Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations - Patents.com

Abstract

The present disclosure relates to a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein m, R 1 ~R 5 , R 5A and L are defined herein. These compounds are useful in methods for stabilizing mutant PAH proteins or reducing blood phenylalanine concentrations in subjects suffering from phenylketonuria. In some embodiments, the mutant PAH protein comprises at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, ​​I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein comprises at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation. TIFF2025507762000719.tif3453

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 314,580, filed February 28, 2022, the entire contents of which are incorporated herein by reference.

[0002] This application relates to compounds that stabilize phenylalanine hydroxylase (PAH) mutations, pharmaceutical compositions containing those compounds, and methