed with THF (8 mL×3). The combined organic layers were concentrated to dryness to give B6 (321 mg), which was used without further purification. LC-MS: m / z 311.2 [M+H]+.

[0533] Step 1F. Synthesis of tert-butyl (3-(dibenzylamino)-2- hydroxycyclohexyl)carbamate (B7)

[0534] To a solution of 2-amino-6-(dibenzylamino)cyclohexan-1-ol (B6) (321 mg, 1.03 mmol) in DCM (4 mL) were added Et3N (314 mg, 3.10 mmol) and tert-butoxycarbonyl tert-butyl carbonate (237 mg, 1.09 mmol). The reaction mixture was stirred at rt for 13 hrs. The reaction mixture was quenched by the addition of H2O (5 mL) at 15°C, diluted with H2O (15 mL) and the aqueous portion extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give B7 (350 mg, 82.5% yield). LC-MS: m / z 411.3 [M+H]+.

[0535] Step 1G. Synthesis of tert-butyl (3-amino-2-hydroxycyclohexyl)carbamate (B8)

[0536] To a solution of tert-butyl (3-(dibenzylamino)-2- hydroxycyclohexyl)carbamate (B7) (350 mg, 853 µmol) in MeOH (5 mL) was added Pd / C (100 mg, 10% Pd) under N2atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2 (15 Psi) at rt for 3 hrs. The reaction mixture was filtered, and the filter cake was washed with MeOH (10 mL×3). The combined organic layers were concentrated to dryness to give B8 (202 mg), which was used without further purification.1H NMR (400 MHz, CDCl3) δ 5.11 (s, 1H), 3.40 (s, 1H), 3.24 (s, 1H), 2.87 (s, 1H), 1.98 (br d, 2H), 1.71 (br dd, 1H), 1.44 (s, 9H), 1.38-1.20 (m, 3H).

[0537] Intermediate Scheme 2: Preparation of intermediate 5- methoxycyclohexane-1,3-diamine (relative stereochemistry is indicated in Intermediate Scheme 2) - 183 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0538] Step 2A. Synthesis of 3,5-bis((tert-butyldiphenylsilyl)oxy)cyclohexan-1-ol (B10).

[0539] To a solution of cis, cis-cyclohexane-1,3,5-triol (B9) (5 g, 37.8 mmol) in THF (100 mL) was added TBDPSCl (21.84 g, 79.5 mmol, 20.4 mL) and TEA (11.49 g, 114 mmol, 15.8 mL) at rt. After addition, the reaction mixture was stirred at rt for 1.5 hrs and treated with NaH (4.54 g, 114 mmol, 60% purity). The reaction mixture was heated to 45°C for 22.5 hrs under N2atmosphere. The reaction mixture was concentrated under reduced pressure. Sat. aq. NH4Cl solution (50 mL) was added to the reaction mixture, and the aqueous portion was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography to give B10 (8.7 g, 35.0% yield). LC-MS: m / z 609.2 (M+H)+.

[0540] Step 2B. Synthesis of ((5-methoxycyclohexane-1,3-diyl)bis(oxy))bis(tert- butyldiphenylsilane) (B11)

[0541] To a solution of 3,5-bis((tert-butyldiphenylsilyl) oxy)cyclohexan-1-ol (B10) (1.0 g, 1.64 mmol) in THF (12 mL) was added NaH (98.5 mg, 2.46 mmol, 60% purity). The reaction mixture was stirred at rt for 30 min and treated with CH3I (280 mg, 1.97 mmol, 123 µL). The reaction mixture was stirred at rt for 16 hrs under N2atmosphere. The reaction mixture was concentrated under reduced pressure. Sat. aq. NH4Cl solution (15 mL) was added, and the aqueous portion extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography to give B11 (1.0 g, 96.8% yield). LC-MS: m / z 623.3 (M+H)+.

[0542] Step 2C. Synthesis of 5-methoxycyclohexane-1,3-diol (B12) - 184 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0543] To a solution of ((5-methoxycyclohexane-1,3-diyl)bis(oxy))bis(tert- butyldiphenylsilane) (B11) (700 mg, 1.12 mmol) in MeOH (7 mL) was added HCl / MeOH (4 M, 7 mL). The reaction mixture was stirred at rt for 15 hrs and concentrated to dryness to afford B12 (170 mg). LC-MS: m / z 147.1 (M+H)+.

[0544] Step 2D. Synthesis of 5-methoxycyclohexane-1,3-diyl bis(4- methylbenzenesulfonate) (B13)

[0545] To a solution of 5-methoxycyclohexane-1,3-diol (B12) (170 mg, 1.16 mmol) in pyridine (7 mL) was added TsCl (887 mg, 4.65 mmol). The reaction mixture was stirred at rt for 63 hrs. The reaction mixture was concentrated to dryness. The residue was purified by flash silica gel chromatography to give B13 (440 mg, 67.4% yield). LC-MS: m / z 477.1 (M+Na)+.

[0546] Step 2E. Synthesis of 1,3-diazido-5-methoxycyclohexane (B14)

[0547] To a solution of 5-methoxycyclohexane-1,3-diyl bis(4- methylbenzenesulfonate) (B13) (440 mg, 968 µmol) in DMF (5 mL) was added NaN3 (378 mg, 5.81 mmol). The reaction mixture was stirred at 70°C for 15 hrs. The reaction mixture was cooled to rt, and EtOAc (100 mL) was added. The organic layer was washed with H2O (40 mL×5), brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness to afford B14 (180 mg).1H NMR (400 MHz, CDCl3) δ 3.75-3.61 (m, 3 H), 3.32 (s, 3 H), 2.35- 2.21 (m, 3 H), 1.41-1.30 (m, 3 H).

[0548] Step 2F. Synthesis of 5-methoxycyclohexane-1,3-diamine (B15)

[0549] To a solution of 1,3-diazido-5-methoxycyclohexane (B14) (180 mg, 917 µmol) in MeOH (2 mL) was added Pd / C (30 mg, 917 µmol, 10% purity) under N2 atmosphere. The reaction mixture was degassed and purged with H23 times and stirred under H2 (15 Psi) at rt for 15 hrs. The reaction mixture was filtered through Celite, and the filtrate concentrated to dryness to afford B15 (90 mg).1H NMR (400 MHz, CDCl3) δ 3.61-3.56 (m, 1 H), 3.25 (s, 3 H), 2.99-2.93 (m, 2 H), 2.02-1.94 (m, 3 H), 1.04-0.97 (m, 2 H), 0.88-0.79 (m, 1 H).

[0550] Alternatively, 5-methoxycyclohexane-1,3-diamine (B15) may be prepared in accordance with Intermediate Scheme 2A (relative stereochemistry is indicated in Intermediate Scheme 2A). Steps 2E and 2F were performed following the procedures set forth in the Electronic Supplementary Materials (Scheme S1) for Dalton Trans., 2019,48, 9576-9580. Steps 2G and 2H were performed following the procedures set forth in New J. Chem., 2005, 29, 1152–1158 (Scheme 2).

[0551] Intermediate Scheme 2A - 185 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0552] Intermediate Scheme 3: Preparation of intermediate tert-butyl-3-amino-2- methoxycyclohexylcarbamate (relative stereochemistry is indicated in Intermediate Scheme 3)

[0553] Step 3A. Synthesis of tert-butyl-(3-(dibenzylamino)-2- methoxycyclohexyl)carbamate (B18)

[0554] To a solution of tert-butyl (3-(dibenzylamino)-2- hydroxycyclohexyl)carbamate (B7) (1.70 g, 4.14 mmol) in CH3I (20 mL) was added silver oxide (2.88 g, 12.4 mmol). The reaction mixture was then degassed under vacuum and purged with N2 several times, and heated at 40°C for 48 hrs under N2 atmosphere in a sealed tube. The reaction mixture was cooled to rt, filtered through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated to dryness to afford B18 (1.72 g), which was used without further purification. LC-MS: m / z 425 [M+H]+.

[0555] Step 3B. Synthesis of tert-butyl-3-amino-2-methoxycyclohexylcarbamate (B19)

[0556] To a solution of tert-butyl-(3-(dibenzylamino)-2- methoxycyclohexyl)carbamate (B18) (1.72 g, 4.05 mmol) in MeOH (10 mL) was added Pd / C (431 mg, 10% wt) under N2atmosphere. The reaction mixture was degassed and purged with H2several times, then heated at 50°C for 18 hrs under H2atmosphere. The reaction mixture was cooled to rt, filtered through a pad of Celite, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated to dryness to afford B19 (857 mg), which was used without further purification. LC-MS: m / z 245 [M+H]+.

[0557] Intermediate Scheme 4: Preparation of intermediates tert-butyl ((1R,3S,5S)-3-((2-bromo-5-nitropyridin-4-yl)amino)-5-methoxycyclohexyl)carbamate and tert-butyl ((1S,3R,5R)-3-((2-bromo-5-nitropyridin-4-yl)amino)-5- methoxycyclohexyl)carbamate (relative stereochemistry is indicated for Steps 4A-4H) - 186 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0558] Step 4A. Synthesis of 3,5-bis(tosyloxy)cyclohexyl benzoate (B20)

[0559] To a solution of cis-5-hydroxycyclohexane-1,3-diyl bis(4- methylbenzenesulfonate) (B16) (15 g, 34 mmol) and benzoic acid (5.0 g, 41 mmol) in THF (100 mL) were added Ph3P (13 g, 51 mmol), and then DIAD (10 g, 51 mmol) at 0°C. The reaction mixture was warmed up to rt and stirred for 16 hrs. Water (200 mL) was added, and the aqueous portion extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B20 (10 g, 54% yield). LC-MS: m / z 545 [M+H]+.

[0560] Step 4B. Synthesis of 3,5-diazidocyclohexyl benzoate (B21)

[0561] To a solution of 3,5-bis(tosyloxy)cyclohexyl benzoate (B20) (10 g, 18 mmol) in DMF (100 mL) was added sodium azide (4.2 g, 64 mmol). The reaction mixture was stirred at 70°C for 16 hrs and then cooled to rt. Water (300 mL) was added, and the aqueous portion extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B21 (4.5 g, 86% yield). LC-MS: m / z 287 [M+H]+.

[0562] Step 4C. Synthesis of 3,5-diazidocyclohexan-1-ol (B22)

[0563] To a solution of 3,5-diazidocyclohexyl benzoate (B21) (4.5 g, 16 mmol) in MeOH (100 mL) was added K2CO3(6.5 g, 47 mmol). The reaction mixture was stirred at 60°C for 16 hrs and then cooled to rt. Water (100 mL) was added, and the aqueous portion - 187 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B22 (2.5 g, 87% yield). LC-MS: m / z 183 [M+H]+.

[0564] Step 4D. Synthesis of 1,3-diazido-5-methoxycyclohexane (B23)

[0565] To a solution of 3,5-diazidocyclohexan-1-ol (B22) (2.5 g, 14 mmol) in DMSO (10 mL) were added KOH (2.3 g, 41 mmol) and MeI (5.8 g, 41 mmol). The reaction mixture was stirred at rt for 16 hrs. Water (100 mL) was added, and the aqueous portion extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B23 (2.3 g, 85% yield). LC-MS: m / z 197 [M+H]+.

[0566] Step 4E. Synthesis of 5-methoxycyclohexane-1,3-diamine (B24)

[0567] To a solution of 1,3-diazido-5-methoxycyclohexane (B23) (2.3 g, 12 mmol) in i-PrOH (20 mL) was added Pd / C (230 mg) under nitrogen. The reaction mixture was degassed under vacuum and purged with H2several times and then stirred at rt for 16 hrs. The reaction mixture was filtered through a pad of Celite®, and the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness to give B24 (1.6 g, 95% yield). LCMS: m / z 145 [M+H]+.

[0568] Step 4F. Synthesis of di-tert-butyl-(5-methoxycyclohexane-1,3- diyl)dicarbamate (B25)

[0569] To a solution of 5-methoxycyclohexane-1,3-diamine (B24) (2.0 g, 13.9 mmol) and DIEA (5.4 g, 41.7 mmol) in DCM (50 mL) was added Boc2O (9.09 g, 41.7 mmol). The reaction mixture was stirred at rt for 16 hrs. and then concentrated to dryness. Water (100 mL) was added to the residue, and the aqueous portion extracted with EtOAc (100 mL×3). The combined organic layers were concentrated to dryness, and the residue was purified by flash column chromatography on silica gel to give B25 (4.5 g, 90% yield). LC- MS: m / z 345 [M+H]+.

[0570] Step 4G. Synthesis of tert-butyl-(3-amino-5-methoxycyclohexyl)carbamate (B26)

[0571] To a solution of di-tert-butyl-(5-methoxycyclohexane-1,3-diyl)dicarbamate (B25) (600 mg, 1.74 mmol) in DCM (20 mL) was added HCl / MeOH(4 M) (2 mL), and then the reaction mixture was stirred at rt for 16 hrs. The reaction mixture was concentrated to dryness to afford B26 (180 mg, quant.). LC-MS: m / z 245 [M+H]+. - 188 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0572] Step 4H. Synthesis of tert-butyl-(3-((2-bromo-5-nitropyridin-4-yl)amino)- 5-methoxycyclohexyl)carbamate (B27)

[0573] To a solution of di-tert-butyl-(5-methoxycyclohexane-1,3-diyl)dicarbamate (B26) (600 mg, 2.46 mmol) in EtOH (10 mL) were added DIEA (793 mg, 6.14 mmol) and 2,4-dibromo-5-nitropyridine (831 mg, 2.95 mmol), and the reaction mixture was stirred at 40°C for 16 hrs. The reaction mixture was then concentrated to dryness, and the residue purified by flash column chromatography on silica gel to give B27 (950 mg, 87% yield). LC- MS: m / z 445 [M+H]+.

[0574] Step 4I. Synthesis of tert-butyl ((1R,3S,5S)-3-((2-bromo-5-nitropyridin-4- yl)amino)-5-methoxycyclohexyl)carbamate (B28) and tert-butyl ((1S,3R,5R)-3-((2-bromo-5- nitropyridin-4-yl)amino)-5-methoxycyclohexyl)carbamate (B29)

[0575] Tert-butyl-(3-((2-bromo-5-nitropyridin-4-yl)amino)-5- methoxycyclohexyl)carbamate (B27) (2.0 g) was separated by chiral SFC to give Enantiomer #1 (772 mg, 39% yield, Rt=0.796 min) and Enantiomer #2 (977 mg, 49% yield, Rt=1.048 min). SFC method: (column: ChiralPak IH (250*30mm, 5µm), mobile phase: [0.1%NH3H2O MeOH]; %:20%-20%,min).

[0576] Enantiomer #1 (B28), tert-butyl ((1R,3S,5S)-3-((2-bromo-5-nitropyridin-4- yl)amino)-5-methoxycyclohexyl)carbamate: LC-MS: m / z 445 [M+H]+; 97% ee.

[0577] Enantiomer #2 (B29), tert-butyl ((1S,3R,5R)-3-((2-bromo-5-nitropyridin-4- yl)amino)-5-methoxycyclohexyl)carbamate: LC-MS : m / z 445 [M+H]+; 98% ee.

[0578] Intermediate Scheme 5: Preparation of tert-butyl (3-amino-2- hydroxycycloheptyl)carbamate (relative stereochemistry is indicated in Intermediate Scheme 5)

[0579] Step 5A. Synthesis of cyclohept-2-en-1-yl acetate (B31) - 189 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0580] To a solution of CeCl3.7H2O (33.8 g, 90.8 mmol) in MeOH (91 mL) was added 2-cyclohepten-1-one (B30) (11.1 g, 90.8 mmol) and stirred at 0°C. NaBH4 (3.47 g, 90.8 mmol) was then added into the reaction mixture in portions, and the reaction mixture was stirred at rt for 16 hrs. 1 M HCl in water (100 mL) was added into the reaction mixture, and the aqueous portion extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The resulting suspension was filtered and washed with DCM, and the filtrate was concentrated to give cyclohept-2-en-1-ol (10.2 g, quant.).

[0581] The cyclohept-2-en-1-ol (10.2 g, 90.8 mmol) was dissolved in DCM (100 mL), triethylamine (25.5 mL, 182 mmol) was added, and the reaction mixture was cooled to 0°C. Ac2O (8.59 mL, 90.9 mmol) was added slowly, followed by DMAP (0.57 g, 4.55 mmol) and the reaction mixture warmed to rt. Sat. aq. NaHCO3 solution (100 mL) was added into the reaction mixture at rt. The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified with a silica pad to give B31 (12.9 g, 92% yield).1H NMR (400 MHz, CDCl3) δ 5.85-5.78 (m, 1 H), 5.65-5.61 (m, 1 H), 5.40 (d, 1 H), 2.24-2.16 (m, 1 H), 2.12-2.07 (m, 1 H), 2.05 (s, 3 H), 1.96-1.81 (m, 2 H), 1.72-1.59 (m, 3 H), 1.44-1.35 (m, 1 H).

[0582] Step 5B. Synthesis of N,N-dibenzylcyclohep-2-en-1-amine (B32)

[0583] [Pd(allyl)2Cl]2 (2.13 g, 5.7 mmol) and PPh3 (4.54 g, 17.1 mmol) in anhydrous DCM (285 mL) was degassed with N2for 1 hr. Cyclohept-2-en-1-yl acetate (B31) (22.0 g, 143 mmol) and Bn2NH (56.3 mL, 287 mmol) was added, and the reaction mixture was stirred at rt for 20 hrs. Sat. aq. NH4Cl solution (250 mL) was added into the reaction mixture at rt, and the resulting mixture was stirred for 1 hr. The organic layer was separated and filtered. The filtrate was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified with a silica pad to give B32 (26.6 g, 64% yield).1H NMR (400 MHz, CDCl3) δ 7.43 (d, 4 H), 7.35-7.31 (m, 4 H), 7.27-7.21 (m, 2 H), 5.98 (d, 1 H), 5.88-5.82 (m, 1 H), 3.75 (d, 2 H), 3.60 (d, 2 H), 3.37 (d, 1 H), 2.21-2.16 (m, 1 H), 2.08-1.91 (m, 3 H), 1.72-1.63 (m, 1 H), 1.58-1.27 (m, 3 H); LC-MS: m / z 292.2 [M+H]+.

[0584] Step 5C. Synthesis of 3-(dibenzylamino)cycloheptane-1,2-diol (B33)

[0585] To a solution of N,N-dibenzylcyclohep-2-en-1-amine (B32) (25.0 g, 85.8 mmol) in 10:1 Acetone / Water (185 mL) was added OsO4 (4% solution in water, 10 mL, 1.57 mmol) and NMO (50% solution in water, 23.1 mL, 112 mmol), and the reaction mixture stirred at rt. After 16 hrs, additional OsO4(4% solution in water, 5 mL, 0.79 mmol) was added, and the reaction mixture stirred for an additional 24 hrs. Sat. aq. Na2SO3 solution - 190 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) (150 mL) was added into the reaction mixture, and the aqueous portion was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give B33 (12.7 g, 46% yield, 55% yield based on recovered starting material).1H NMR (400 MHz, CDCl3) δ 7.34-7.30 (m, 4 H), 7.22-7.28 (m, 6 H), 4.96 (s, 1 H), 4.10-4.08 (m, 1 H), 3.81 (d, 2 H), 3.49 (dd, 1 H), 3.36 (d, 2 H), 2.85 (td, 1 H), 2.43 (s, 1 H), 2.05-1.99 (m, 1 H), 1.83-1.65 (m, 3 H), 1.60-1.31 (m, 4 H); LC-MS: m / z 326.2 [M+H]+.

[0586] Step 5D. Synthesis of 4-(dibenzylamino)hexahydro-4H- cyclohepta[d][1,3,2]dioxathiole 2,2-dioxide (B34)

[0587] To a solution of 3-(dibenzylamino)cycloheptane-1,2-diol (B33) (12.5 g, 38.5 mmol) in dry THF (250 mL) was added sulfonyl diimidazole (11.8 g, 58.5 mmol) at 0°C. A suspension of NaH (3.85 g, 96.3 mmol) in THF (50 mL) was added at 0°C, and the reaction mixture was allowed to warm to rt. After 18 hrs, the reaction mixture was cooled to 0°C. Sat. aq. NH4Cl solution (100 mL) was slowly added, and the aqueous portion extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel to give B34 (12.0 g, 80% yield).1H NMR (400 MHz, CDCl3) δ 7.41-7.22 (m, 10 H), 5.22 (dd, 1 H), 4.79 (ddd, 1 H), 3.80 (d, 2 H), 3.57 (d, 2 H), 3.13 (t, 1H), 2.03-2.12 (m, 1 H), 2.02-1.79 (m, 4 H), 1.31-1.11 (m, 3 H); LC-MS: m / z 388.1 [M+H]+.

[0588] Step 5E. Synthesis of sodium-2-azido-7-(dibenzylamino)cycloheptyl sulfate (B35)

[0589] To a solution of 4-(dibenzylamino)hexahydro-4H-cyclohepta[d] [1,3,2]dioxathiole 2,2-dioxide (B34) (12 g, 30.9 mmol) in DMF (250 mL) was added sodium azide (4.01 g, 61.7 mmol). The reaction mixture was stirred at 50oC for 3 hrs, and then stirred at rt for 16 hrs. Brine (150 mL) was added into the reaction mixture, and the aqueous portion was extracted with EtOAc (3×60 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give B35 (7.3 g, 52% yield). LC-MS: m / z 429.1 [M-Na]-.

[0590] Step 5F. Synthesis of 2-azido-7-(dibenzylamino)cycloheptan-1-ol (B36)

[0591] To a solution of sodium-2-azido-7-(dibenzylamino)cycloheptyl sulfate (B35) (7.28 g, 16.1 mmol) in dioxane (86 mL) was added aq. HCl (4 M in water, 10 mL, 40 mmol), and the reaction mixture was stirred at 80°C for 4 hrs. Sat. aq. NaHCO3solution (80 mL) was then added into the reaction mixture at rt, and the aqueous portion extracted with - 191 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) EtOAc (3×30 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give B36 (5.38 g, 95% yield).1H NMR (400 MHz, CDCl3) δ 7.35-7.24 (m, 10 H), 4.94 (s, 1 H), 3.83 (d, 2 H), 3.50 (dd, 1 H), 3.31 (d, 2 H), 3.17-3.12 (m, 1 H), 2.50 (t, 1 H), 2.03-1.99 (m, 1 H), 1.83-1.63 (m, 3 H), 1.58-1.30 (m, 4 H); LC-MS: m / z 351.2 [M+H]+.

[0592] Step 5G. Synthesis of tert-butyl (3-(dibenzylamino)-2- hydroxycycloheptyl)carbamate (B37)

[0593] To a solution of 2-azido-7-(dibenzylamino)cycloheptan-1-ol (B36) (5.35 g, 15.3 mmol) in THF (90 mL) was added PtO2(0.89 g). The reaction mixture was degassed under vacuum and purged with H2 several times and then stirred under H2 (1 atm) at rt for 5 hrs. The reaction mixture was filtered through celite, and the filtrate was concentrated to ~50 mL volume.

[0594] To the solution was added Boc2O (6.34 g, 29.1 mmol), followed by triethylamine (2.6 mL, 18.4 mmol), and stirred at rt for 2 hrs. Brine (50 mL) was added into the reaction mixture, and the aqueous portion was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give B37 (4.90 g, 75% yield).1H NMR (400 MHz, CDCl3) δ 7.34-7.22 (m, 10 H), 4.90 (s, 1 H), 4.78 (s, 1 H), 3.81 (d, 2 H), 3.35-3.28 (m, 3 H), 3.17-3.09 (m, 1 H), 2.51 (t, 1 H), 2.02-1.89 (m, 2 H), 1.82-1.70 (m, 1 H), 1.68-1.59 (m, 1 H), 1.59-1.32 (m, 4 H), 1.41 (s, 9 H); LC-MS: m / z 425.2 [M+H]+.

[0595] Step 5H. Synthesis of (tert-butyl (3-amino-2- hydroxycycloheptyl)carbamate (B38)

[0596] To a solution of tert-butyl (3-(dibenzylamino)-2- hydroxycycloheptyl)carbamate (B37) (4.0 g, 9.42 mmol) in MeOH (35 mL) was added Pd(OH)2 / C (0.47 g). The reaction mixture was degassed under vacuum and purged with H2several times. The reaction mixture was stirred under H2(1 atm) at rt for 16 hrs. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give B68 (2.22 g, 96% yield).1H NMR (400 MHz, CDCl3) δ 4.78 (s, 1 H), 3.50-3.39 (m, 1 H), 3.01 (dd, 1 H), 2.67 (dt, 1 H), 2.60-1.70 (br s, 3 H), 1.91-1.87 (m, 1 H), 1.80-1.71 (m, 1 H), 1.70-1.35 (m, 6 H), 1.45 (s, 9 H); LC-MS: m / z 245.2 [M+H]+.

[0597] Intermediate Scheme 6: Synthesis of 1-methylpiperidine-3,5-diamine (B47) - 192 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)H), 2.98 (s, 2 H).

[0600] Step 6B. Synthesis of di-tert-butyl 2,3-diazabicyclo[2.2.1]hept-5-ene-2,3- dicarboxylate (B41)

[0601] A solution of di-tert-butyl (E)-diazene-1,2-dicarboxylate (5 g, 21.7 mmol) in DCM (50 mL) was cooled to 0°C. Cyclopenta-1,3-diene (B40) (7.18 g, 109 mmol) was then added. The reaction mixture was stirred at 0oC for 4 hrs, and then allowed to warm to rt for 12 hrs. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel to give B41 (6.3 g, 97.9% yield). LC-MS: m / z 319.3 [M+Na]+.

[0602] Step 6C. Synthesis of di-tert-butyl 3,5-diformylpyrazolidine-1,2- dicarboxylate (B42)

[0603] To a solution of di-tert-butyl 2,3-diazabicyclo[2.2.1]hept-5-ene-2,3- dicarboxylate (B41) (1.0 g, 3.37 mmol) and K2OsO4.2H2O (124 mg, 337 µmol) in THF (30 mL) was added a solution of NaIO4(3.61 g, 16.9 mmol, 935 µL) in H2O (15 mL). After the addition was complete, the reaction mixture was stirred at rt for 16 hrs. Aq. sat. Na2SO3solution (50 mL) was added, and the aqueous portion extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (35 mL), dried over Na2SO4, filtered, and - 193 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) concentrated to dryness. The residue was purified by column chromatography on silica gel to give B42 (0.57 g, 51.5% yield).1H NMR (400 MHz, CDCl3) δ 9.65 (s, 2 H), 4.72 (t, 2 H), 2.61 (t, 2 H), 1.50 (s, 18 H).

[0604] Step 6D. Synthesis of di-tert-butyl 3-benzyl-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate (B43)

[0605] A solution of di-tert-butyl 3,5-diformylpyrazolidine-1,2-dicarboxylate (B42) (570 mg, 1.74 mmol), phenylmethanamine (186 mg, 1.74 mmol, 189 µL) and one drop of AcOH (10 µL) in DCE (5 mL) was stirred at rt for 1 hr. Then NaBH(OAc)3 (1.47 g, 6.94 mmol) was added, and the reaction mixture was stirred at rt for another 16 hrs. Water (20 mL) was added, and the aqueous portion was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give B43 (0.3 g, 39.9% yield).1H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m, 5 H), 4.46-4.32 (m, 3 H), 3.68-3.50 (m, 3 H), 3.25-3.09 (m, 2 H), 2.14-1.91 (m, 2 H) 1.51 (s, 18 H); LC-MS: m / z 404.3 [M+H]+.

[0606] Step 6E. Synthesis of di-tert-butyl 3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate (B44)

[0607] To a solution of di-tert-butyl 3-benzyl-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate (B43) (100 mg, 248 µmol) in MeOH (2 mL) was added Pd / C (0.02 g, 10% Pd) under N2. The suspension was degassed under vacuum and purged with H2several times. The reaction mixture was stirred under H2 (15 psi) at rt for 16 hrs, and then filtered. The filtrate was concentrated to dryness to give B44 (80 mg). LC-MS: m / z 314.3 [M+H]+.

[0608] Step 6F. Synthesis of di-tert-butyl 3-methyl-3,6,7- triazabicyclo[3.2.1]octane-6,7-dicarboxylate (B45)

[0609] To a solution of di-tert-butyl 3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate (B44) (0.2 g, 638 µmol) and one drop of AcOH (10 µL) in DCE (5 mL) was added formaldehyde (77.7 mg, 957 µmol, 71.3 µL) (37% in H2O). After the addition was complete, the reaction mixture was stirred at rt for 1 hr. Then NaBH(OAc)3 (271 mg, 1.28 mmol) was added, and the reaction mixture was stirred at rt for another 16 hrs. The reaction mixture was concentrated to dryness, and the residue was purified by column chromatography on silica gel to give B45 (0.2 g, 87.7% yield).1H NMR (400 MHz, CD3OD) δ 4.40-4.15 (m, 2 H), 3.20-2.95 (m, 2 H), 2.23 (s, 3 H), 2.17-1.80 (m, 4 H), 1.47 (s, 18 H); LC-MS: m / z 328.2 [M+H]+.

[0610] Step 6G. Synthesis of 3-methyl-3,6,7-triazabicyclo[3.2.1]octane (B46) - 194 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0611] A solution of di-tert-butyl 3-methyl-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate (B45) (0.2 g, 611 µmol) in HCl (4 M, 6.78 mL) (4M in 1,4-dioxane) was stirred at rt for 1 hr. The reaction mixture was concentrated to dryness to give B46 (0.15 g).

[0612] Step 6H. Synthesis of 1-methylpiperidine-3,5-diamine (B47) (relative stereochemistry at centers 3 and 5 of piperidine ring is cis)

[0613] To a solution of 3-methyl-3,6,7-triazabicyclo[3.2.1]octane (B46) (150 mg, 750 µmol, 2HCl) in MeOH (2 mL) was added Pd / C (0.01 g, 10% Pd) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 50°C for 16 hrs and then cooled to rt. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give B47 (0.14 g, 92.4% yield, 2HCl salt)8.46 (m, 5 H), 3.17-3.16 (m, 2 H), 2.99 (d, 2 H), 2.39- 2.27 (m, 1 H), 2.26 (s, 3 H), 1.90 (t, 2 H), 1.45-1.42 (m, 1 H); LC-MS: m / z 130.3 [M+H]+.

[0614] Intermediate Scheme 7: Synthesis of 1-(3,5-diaminopiperidin-1-yl)ethan-1- one (B50)

[0615] 1-(3,5-diaminopiperidin-1-yl)ethan-1-one (B50) (relative stereochemistry at centers 3 and 5 of piperidine ring is cis) may be prepared in accordance with the above scheme by first reacting B44 with acetic anhydride and a base such as TEA to afford di-tert- butyl 3-acetyl-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate (B48). The Boc-protecting groups can then be removed by subjecting B48 to acidic conditions such as HCL in 1,4- dioxane to afford 1-(3,6,7-triazabicyclo[3.2.1]octan-3-yl)ethan-1-one (B49). B49 can then be reacted with Pd / C and H2 gas to afford B50.

[0616] Intermediate Scheme 8: Synthesis of alkyl 3,5-diaminopiperidine-1- carboxylate (B53)

[0617] Alkyl 3,5-diaminopiperidine-1-carboxylates (B53) (relative stereochemistry at centers 3 and 5 of piperidine ring is cis) may be prepared in accordance with the above scheme by first reacting B44 with an alkyl chloroformate such as methyl chloroformate and a base such as TEA to afford a 6,7-di-tert-butyl-3-alkyl 3,6,7-triazabicyclo[3.2.1]octane-3,6,7- - 195 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) tricarboxylate (B51). The Boc-protecting groups can then be removed by subjecting B51 to acidic conditions such as HCl in 1,4-dioxane to afford an alkyl 3,6,7- triazabicyclo[3.2.1]octan-3-carboxylate (B52). B52 can then be reacted with Pd / C and H2gas to afford B53.

[0618] Intermediate Scheme 9: Synthesis of 1-(alkylsulfonyl)piperidine-3,5- diamines (B56)

[0619] 1-(alkylsulfonyl)piperidine-3,5-diamines and 1- cycloalkylsulfonyl)piperidine-3,5-diamines (B56) (relative stereochemistry at centers 3 and 5 of piperidine ring is cis) may be prepared in accordance with the above scheme by first reacting B44 with alkylsulfonylchloride or cycloalkylsulfonylchloride and a base such as TEA to afford di-tert-butyl 3-(alkylsulfonyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate or di-tert-butyl 3-(cycloalkylsulfonyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7- dicarboxylate (B54). The Boc-protecting groups can then be removed by subjecting B54 to acidic conditions such as HCl in 1,4-dioxane to afford 3-(alkylsulfonyl)-3,6,7- triazabicyclo[3.2.1]octane or 3-(cycloalkylsulfonyl)-3,6,7-triazabicyclo[3.2.1]octane (B55). B55 can then be reacted with Pd / C and H2 gas to afford B56.

[0620] Intermediate Scheme 10: Preparation of tert-butyl (5-((5-bromo-2- nitrophenyl)amino)-3,3-difluorocyclohexyl)carbamate (relative stereochemistry is indicated in Intermediate Scheme 10)

[0621] Step 10A. Synthesis of 3,5-diaminocyclohexan-1-ol (B57)

[0622] To a solution of 3,5-diazidocyclohexan-1-ol (B17) (5 g, 27.4 mmol) in isopropanol (30 mL) was added Pearlman's catalyst (2.92 g, 27.4 mmol) under nitrogen. The reaction mixture was degassed under vacuum and purged with H2several times and then - 196 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) stirred at rt for 12 hrs. The reaction mixture was filtered through a pad of Celite®, and the filter cake was washed with MeOH (20 mL). The filtrates were concentrated to dryness to give B57 (3.3 g, 92% yield). LCMS: m / z 131 [M+H]+.

[0623] Step 10B. Synthesis of di-tert-butyl (5-hydroxycyclohexane-1,3- diyl)dicarbamate (B58)

[0624] To a solution of 3,5-diaminocyclohexan-1-ol (B57) (2.8 g, 21.5 mmol) in MeOH (30 mL) were added TEA (10.9 g, 107 mmol) and di-tert-butyl dicarbonate (18.8 g, 86.0 mmol), and the reaction mixture was stirred at rt for 12 hrs. After completion, the reaction mixture was washed with aq. 1N HCl solution (20 mL), and the aqueous portion extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to afford B58 (6.3 g, 89% yield). LC-MS: m / z 331 [M+H]+.

[0625] Step 10C. Synthesis of di-tert-butyl (5-oxocyclohexane-1,3- diyl)dicarbamate (B59)

[0626] To a solution of di-tert-butyl (5-hydroxycyclohexane-1,3-diyl)dicarbamate (B58) (5.8 g, 17.6 mmol) in DMF (100 mL) was added Dess-Martin periodinane (14.9 g, 35.1 mmol), and the reaction mixture was stirred at rt for 2 hrs. After completion, the reaction mixture was quenched by the addition of sat. aq. NaHCO3 solution (20 mL) and sat. aq. Na2S2O3solution (20 mL), and the aqueous portion extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to afford B59 (5.1 g, 88% yield). LC-MS: m / z 329 [M+H]+.

[0627] Step 10D. Synthesis of di-tert-butyl (5,5-difluorocyclohexane-1,3- diyl)dicarbamate (B60)

[0628] To a solution of di-tert-butyl (5-oxocyclohexane-1,3-diyl)dicarbamate (B59) (5.1 g, 15.5 mmol) in DCE (100 mL) was added BAST (27.5 g, 124 mmol). The reaction mixture was stirred at 60°C for 12 hrs. After completion, the reaction mixture was cooled to rt and then quenched by the addition of sat. aq. NaHCO3 solution (50 mL). The aqueous portion was extracted with DCM (100 mL×3), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to afford B60 (850 mg, 16% yield). LC-MS: m / z 351 [M+H]+. - 197 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0629] Step 10E. Synthesis of tert-butyl (5-amino-3,3- difluorocyclohexyl)carbamate (B61)

[0630] To a solution of di-tert-butyl (5,5-difluorocyclohexane-1,3- diyl)dicarbamate (B60) (500 mg, 1.43 mmol) in DCM (10 mL) was added HCl / MeOH (0.5 mL, 2.15 mmol, 4 M). The reaction mixture was stirred at rt for 12 hrs. After completion, water (20 mL) was added to the reaction mixture, and the aqueous portion extracted with EtOAc (20 mL×2). Sat. aq. NaHCO3solution was added to the aqueous portion until the pH was 9. The aqueous portion was extracted with DCM (20 mL×3), and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to dryness to give B61 (300 mg, quant.), which was used without further purification. LCMS: m / z 251 [M+H]+.

[0631] Step 10F. Synthesis of tert-butyl (5-((5-bromo-2-nitrophenyl)amino)-3,3- difluorocyclohexyl)carbamate (B62)

[0632] To a solution of tert-butyl (5-amino-3,3-difluorocyclohexyl)carbamate (B61) (554 mg, 2.52 mmol) and 4-bromo-2-fluoro-1-nitrobenzene (554 mg, 2.52 mmol) in NMP (10 mL) was added DIEA (651 mg, 5.03 mmol). The reaction mixture was stirred at 80°C for 1 hr under N2atmosphere. The reaction mixture was cooled to rt, and water (10 mL) was added. The aqueous portion was extracted with EtOAc (20 mL×3), and the combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B62 (561 mg, 50% yield). LC-MS: m / z 450 [M+H]+.

[0633] Intermediate tert-butyl (5-((2-bromo-5-nitropyridin-4-yl)amino)-3,3- difluorocyclohexyl)carbamatemay be prepared by following the procedure in Steps 10A to 10E of Intermediate Scheme 10 and then reacting tert-butyl (5-amino-3,3- difluorocyclohexyl)carbamate (B61) with 2,4-dibromo-5-nitropyridine in Step 10F.

[0634] Intermediate Scheme 11: Synthesis of (relative stereochemistry is indicated in Intermediate Scheme 11) - 198 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0635] Step 11A. Synthesis of 5-(difluoromethoxy)cyclohexane-1,3-diyl bis(4- methylbenzenesulfonate) (B63)

[0636] To a solution of 5-hydroxycyclohexane-1,3-diyl bis(4- methylbenzenesulfonate) (B16) (7.6 g, 17 mmol) and CuI (0.66 g, 3.5 mmol) in MeCN (100 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.1 g, 35 mmol). The reaction mixture was stirred at 80°C for 2 hrs and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B63 (5.1 g, 60% yield). LC- MS: m / z 491 [M+H]+.

[0637] Step 11B. Synthesis of 1,3-diazido-5-(difluoromethoxy)cyclohexane (B64)

[0638] To a solution of 5-(difluoromethoxy)cyclohexane-1,3-diyl bis(4- methylbenzenesulfonate) (B63) (5.3 g, 11 mmol) in DMF (60 mL) was added sodium azide (2.1 g, 32 mmol) at rt. The reaction mixture was then stirred at 70°C for 15 hrs. The reaction mixture was cooled to rt, and sat. aq. NH4Cl solution was added (50 mL). The aqueous portion was extracted with EtOAc (60 mL×3), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B64 (2.4 g, 96% yield). LC-MS: m / z 233 [M+H]+.

[0639] Step 11C. Synthesis of 5-(difluoromethoxy)cyclohexane-1,3-diamine (B65)

[0640] To the solution of 1,3-diazido-5-(difluoromethoxy)cyclohexane (B64) (2.3 g, 9.9 mmol) in i-PrOH (30 mL) was added Pd / C (500 mg, 9.9 mmol) under N2 atmosphere. The reaction mixture was degassed and purged with H2several times, and then heated at 25°C for additional 15 hrs under H2atmosphere. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (20 mL). The filtrate was - 199 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) concentrated to dryness to give B65 (1.7 g, quant.), which was used without further purification. LC-MS: m / z 181 [M+H]+.

[0641] Step 11D. Synthesis of di-tert-butyl (5-(difluoromethoxy)cyclohexane-1,3- diyl)dicarbamate (B66)

[0642] To a solution of 5-(difluoromethoxy)cyclohexane-1,3-diamine (B65) (1.4 g, 7.8 mmol) in MeOH (25 mL) were added DIEA (4.0 g, 31 mmol) and di-tert-butyl dicarbonate (4.2 g, 19 mmol), and the reaction mixture was stirred at rt for 15 hrs. After completion, the reaction mixture was filtered, and the wet cake was washed with MeOH (20 mL). The wet cake was dried to give B66 (1.7 g, 58% yield). LC-MS: m / z 381 [M+H]+.

[0643] Step 11E. Synthesis of tert-butyl (3-amino-5-(difluoromethoxy)cyclohexyl) carbamate (B67)

[0644] To a solution of di-tert-butyl (5-(difluoromethoxy)cyclohexane-1,3- diyl)dicarbamate (B66) (2.0 g, 5.3 mmol) in MeOH (25 mL) was added HCl / MeOH (1.2 g, 16 wt%, 5.3 mmol). Then the reaction mixture was stirred at rt for 15 hrs. After completion, the reaction mixture was poured into H2O (20 mL), and the aqueous portion extracted with EtOAc (40 mL×2). Sat. aq. NaHCO3solution was added slowly until the pH was equal to 9. The aqueous portion was then extracted with DCM / MeOH (50 mL×3), and the combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated to dryness to give B67 (400 mg, 27% yield), which was used without further purification. LCMS: m / z 281 [M+H]+.

[0645] Step 11F. Synthesis of tert-butyl (3-((2-bromo-5-nitropyridin-4-yl)amino)- 5-(difluoromethoxy)cyclohexyl)carbamate (B68)

[0646] To a solution of tert-butyl ((1R,3S,5R)-3-amino-5- (difluoromethoxy)cyclohexyl)carbamate (B67) (450 mg, 1.61 mmol) and 2,4-dibromo-5- nitropyridine (498 mg, 1.77 mmol) in THF / EtOH (5 mL / 5 mL) was added DIEA (622 mg, 4.82 mmol), and the reaction mixture was stirred at rt for 15 hrs under N2atmosphere. Water (15 mL) was added, and the aqueous portion extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel to give B68 (580 mg, 75% yield). LC-MS: m / z 481 [M+H]+.

[0647] Intermediate Scheme 12: Preparation of 3,5-diaminotetrahydro-2H- thiopyran 1,1-dioxide (relative stereochemistry is indicated in Intermediate Scheme 12 for Steps 12H, 12I, and 12J) - 200 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0648] Step 12A. Synthesis of methyl 2-((2-oxopropyl)thio)acetate (B69)

[0649] A solution of 300 mL of anhydrous methanol and 10.18 g of sodium methoxide (190 mmol) was cooled in an ice bath and then 16.9 mL of methyl thioglycolate (190 mmol) was added. After 5 minutes of stirring, to the reaction mixture was slowly added 17.4 g of chloroacetone (15 mL, 190 mmol). Upon completion of chloroacetone addition, the reaction mixture was warmed to rt for 15 minutes and then heated to 70oC for 1 hr. The reaction mixture was cooled, filtered, and concentrated. MTBE was added, followed by water. The aqueous layer was extracted 3 times with MTBE, and the combined organic layers were washed with sat. sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated to dryness to afford 26.72 g of B69, which was used without further purification.1H NMR (400 MHz, CDCl3) δ 3.73 (d, 3H), 3.42 (s, 2H), 3.26 (s, 2H), 2.28 (s, 3H).

[0650] Step 12B. Synthesis of 2H-thiopyran-3,5(4H,6H)-dione (B70)

[0651] A solution of 8.33 g of sodium hydride (60% dispersion in oil, 210 mmol) in 100 mL of anhydrous THF was cooled in an ice water bath and then 26.72 g (165 mmol) of methyl 2-((2-oxopropyl)thio)acetate (B69) as a solution in 105 mL of THF was slowly added to the reaction mixture via cannula. The reaction mixture was stirred for several hours. Water (150 mL) was added, and the aqueous portion extracted several times with MTBE. The aqueous layer was acidified to a pH between 1.5-2.5 and extracted several times with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to - 201 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) dryness. The residue was dissolved in minimal MTBE with minimal DCM and placed in the -20oC fridge for two days and then the material was washed once again with MTBE containing heptanes. The material was decanted and then dried to afford 12.73 grams of B70, which was used without further purification (59.4% yield). LC-MS: m / z 131.0 [M+H]+.

[0652] Step 12C. Synthesis of 5-(benzylamino)-2H-thiopyran-3(6H)-one (B71)

[0653] A solution of 14.05 g of 2H-thiopyran-3,5(4H,6H)-dione (B70) (108 mmol) in 300 mL of DCM was cooled in an ice bath and then 11.8 mL of benzyl amine (108 mmol) were added, and the reaction mixture allowed to stir for 20 hrs. Precipitation was observed during the initial stages of the reaction. After the 20 hrs, the precipitate was separated from the reaction mixture using a fritted filter funnel and washed with DCM several times. The precipitate was dried to afford 10.37 g of B71. The filtrate solution’s solvent was concentrated to dryness, and the residue was purified by column chromatography (330g normal phase isco column; eluent 25-100% EtOAc:heptanes) to afford 3.5 grams of B70 (58.6% total yield from precipitation and column chromatography).NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.39-7.24 (m, 2H), 4.82 (s, 1H), 4.23 (d, 1H), 3.44 (s, 1H), 3.09 (s, 1H); LC-MS: m / z 220.1 [M+H]+.

[0654] Step 12D. Synthesis of tert-butyl benzyl(5-oxo-5,6-dihydro-2H-thiopyran- 3-yl)carbamate (B72)

[0655] To a solution of 5.94 g of 5-(benzylamino)-2H-thiopyran-3(6H)-one (B71) (27.1 mmol) in 100 mL DCM, 5.7 mL of triethyl amine (4.14 g, 41 mmol), 662 mg of DMAP (5.42 mmol) and 8.57 g of Boc anhydride (39.3 mmol) were added. The flask was flushed with argon, and the reaction mixture allowed to stir overnight at rt and then concentrated to dryness. The residue was purified by column chromatography (normal phase isco column; eluent 0-25% EtOAc:heptanes) to afford 2.86 g of B72 (38.1% yield). LC-MS: m / z 264.1 [M+H+-Tbutyl].

[0656] Step 12E. Synthesis of tert-butyl benzyl(1,1-dioxido-5-oxo-5,6-dihydro- 2H-thiopyran-3-yl)carbamate (B73)

[0657] A solution of 4.29 g of tert-butyl benzyl(5-oxo-5,6-dihydro-2H-thiopyran- 3-yl)carbamate (B72) (13.4 mmol) in 300 mL DCM was cooled in an ice water bath. Then, 7.52 g mCPBA (33.6 mmol; 77% purity) was added portion wise. After 15 minutes the reaction mixture was allowed to warm to rt and stirred for an additional 2 hrs. The reaction mixture was quenched by the addition of solid sodium sulfite and solid sodium bicarbonate, and then sat. aq. sodium bicarbonate solution, sat. aq. sodium sulfite, and deionized water were added. The aqueous portion was extracted with DCM (2x), and the combined organic - 202 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) layers dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (80g normal phase isco gold column; eluent 0-45% EtOAc:heptanes) to afford 4.26 g of B73 (90.3% yield). LC-MS: m / z 350.1 [M-H]+.

[0658] Step 12F. Synthesis of tert-butyl benzyl(5-hydroxy-1,1-dioxidotetrahydro- 2H-thiopyran-3-yl)carbamate (B74)

[0659] 9.4 g of tert-butyl benzyl(1,1-dioxido-5-oxo-5,6-dihydro-2H-thiopyran-3- yl)carbamate (B73) (26.7 mmol) and 2.84 g of sodium carbonate (26.8 mmol) were dissolved / suspended in 450 mL of 200 proof EtOH and 5.5 g of 10% Pd / C were added. The reaction mixture was sparged with hydrogen, and the flask flushed with hydrogen gas. The reaction mixture was then heated to 75oC under a hydrogen atmosphere overnight. The reaction mixture was then filtered, and the filtrate concentrated. The residue was dry loaded onto silica gel, and purified by column chromatography (normal phase isco column, gradient 0–50% ethyl acetate in heptanes) to afford 798 mg of B74 (8.39% yield). LC-MS: m / z 256.1 [M+H+- BOC].

[0660] Step 12G. Synthesis of tert-butyl benzyl(1,1-dioxido-5-oxotetrahydro-2H- thiopyran-3-yl)carbamate (B75)

[0661] 760 mg (2.14 mmol) of tert-butyl benzyl(5-hydroxy-1,1-dioxidotetrahydro- 2H-thiopyran-3-yl)carbamate (B74), PCC (553mg, 2.56 mmol) and 100 mg of crushed 4Å molecular sieves were dissolved / suspended in 7 mL of dry DCM, and the reaction mixture stirred at rt for 3 hrs. After 2.5 hrs, additional PCC (~0.5 eq) was added and within 30 minutes LC-MS showed full consumption of starting material. The reaction mixture was passed through a plug of silica using 40% ethyl acetate in heptanes to afford 610 mg of B75 (80.7% yield), which was used without further purification. LC-MS: m / z 352.2 [M-H+].

[0662] Step 12H. Synthesis of tert-butyl benzyl(5-(benzylamino)-1,1- dioxidotetrahydro-2H-thiopyran-3-yl)carbamate (B76)

[0663] To a solution of tert-butyl benzyl(1,1-dioxido-5-oxotetrahydro-2H- thiopyran-3-yl)carbamate (B75) (610 mg, 1.73 mmol) in 9 mL of DCM was added 185 mg (188 µL, 1.73 mmol) of benzyl amine. The reaction mixture was allowed to stir for 1 hr and 45 min, and then sodium triacetoxy borohydride was added (733 mg, 3.46 mmol). The reaction mixture was then allowed to stir overnight. Additional aliquots of benzyl amine and sodium triacetoxy borohydride were added until all the starting material was consumed by LC-MS. After reaction completion, sat. aq. sodium bicarbonate solution was added, and the aqueous portion extracted several times with EtOAc. The combined organic extracts were concentrated to dryness, and the residue held under high vacuum for several hours. The - 203 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) residue was then dissolved in DCM and passed through a silica plug which had been neutralized with Hüing’s base (eluent EtOAc) to give 620 mg of B76 (80.8% yield), which was used without further purification. LC-MS: m / z 445.2 [M+H+].

[0664] Step 12I. Synthesis of 3,5-bis(benzylamino)tetrahydro-2H-thiopyran 1,1- dioxide (B77)

[0665] 620 mg (1.39 mmol) of tert-butyl benzyl-5-(benzylamino)-1,1- dioxidotetrahydro-2H-thiopyran-3-yl)carbamate (B76) was dissolved in 30 mL of 20% TFA in DCM and allowed to stir at rt until LC-MS showed complete loss of the Boc protecting group. The reaction mixture was then quenched by adding solid sodium carbonate followed by minimal sat. aq. sodium bicarbonate solution. The aqueous portion was extracted with EtOAc, and the organic layer concentrated to dryness. The residue was dissolved in DCM and passed through a silica plug (eluent EtOAc) and concentrated to dryness to afford B77, which was used without further purification. LC-MS: m / z 345.2 [M+H+].

[0666] Step 12J. Synthesis of 3,5-diaminotetrahydro-2H-thiopyran 1,1-dioxide (B78)

[0667] 3,5-bis(benzylamino)tetrahydro-2H-thiopyran 1,1-dioxide (B77) was dissolved in 8 ml of methanol and 250 mg of 20% PdOH / C was added. The reaction mixture was then flushed with hydrogen and kept under an atmosphere of hydrogen via a hydrogen balloon and heated to 80oC overnight. The reaction mixture was cooled and passed through a celite plug after LC-MS indicated that the hydrogenolysis was complete. The celite was washed with MeOH and EtOAc. The organic portion were concentrated to dryness to afford B78, which was used without further purification.NMR (400 MHz, CD3OD) δ 3.58-3.51 (m, 1H), 3.26 (ddd, 1H), 2.97 (ddd, 1H), 1.84 (t, 1H); LC-MS: m / z 165.0 [M+H+].

[0668] Intermediate Scheme 13: Preparation of benzyl tert-butyl (5- cyanocyclohexane-1,3-diyl)dicarbamate (relative stereochemistry is indicated in Intermediate Scheme 13). - 204 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)

[0669] Step 13A. Synthesis of tert-butyl 3,7-dioxo-6-azabicyclo[3.2.1]octane-6- carboxylate (B79)

[0670] To a solution of tert-butyl 3-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (3.2 g, 14.2 mmol) in EtOAc (20 mL) was added a solution of RuCl3.H2O (160 mg, 710 µmol) and NaIO4(12.15 g, 56.8 mmol, 3.15 mL) in H2O (15 mL). The reaction mixture was stirred at rt for 18 hrs. Isopropanol (6 mL) was added, and the reaction mixture was stirred at rt for another 20 min and concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography to give B79 (2.8 g, 82.4% yield).1H NMR (400 MHz, CDCl3) δ 4.59-4.58 (m, 1 H), 2.92-2.90 (m, 2 H), 2.78-2.76 (m, 1 H), 2.64-2.51 (m, 3 H), 1.94-1.91 (m, 1 H), 1.53 (s, 9 H).

[0671] Step 13B. Synthesis of 3-((tert-butoxycarbonyl)amino)-5-oxocyclohexane- 1-carboxylic acid (B80)

[0672] To a mixture of tert-butyl 3,7-dioxo-6-azabicyclo[3.2.1]octane-6- carboxylate (B79) (2.8 g, 11.7 mmol) in THF (30 mL) / H2O (20 mL) was added LiOH.H2O (1.23 g, 29.3 mmol), and the reaction mixture was stirred at rt for 18 hrs. Water (50 mL) was added to the reaction mixture, and the pH was adjusted to 3 by the addition of 0.5 M HCl. The aqueous portion was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over Na2SO4, filtered, and concentrated to dryness to give B80 (3.0 g, 99.6% yield), which was used without further purification.1H NMR (400 MHz, CDCl3) δ 4.62 (br s, 1 H), 3.87 (br s, 1 H), 2.78-2.73 (m, 2 H), 2.64-2.62 (m, 1 H), 2.52-2.46 (m, 2 H), 2.28-2.23 (m, 1 H), 1.46 (s, 9 H).

[0673] Step 13C. Synthesis of methyl-5-((tert-butoxycarbonyl)amino)-3,3- dimethoxycyclohexane-1-carboxylate (B81)

[0674] A mixture of 3-(tert-butoxycarbonylamino)-5-oxo-cyclohexanecarboxylic acid (B80) (3.0 g, 11.7 mmol), trimethoxymethane (4.95 g, 46.6 mmol, 5.11 mL) and TsOH - 205 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) (201 mg, 1.17 mmol) in MeOH (40 mL) was stirred at 50°C for 18 hrs. The reaction mixture was concentrated to dryness. The residue was purified by flash silica gel chromatography to give B81 (2.5 g, 67.6% yield).1H NMR (400 MHz, CDCl3) δ 4.41-4.39 (m, 1 H), 3.68 (s, 3 H), 3.65 (br s, 1 H), 3.22 (s, 3 H), 3.20 (s, 3 H), 2.66-2.61 (m, 1 H), 2.37-2.27 (m, 3 H), 1.46 (s, 9 H), 1.41-1.37 (m, 1 H), 1.26-1.09 (m, 2 H); LC-MS: m / z 340.1 (M+Na)+.

[0675] Step 13D. Synthesis of 5-((tert-butoxycarbonyl)amino)-3,3- dimethoxycyclohexane-1-carboxylic acid (B82)

[0676] A mixture of methyl-5-((tert-butoxycarbonyl)amino)-3,3- dimethoxycyclohexane-1-carboxylate (B81) (1.8 g, 5.67 mmol) and LiOH.H2O (1.19 g, 28.4 mmol) in THF (8 mL) / H2O (8 mL) / EtOH (2 mL) was stirred at rt for 18 hrs. Water (50 mL) was added to the reaction mixture, and the pH adjusted to 4 by adding aq. citric acid solution. The aqueous portion was extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered, and concentrated to dryness to give B82 (1.7 g), which was used without further purification.1H NMR (400 MHz, CDCl3) δ 4.44-4.42 (m, 1 H), 3.65 (br s, 1 H), 3.23 (s, 3 H), 3.20 (s, 3 H), 2.68-2.62 (m, 1 H), 2.37-2.24 (m, 3 H), 1.45 (s, 9 H), 1.39-1.21 (m, 3 H).

[0677] Step 13E. Synthesis of benzyl tert-butyl (5,5-dimethoxycyclohexane-1,3- diyl)dicarbamate (B83)

[0678] To a solution of 5-((tert-butoxycarbonyl)amino)-3,3- dimethoxycyclohexane-1-carboxylic acid (B82) (2.3 g, 7.58 mmol) and Et3N (1.15 g, 11.4 mmol, 1.58 mL) in toluene (35 mL) was added DPPA (2.71 g, 9.86 mmol, 2.14 mL), and the reaction mixture was stirred at rt for 2 hrs. Then BnOH (1.64 g, 15.2 mmol, 1.58 mL) was added and the reaction mixture was stirred at 100°C for 18 hrs. The reaction mixture was concentrated to dryness, and the residue was purified by flash silica gel chromatography to give B83 (2.2 g, 71.0% yield). LC-MS: 431.0 (M+Na)+.

[0679] Step 13F. Synthesis of benzyl tert-butyl (5-oxocyclohexane-1,3- diyl)dicarbamate (B84)

[0680] To a solution of tert-butyl N-[5-(benzyloxycarbonylamino)-3,3-dimethoxy- cyclohexyl]carbamate (B83) (2.2 g, 5.39 mmol) in THF (20 mL) was added HCl (2 M, 8.08 mL). The reaction mixture was stirred at 60°C for 18 hrs and then cooled to rt. THF (10 mL) was added to the reaction mixture, and pH adjusted to 8 by adding sat. aq. Na2CO3 solution. Boc2O (2.35 g, 10.77 mmol, 2.47 mL) was added, and the reaction mixture was stirred at rt for 2 hrs. Water (50 mL) was added, and the aqueous portion extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, - 206 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography to give B84 (1.5 g, 76.9% yield). NMR (400 MHz, CDCl3) δ 7.41-7.33 (m, 5 H), 5.12 (s, 2 H), 4.83 (br s, 1 H), 4.55 (br s, 1 H), 3.89-3.83 (m, 2 H), 2.79-2.72 (m, 2 H), 2.51-2.48 (m, 1 H), 2.28-2.22 (m, 2 H), 1.68 (br s, 1 H), 1.46 (s, 9 H); LC-MS: 484.2 (M+Na)+.

[0681] Step 13G. Synthesis of benzyl tert-butyl (5-cyanocyclohexane-1,3- diyl)dicarbamate (B85)

[0682] To a solution of benzyl tert-butyl (5-oxocyclohexane-1,3-diyl)dicarbamate (B84) (1.5 g, 4.14 mmol), 1-(isocyanomethylsulfonyl)-4-methyl-benzene (970 mg, 4.97 mmol) and EtOH (229 mg, 4.97 mmol) in DME (10 mL) was added t-BuOK (604 mg, 5.38 mmol) at 0°C, and the reaction mixture was stirred at 0°C to rt for 1 hr. The reaction mixture was then heated to 40°C and stirred for 18 hrs. The reaction mixture was then concentrated to dryness to give a residue. The residue was purified by silica gel chromatography to give B85 (370 mg, 23.9% yield). LC-MS: 396.0 (M+Na)+.

[0683] Intermediate Scheme 14: Preparation of intermediate rel-tert-butyl ((1R,3S)-3-amino-2-hydroxy-2-methylcyclohexyl)carbamate (relative stereochemistry is indicated in Intermediate Scheme 14 for steps 14A and 14B)

[0684] Step 14A. Synthesis of benzyl tert-butyl (2-hydroxycyclohexane-1,3- diyl)dicarbamate (B86)

[0685] To a solution of tert-butyl (3-amino-2-hydroxycyclohexyl)carbamate (B8) (60 mg, 261 µmol) in DCM (3 mL) was added benzyl carbonochloridate (53.3 mg, 313 µmol, 44.4 µL), and then aq. NaOH solution (52.1 mg, 521 µmol, 1 M) was added. The reaction mixture was stirred at rt for 3 hrs and concentrated to dryness. EtOAc (10 mL) was added to - 207 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) the residue, and it was stirred for 1 hr. The organic layer was washed with brine (5 mL×3), dried over Na2SO4, filtered, and concentrated to dryness to afford B86 (90 mg), which was used without further purification. LC-MS: m / z 365.2 [M+H]+.

[0686] Step 14B. Synthesis of benzyl tert-butyl (2-oxocyclohexane-1,3-diyl) dicarbamate (B87)

[0687] To a solution of tert-butyl (2-hydroxycyclohexane-1,3-diyl)dicarbama...

Claims

128748-02920 (AGI-BCAT-03WO) What is claimed:

1. A compound of Formula I or II:or a pharmaceutically acceptable salt thereof, wherein: R1is optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted 4-, 5- or 6-membered heterocycloalkyl; R1ais hydrogen or fluoro; R1bis optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted 4-, 5- or 6-membered heterocycloalkyl; R1cis hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; X is CH or N; Cy is optionally substituted C5-C7 cycloalkyl or optionally substituted 6- or 7-membered heterocycloalkyl;L is a bond, -O-, -NRa-, or optionally substituted C1-C4alkylene; Rais hydrogen or C1-C4alkyl; R2is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted 5- membered heteroaryl, optionally substituted 4-, 5-, or 6-membered heterocycloalkyl, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6haloalkoxy, optionally substituted C3-C6cycloalkyl, or NRbRc; Rband Rcare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, OH, C1-C4alkoxy, C1-C6hydroxyalkyl, or C3-C6cycloalkyl; - 311 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) Ar1is optionally substituted 6-membered heteroaryl, optionally substituted phenyl, orU is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl; V is an optionally substituted phenyl, optionally substituted 5- or 6-membered heterocycloalkyl, or optionally substituted 5- or 6-membered heteroaryl; and wherein the point of attachment to the carbonyl group of –NHC(O) for variable Z occurs at the optionally substituted phenyl or optionally substituted 6-membered heteroaryl of U; Y is O or NH; R3ais hydrogen, C1-C3alkyl, or oxo; R3bis hydrogen or C1-C3alkyl; or alternatively, R3aand R3bare taken together to form cyclopropyl; each R4is independently halo, cyano, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; and m is 0, 1, 2, 3, or 4.

2. The compound according to claim 1, wherein the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein the compound of Formula I is a compound of Formula I-A:or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, wherein the compound of Formula I is a compound Formula I-B or Formula I-C: - 312 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)or a pharmaceutically acceptable salt thereof.

5. The compounds according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula I-B.

6. The compounds according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula I-C.

7. The compound according to claim 2, wherein the compound of Formula I is a compound Formula I-D, Formula I-E, or Formula I-F:or a pharmaceutically acceptable salt thereof.

8. The compounds according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula I-D.

9. The compounds according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula I-E.

10. The compounds according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula I-F. - 313 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 11. The compound according to claim 1, wherein the compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 11, wherein the compound of Formula II is a compound of Formula II-A:or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 11, wherein the compound of Formula II is a compound of Formula II-B or Formula II-C:or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula II-B.

15. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula II-C.

16. The compound according to claim 11, wherein the compound of Formula II is a compound of Formula II-D, Formula II-E, or Formula II-F: - 314 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula II-D.

18. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula II-E.

19. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula II-F.

20. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X is CH.

21. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X is N.

22. The compound according to any one of claims 1, 2, 7, 8, 10, 11, 16, 17, or 19- 21, or a pharmaceutically acceptable salt thereof, wherein Y is O.

23. The compound according to any one of claims 1, 2, 7, 8, 10, 11, 16, 17, or 19- 21, or a pharmaceutically acceptable salt thereof, wherein Y is NH.

24. The compound according to any one of claims 1, 2, 4-6, 11, 13-15, 20, or 21, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare hydrogen. - 315 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 25. The compound according to any one of claims 1, 2, 4-6, 11, 13-15, 20, or 21, or a pharmaceutically acceptable salt thereof, wherein R3ais oxo and R3bis hydrogen.

26. The compound according to any one of claims 1, 2, 4-11, or 13-25, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halo.

27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein each R4is independently F or Cl.

28. The compound according to any one of claims 1, 2, 4-11, or 13-27, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

29. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted C5-C7 cycloalkyl.

30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein Cy is unsubstituted C5-C7 cycloalkyl.

31. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein Cy is C5-C7cycloalkyl substituted with one or more of OH, deuterium, halo, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe, wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)(C1-C4alkyl), SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl).

32. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C5-C7cycloalkyl is an optionally substituted cyclohexyl or an optionally substituted cycloheptyl. - 316 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 33. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cyclohexyl34. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cyclohexyl35. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cyclohexyl is substituted with one of OH, C1-C3alkoxy, C1-C3haloalkoxy or NRdRe, wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen or C1-C4alkyl.

36. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cyclohexyl.

37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cyclohexyl is. - 317 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 38. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cycloheptyl39. The compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cycloheptyl40. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted cycloheptyl is substituted with one of OH or C1-C3alkoxy.

41. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted 6-membered heterocycloalkyl.

42. The compound according to claim 41, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, optionally substituted thianyl, optionally substituted thianyl sulfone, optionally substituted thianyl sulfoxide, or optionally substituted 1- oxo-1-imino-1-thiacyclohexyl.

43. The compound according to claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted piperidinyl.

44. The compound according to claim 43, or a pharmaceutically acceptable salt thereof, wherein the nitrogen in the piperidinyl is substituted with C1-C6alkyl, C(O)(C1-C6alkyl), oxo, OH, C1-C6alkoxy, CO2(C1-C6alkyl), SO2(C1-C6alkyl), or SO2(C3-C6cycloalkyl). - 318 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 45. The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein the nitrogen in the piperidinyl is substituted with C1-C4alkyl or C(O)(C1-C4alkyl).

46. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted 7-membered heterocycloalkyl, such as optionally substituted oxazepanyl, optionally substituted thiepanyl, optionally substituted thiepanyl-1-oxide, optionally substituted thiepanyl-1,1-dioxide, optionally substituted azepanyl, or optionally substituted 1-imino-1-oxide-thiepanyl.

47. The compound according to any one of claims 1 or 2, wherein the compound of Formula I is a compound of Formula I-G:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1- C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl).

48. The compound according to claim 47, wherein the compound of Formula I-G is a compound of Formula I-G-1: - 319 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)or a pharmaceutically acceptable salt thereof.

49. The compound according to any one of claims 1 or 11, wherein the compound of Formula II is a compound of Formula II-G:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1-C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl).

50. The compound according to claim 49, wherein the compound of Formula II-G is a compound of Formula II-G-1:or a pharmaceutically acceptable salt thereof. - 320 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 51. The compound according to any one of claims 47-50, or a pharmaceutically acceptable salt thereof, wherein R5is OH, C1-C3alkoxy, C1-C3haloalkoxy, or NH2, and R6is hydrogen.

52. The compound according to any one of claims 47-50, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen and R6is OH, C1-C3alkoxy, C1-C3haloalkoxy, or NH2.

53. The compound according to claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein the C1-C3alkoxy is OCH3 and the C1-C3haloalkoxy is OCF3 or OCHF2.

54. The compound according to any one of claims 1 or 2, wherein the compound of Formula I is a compound of Formula I-H or Formula I-J:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1- C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl).

55. The compound according to claim 54, wherein the compound of Formula I-H is a compound of Formula I-H-1, or a pharmaceutically acceptable salt thereof, and the compound of Formula I-J is a compound of Formula I-J-1, or a pharmaceutically acceptable salt thereof: - 321 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)56. The compound according to any one of claims 1 or 11, wherein the compound of Formula II is a compound of Formula II-H or Formula II-J:or a pharmaceutically acceptable salt thereof, wherein: one of R5or R6is OH, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, deuterated C1-C4alkoxy, C1-C4haloalkoxy, OCO2(C1-C4alkyl), OCO2(C3-C4cycloalkyl), OSO2(C1-C4alkyl), OSO2(C3-C4cycloalkyl), OC(O)(C1-C4alkyl), OC(O)(C3- C4cycloalkyl), N3, or NRdRe; and the other of R5or R6is hydrogen or deuterium; and wherein Rdis hydrogen or C1-C4alkyl and Reis hydrogen, C1-C4alkyl, CO2(C1- C4alkyl), C(O)C1-C4alkyl, SO2(C1-C4alkyl), or SO2(C3-C4cycloalkyl).

57. The compound according to claim 56, wherein the compound of Formula II-H is a compound of Formula II-H-1, or a pharmaceutically acceptable salt thereof, and the compound of Formula II-J is a compound of Formula II-J-1, or a pharmaceutically acceptable salt thereof: - 322 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)58. The compound according to any one of claims 54-57, or a pharmaceutically acceptable salt thereof, wherein R5is OH or C1-C3alkoxy and R6is hydrogen.

59. The compound according to any one of claims 54-57, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen and R6is OH or C1-C3alkoxy.

60. The compound according to any one of claims 58 or 59, or a pharmaceutically acceptable salt thereof, wherein the C1-C3alkoxy is OCH3.

61. The compound according to any one of claims 1 or 2, wherein the compound of Formula I is a compound of Formula I-K:or a pharmaceutically acceptable salt thereof, wherein: R7is hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, oxo, OH, C1-C6alkoxy, C(O)NRfRg, C1- C6hydroxyalkyl, CO2(C1-C6alkyl), SO2(C1-C6alkyl), or SO2(C3-C6cycloalkyl); and each Rfand Rgis independently hydrogen or C1-C4alkyl.

62. The compound according to claim 61, wherein the compound of Formula I-K is a compound of Formula I-K-1: - 323 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)or a pharmaceutically acceptable salt thereof.

63. The compound according to any one of claims 1 or 11, wherein the compound of Formula II is a compound of Formula II-K:or a pharmaceutically acceptable salt thereof, wherein: R7is hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, oxo, OH, C1-C6alkoxy, C(O)NRfRg, C1- C6hydroxyalkyl, CO2(C1-C6alkyl), SO2(C1-C6alkyl), or SO2(C3-C6cycloalkyl); and each Rfand Rgis independently hydrogen or C1-C4alkyl.

64. The compound according to claim 63, wherein the compound of Formula II-K is a compound of Formula II-K-1:or a pharmaceutically acceptable salt thereof.

65. The compound of any one of claims 61-64, or a pharmaceutically acceptable salt thereof, wherein R7is C1-C4alkyl or C(O)C1-C4alkyl. - 324 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 66. The compound according to claim 65, or a pharmaceutically acceptable salt thereof, wherein R7is CH3, CH2CH3, or C(O)CH3.

67. The compound according to claim 1, 2, 11, 20, 21, or 29-66 or a pharmaceutically acceptable salt thereof, wherein Z is –NHC(O)Ar1.

68. The compound according to any one of claims 1-3, 11, 12, 20, 21, or 29-67, or a pharmaceutically acceptable salt thereof, wherein Ar1is optionally substituted 6-membered heteroaryl or optionally substituted phenyl.

69. The compound according to claim 68, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-membered heteroaryl is pyridinyl, pyrimidinyl, or pyridazinyl, each optionally substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, C1-C6hydroxyalkyl, cyano, OH, oxo, or NRjRk; and each Rjand Rkis independently hydrogen or C1-C4alkyl.

70. The compound according to claim 69, or a pharmaceutically acceptable salt71. The compound according to claim 68, or a pharmaceutically acceptable salt thereof, wherein:R8, R9, R10, and R11are each independently hydrogen, halo, C1-C4alkyl, C1- C4haloalkyl, C1-C4alkoxy, or C1-C4haloalkoxy. - 325 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 72. The compound according to claim 71, or a pharmaceutically acceptable salt thereof, wherein at least two of R8, R9, R10, and R11are hydrogen.

73. The compound according to claim 68, or a pharmaceutically acceptable salt thereof, wherein: Ar1is phenyl, optionally substituted with one or more of halo, C1-C6alkyl, C3- C6cycloalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, OH, NRjRk, C(O)NRfRg, CO2(C1-C6alkyl), SO2(C1-C4alkyl), SO2(C3- C4cycloalkyl), C1-C4alkylene-R12, or O-R13; R12is cyano, NRjRk, OH, or C1-C4alkoxy; R13is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6- membered heterocycloalkyl, (C1-C4alkylene)C1-C4alkoxy, (C1- C4alkylene)NRjRk, or (C1-C4alkylene)-(optionally substituted 4-, 5-, or 6- membered heterocycloalkyl), and each Rf, Rg, Rj, and Rkis independently hydrogen or C1-C4alkyl.

74. The compound according to claim 73, or a pharmaceutically acceptable salt, - 326 - ME148476702v.1128748-02920 (AGI-BCAT-03WO). The compound according to claim 68, or a pharmaceutically acceptable salt thereof, wherein:R14is hydrogen, halo, cyano, or C1-C6haloalkyl; R15is halo, C1-C6alkoxy, C1-C6haloalkoxy, OH, NRjRk, C1-C4alkylene-R16, or O-R17; R16is NRjRkor OH; R17is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6- membered heterocycloalkyl, (C1-C4alkylene)C1-C4alkoxy, (C1- C4alkylene)NRjRk, or (C1-C4alkylene)-(optionally substituted 4-, 5-, or 6- membered heterocycloalkyl); and each Rjand Rkis independently hydrogen or C1-C4alkyl. - 327 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 76. The compound according to any one of claims 1-3, 11, 12, 20, 21, or 29-67, or a pharmaceutically acceptable salt thereof, wherein Ar1is.

77. The compound according to claim 76, or a pharmaceutically acceptable salt thereof, wherein U is optionally substituted phenyl, and V is optionally substituted 5-membered heterocycloalkyl or optionally substituted 5- membered heteroaryl.

78. The compound according to claim 77, or a pharmaceutically acceptable salt thereof, wherein V is optionally substituted furanyl, optionally substituted isofuranyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted thiophenyl.

79. The compound according to claim 77 or 78, or a pharmaceutically acceptable salt thereof, wherein V is unsubstituted furanyl, unsubstituted isofuranyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted thiazolyl, unsubstituted isothiazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, or unsubstituted thiophenyl.

80. The compound according to any one of claims 76-79, or a pharmaceutically acceptable salt thereof, wherein U is phenyl substituted with one or more of halo, cyano, or C1-C6haloalkyl.

81. The compound according to claim 80, or a pharmaceutically acceptable salt thereof, wherein U is phenyl substituted with one or more halo; and V is unsubstituted furanyl.

82. The compound according to any one of claims 1, 2, 11, 20-23, or 29-67, or a pharmaceutically acceptable salt thereof, wherein: - 328 - ME148476702v.1128748-02920 (AGI-BCAT-03WO)R3ais hydrogen or oxo.

83. The compound according to claim 82, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halo and m is 1 or 2.

84. The compound according to claim 83, or a pharmaceutically acceptable salt thereof, wherein each R4is independently F or Cl.

85. The compound according to claim 84, or a pharmaceutically acceptable salt86. The compound according to any one of claims 1-10, 20-48, 51-55, 58-62, or 65-85, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted heteroaryl. - 329 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 87. The compound according to claim 86, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted 5- or 6-membered heteroaryl.

88. The compound according to claim 87, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted 5-membered heteroaryl.

89. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroaryl is optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl.

90. The compound according to claim 88 or claim 89, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroaryl is substituted with one or more of oxo, NRhRi, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, C1-C6alkoxy, C1-C6haloalkoxy, CO2(C1-C6alkyl), or C(O)NRfRg; and wherein each Rf, Rg, Rhand Riis independently hydrogen or C1-C4alkyl.

91. The compound according to claim 87, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted 6-membered heteroaryl.

92. The compound according to claim 91, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-membered heteroaryl is optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl.

93. The compound according to claim 91 or claim 92, or a pharmaceutically acceptable salt thereof, wherein the 6-membered heteroaryl is substituted with one or more of oxo, NRhRi, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, C1-C6alkoxy, C1-C6haloalkoxy, CO2(C1-C6alkyl), or C(O)NRfRg; and wherein each Rf, Rg, Rhand Riis independently hydrogen or C1-C4alkyl. - 330 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 94. The compound according to claim 87, or a pharmaceutically acceptable salt thereof, wherein:R18is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; R19is hydrogen or C1-C6alkyl; R20and R21are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, or CO2(C1-C6alkyl); W is O or S; R22is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C1-C6hydroxyalkyl, or NRhRi; R23is hydrogen or C1-C6alkyl; R24, R25, and R26are each independently hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; and each Rhand Riis independently hydrogen or C1-C4alkyl.

95. The compound according to claim 86, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted 9-membered heteroaryl, such as optionally substituted benzofuranyl, optionally substituted isobenzofuranyl, optionally substituted benzoxazolyl, optionally substituted benzoisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoisothiazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, or optionally substituted benzothiophenyl.

96. The compound according to any one of claims 1-10, 20-48, 51-55, 58-62, or 65-85, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted aryl.

97. The compound according to claim 96, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted aryl is phenyl, optionally - 331 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) substituted with C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, or C1-C6cyanoalkyl.

98. The compound according to any one of claims 1-10, 20-48, 51-55, 58-62, or 65-85, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted 4-, 5- or 6-membered heterocycloalkyl, such as optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted dioxanyl.

99. The compound according to claim 98, or a pharmaceutically acceptable salt thereof, wherein R1is pyrrolidinyl optionally substituted with one or more of oxo, C1-C6hydroxyalkyl, C1-C6alkyl, C1-C6alkoxy(alkylene), C1-C6cyanoalkyl, OH, cyano, C(O)NRfRg, and wherein each Rfand Rgis independently hydrogen or C1-C4alkyl.

100. The compound according to any one of claims 1, 11-19, 22-46, 49-53, 56-60, or 63-85, or a pharmaceutically acceptable salt thereof, wherein R1bis optionally substituted heteroaryl.

101. The compound according to claim 100, or a pharmaceutically acceptable salt thereof, wherein R1bis optionally substituted 5- or 6-membered heteroaryl.

102. The compound according to claim 101, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- or 6-membered heteroaryl is optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted tetrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl.

103. The compound according to any one of claims 101 or 102, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- or 6-membered heteroaryl is substituted with one or more of oxo, NRhRi, C1- - 332 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, C1-C6alkoxy, C1- C6haloalkoxy, CO2(C1-C6alkyl), or C(O)NRfRg; and wherein each Rf, Rg, Rhand Riis independently hydrogen or C1-C4alkyl.

104. The compound according to claim 101, or a pharmaceutically acceptable salt thereof, wherein:R18is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; R19is hydrogen or C1-C6alkyl; R20and R21are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, or CO2(C1-C6alkyl); W is O or S; R22is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C1-C6hydroxyalkyl, or NRhRi; R23is hydrogen or C1-C6alkyl; R24, R25, and R26are each independently hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; and each Rhand Riis independently hydrogen or C1-C4alkyl.

105. The compound according to claim 100, or a pharmaceutically acceptable salt thereof, wherein R1bis optionally substituted 9-membered heteroaryl, such as optionally substituted benzofuranyl, optionally substituted isobenzofuranyl, optionally substituted benzoxazolyl, optionally substituted benzoisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoisothiazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, or optionally substituted benzothiophenyl. - 333 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 106. The compound according to any one of claims 1, 11-19, 22-46, 49-53, 56-60, or 63-85, or a pharmaceutically acceptable salt thereof, wherein R1bis optionally substituted aryl.

107. The compound according to claim 106, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted aryl is phenyl, optionally substituted with C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, cyano, or C1-C6cyanoalkyl.

108. The compound according to any one of claims 1, 11-19, 22-46, 49-53, 56-60, or 63-85, or a pharmaceutically acceptable salt thereof, wherein R1bis optionally substituted 4-, 5- or 6-membered heterocycloalkyl, such as optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted dioxanyl.

109. The compound according to claim 108, or a pharmaceutically acceptable salt thereof, wherein R1bis pyrrolidinyl, optionally substituted with one or more of oxo, C1-C6hydroxyalkyl, C1-C6alkyl, C1-C6alkoxy(alkylene), C1-C6cyanoalkyl, OH, cyano, C(O)NRfRg, and wherein each Rfand Rgis independently hydrogen or C1-C4alkyl.

110. The compound according to any one of claims 1, 11-19, 22-46, 49-53, 56-60, 63-85, or 100-109, or a pharmaceutically acceptable salt thereof, wherein R1ais hydrogen.

111. The compound according to any one of claims 1, 11-19, 22-46, 49-53, 56-60, 63-85, or 100-109, or a pharmaceutically acceptable salt thereof, wherein R1ais fluoro.

112. The compound according to any one of claims 1, 11-19, 22-46, 49-53, 56-60, 63-85, or 100-111, or a pharmaceutically acceptable salt thereof, wherein R1cis hydrogen. - 334 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 113. The compound according to any one of claims 1-112, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

114. The compound according to any one of claims 1-112, or a pharmaceutically acceptable salt thereof, wherein L is -O-.

115. The compound according to any one of claims 1-112, or a pharmaceutically acceptable salt thereof, wherein L is -NRa-, wherein Rais hydrogen or C1- C4alkyl.

116. The compound according to any one of claims 1-112, or a pharmaceutically acceptable salt thereof, wherein L is optionally substituted C1-C4alkylene.

117. The compound according to claim 116, or a pharmaceutically acceptable salt thereof, wherein L is C1-C4alkylene substituted with deuterium, oxo, halo, NH2, NH(C1-C4alkyl), N(C1-C4alkyl)2, OH, C1-C3alkoxy, NRlC(O)(C1- C4alkyl), NRlCO2(C1-C4alkyl), or an optionally substituted 4-, 5-, or 6- membered heterocycloalkyl containing a nitrogen wherein the nitrogen is connected to the alkylene carbon, and each Rlis independently hydrogen or C1-C4alkyl.

118. The compound according to claim 116, or a pharmaceutically acceptable salt thereof, wherein L is unsubstituted C1-C4alkylene.

119. The compound according to any one of claims 1-118, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or NRbRc.

120. The compound according to any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein: R2is phenyl or pyridinyl, each optionally substituted with one or more of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, OH, - 335 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) NRmRn, C(O)NRfRg, CO2(C1-C6alkyl), COOH, C1-C4alkylene-R27, or O- R28; R27is cyano, NRmRn, or COOH; R28is C1-C6hydroxyalkyl, C3-C6cycloalkyl, optionally substituted 4-, 5-, or 6- membered heterocycloalkyl, or (C1-C4alkylene)C1-C4alkoxy; and each Rf, Rg, Rm, and Rnis independently hydrogen or C1-C4alkyl.

121. The compound according to any one of claims 1-113, or a pharmaceutically acceptable salt thereof, wherein: L is a bond;R29, R30, R31, R32, R33, R34, and R35are each independently hydrogen, halo, OH, cyano, C1-C4alkoxy, C1-C4haloalkoxy, C(O)NRfRg, or O-R28; R28is C1-C6hydroxyalkyl or (C1-C4alkylene)C1-C4alkoxy; and wherein each Rfand Rgis independently hydrogen or C1-C4alkyl.

122. The compound according to claim 121, or a pharmaceutically acceptable salt thereof, whereinare each hydrogen, and R33is hydrogen, halo, or C1-C4haloalkoxy.

123. The compound according to claim 122, or a pharmaceutically acceptable salt thereof, wherein R33is hydrogen, F, or OCHF2. - 336 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 124. The compound according to claim 121, or a pharmaceutically acceptable salt thereof, whereinleast two of R29, R30, R31, and R32are hydrogen.

125. The compound according to claim 124, or a pharmaceutically acceptable salt thereof, wherein one of R29and R32is halo, OH, C1-C4alkoxy, or C1- C4haloalkoxy and the other of R29and R32is halo; and R30and R31are hydrogen.

126. The compound according to claim 124, or a pharmaceutically acceptable salt thereof, wherein R29is halo, cyano, OH, C1-C4haloalkoxy, C1-C4alkoxy, C(O)NRfRg, or O-R28, and R30, R31, and R32are each hydrogen.

127. The compound according to claim 120, or a pharmaceutically acceptable salt.

128. The compound according to any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, optionally substituted with - 337 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) cyano, OH, or C(O)NRiRj, and wherein each Riand Rjis independently hydrogen or C1-C4alkyl.

129. The compound according to claim 128, or a pharmaceutically acceptable salt thereof, wherein R2is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, CH2C(CH3)3, C(CH3)2OH, CH(OH)(CH3), C(CH3)2CN, C(CH3)2C(O)NH2, or C(CH3)(CH2CH2OH).

130. The compound according to any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkoxy, optionally substituted with OH.

131. The compound according to claim 130, or a pharmaceutically acceptable salt thereof, wherein R2is OCH3, OCH(CH3)2, or OCH2CH2OH.

132. The compound according to any one of claims 1-118, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6haloalkyl or C1-C6haloalkoxy.

133. The compound according to claim 132, or a pharmaceutically acceptable salt thereof, wherein R2is CF3, CH(CH3)(CF3), CH2CF3, C(CH3)2F, CH2C(CH3)2F, C(CH3)F2, CH2C(CH3)F2, CHFCH(CH3)2, CF2CH(CH3)2, OCF3, OCH2CF3, OCHF2, OCH2F, or OCH(CH3)(CF3).

134. The compound according to any one of claims 1-118, or a pharmaceutically acceptable salt thereof, wherein R2is C3-C6cycloalkyl, optionally substituted with one or more of C1-C4alkyl or C1-C4haloalkyl.

135. The compound according to any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein R2is NRbRcand Rband Rcare each independently hydrogen or C1-C4alkyl.

136. The compound according to claim 135, or a pharmaceutically acceptable salt thereof, wherein R2is NH(CH3), N(CH3)2, N(CH3)(CH2CH3), or NH(CH2CH3). - 338 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 137. The compound according to any one of claims 1-118, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted 5-membered heteroaryl, such as optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl.

138. The compound according to any one of claims 1-118, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted 4-, 5- or 6- membered heterocycloalkyl, such as optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted dioxanyl.

139. The compound of claim 1 that is a compound of Tables 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

140. A pharmaceutical composition comprising a compound according to any one of claims 1-139, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

141. A method of reducing plasma methylmalonic acid in a subject having an elevated methylmalonic acid level comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof.

142. A method of treating a BCAA-catabolism-related diseases in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof.

143. The method according to claim 142, wherein the BCAA-catabolism-related disease is methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), maple syrup urine disease, methylmalonic semialdehyde (MMSDH) deficiency, 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) - 339 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) deficiency, isobutyryl-CoA (IBD) deficiency, acetyl-CoA carboxylase 1 (ACC) deficiency, mitochondrial short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency, methylbutyryl CoA dehydrogenase (SBCAD) deficiency, beta- ketothiolase deficiency (BKT), hydroxy-3-methylglutaconyl-CoA lysase (HMGCL) deficiency, 3-methylglutaconyl-CoA-hydratase deficiency, or 3- methylcrotonyl-CoA (3-MCC) deficiency.

144. A method of reducing blood ammonia in a subject having an elevated ammonia level comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof.

145. A method of reducing blood 2-methylcitrate in a subject having an elevated 2- methylcitrate level comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof.

146. A mouse (Mus musculus) as an animal model for Branched Chain Amino Acid Transaminase 2 (BCAT2) deficiency, wherein the mouse comprises one or more genomic mutations in an endogenous BCAT2 gene that results in a knockout of the endogenous BCAT2 gene.

147. The mouse of claim 146, wherein the one or more mutations are in exon 3 of the BCAT2 gene.

148. The mouse of claim 146 or 147, wherein the one or more mutations in exon 3 of the BCAT2 gene comprise a deletion of adenine (A) at position 245 of SEQ ID NO:

1.

149. The mouse of any one of claims 146 to 148, wherein the one or more mutations result in a premature stop codon in the BCAT2 gene.

150. The mouse of claim 149, wherein the premature stop codon is in exon 4 of the BCAT2 gene. - 340 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 151. The mouse of claim 149 or 150, wherein the premature stop codon is a TGA stop codon at positions 344-346 of SEQ ID NO:

1.

152. The mouse of any one of claims 146 to 151, wherein the mouse is homozygous for the knockout of the endogenous BCAT2 gene.

153. The mouse of any one of claims 146 to 152, which is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous BCAT2 gene.

154. The mouse of claim 153, wherein a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 8 and an sgRNA encoded by the polynucleotide sequence of SEQ ID NO: 9 are used for the CRISPR / Cas9- mediated HDR.

155. The mouse of any one of claims 146 to 154, wherein the mouse has increased plasma isoleucine levels relative to a mouse that does not comprise a knockout of the endogenous BCAT2 gene.

156. A mouse (Mus musculus) as an animal model for methylmalonic acidemia, wherein the mouse comprises one or more genomic mutations in at least one endogenous methylmalonyl Coenzyme A (MMA-CoA) mutase gene that results in an M698K substitution relative to the amino acid sequence of SEQ ID NO: 4 in a MMA-CoA protein encoded by the gene.

157. The mouse of claim 156, wherein the one or more genomic mutations is a T2228A substitution relative to the nucleic acid sequence of SEQ ID NO:

3.

158. The mouse of claim 156 or 157, which is homozygous for the one or more genomic mutations in the endogenous MMA-CoA mutase gene that results in the M698K substitution.

159. The mouse of claim 156 or 157, which is heterozygous for the one or more genomic mutations in the endogenous MMA-CoA mutase gene that results in the M698K substitution. - 341 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 160. The mouse of claim 159, wherein the mouse comprises the one or more genomic mutations that results in the M698K substitution at a first locus of an endogenous MMA-CoA mutase gene, and further comprises one or more genomic mutations that result in a knockout of an endogenous MMA-CoA mutase gene at a second locus of an endogenous MMA-CoA mutase gene.

161. The mouse of claim 160, wherein the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene is in exon 2 of the endogenous MMA-CoA mutase gene.

162. The mouse of claim 160 or 161, wherein the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene introduce a premature stop codon into the endogenous MMA-CoA mutase gene.

163. The mouse of any one of claims 160 to 162, wherein the one or more genomic mutations that result in a knock out of the endogenous MMA-CoA mutase gene comprise a G311A substitution relative to the nucleic acid sequence of SEQ ID NO:

3.

164. The mouse of any one of claims 160 to 163, wherein the mouse is homozygous for the knockout of the endogenous MMA-CoA mutase gene.

165. The mouse of any one of claims 156 to 164, which is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous MMA-CoA mutase gene that results in the M698K substitution.

166. The mouse of claim 165, wherein a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 19 and an sgRNA encoded by the polynucleotide sequence of SEQ ID NO: 20 are used for the CRISPR / Cas9- mediated HDR. - 342 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 167. The mouse of claim 165 or 166, wherein the CRISPR / Cas9-mediated HDR utilizes a donor DNA having the polynucleotide sequence of SEQ ID NO:

21.

168. The mouse of any one of claims 160 to 167, which is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous MMA-CoA mutase gene that results in a knockout of an endogenous MMA-CoA mutase gene.

169. The mouse of claim 168, wherein a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 14 is used for the CRISPR / Cas9- mediated HDR.

170. The mouse of any one of claims 156 to 169, wherein the mouse further comprises one or more genomic mutations in an endogenous BCAT2 gene that results in a knockout of the endogenous BCAT2 gene.

171. The mouse of claim 170, wherein the mouse is homozygous for the knockout of the endogenous BCAT2 gene.

172. The mouse of any one of claims 156 to 171, wherein the mouse has increased plasma levels of a compound selected from the group consisting of 3-OH- isobutyric acid (3-HIB), methylmalonic acid (MMA) and plasma keto isoleucine (Keto-Ile) relative to a syngeneic wildtype mouse.

173. A mouse (Mus musculus) as an animal model for propionic acidemia, wherein the mouse comprises one or more genomic mutations in at least one endogenous propionyl-Coenzyme A carboxylase α subunit (PCCA) gene that results in an A134T substitution relative to the amino acid sequence of SEQ ID NO: 6 in a PCCA protein encoded by the gene.

174. The mouse of claim 173, wherein the one or more genomic mutations is a G439A substitution relative to the nucleic acid sequence of SEQ ID NO:

5. - 343 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) 175. The mouse of claim 173 or 174, which is homozygous for the one or more genomic mutations in the endogenous PCCA gene that results in the A134T substitution.

176. The mouse of claim 173 or 174, which is heterozygous for the one or more genomic mutations in the endogenous PCCA gene that results in the A134T substitution.

177. The mouse of claim 173 or 174, wherein the mouse comprises the one or more genomic mutations that results in the A134T substitution at a first locus of an endogenous PCCA gene, and further comprises one or more genomic mutations that result in a knockout of an endogenous PCCA gene at a second locus of an endogenous PCCA gene.

178. The mouse of claim 177, wherein the one or more genomic mutations that result in a knock out of the endogenous PCCA gene are in exon 5 of the endogenous PCCA gene.

179. The mouse of claim 177 or 178, wherein the one or more genomic mutations that result in a knock out of the endogenous PCCA gene introduce a premature stop codon into the endogenous PCCA mutase gene.

180. The mouse of any one of claims 177 to 179, wherein the one or more genomic mutations that result in a knock out of the endogenous PCCA gene comprise the addition of one or more nucleotides to exon 5 of the endogenous PCCA gene.

181. The mouse of any one of claims 177 to 180, wherein the one or more genomic mutations that result in a knock out of the endogenous PCCA gene comprise the addition of a nucleotide at position 379 of SEQ ID NO:

5.

182. The mouse of claim 181, wherein the nucleotide is adenine.

183. The mouse of any one of claims 173 to 182, which is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the - 344 - ME148476702v.1128748-02920 (AGI-BCAT-03WO) one or more genomic mutations into the endogenous PCCA gene that results in an A134T substitution.

184. The mouse of claim 183, wherein a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 31 is used for the CRISPR / Cas9- mediated HDR.

185. The mouse of claim 183 or 184, wherein the CRISPR / Cas9-mediated HDR utilizes a donor DNA having the polynucleotide sequence of SEQ ID NO:

32.

186. The mouse of any one of claims 173 to 185, which is generated by CRISPR / Cas9-mediated homology-directed repair (HDR) that introduces the one or more genomic mutations into the endogenous PCCA gene that results in a knockout of an endogenous PCCA gene.

187. The mouse of claim 186, wherein a single guide RNA (sgRNA) encoded by the polynucleotide sequence of SEQ ID NO: 26 is used for the CRISPR / Cas9- mediated HDR.

188. The mouse of any one of claims 173 to 187, wherein the mouse has increased plasma propionyl carnitine levels relative to a mouse that does not comprise the A134T substitution and / or a knockout in an endogenous PCCA gene.

189. The mouse of any one of claims 146 to 188, which is a male.

190. The mouse of any one of claims 146 to 188, which is a female.

191. The mouse of any one of claims 146 to 190, which is a C57BL / 6 mouse. - 345 - ME148476702v.1

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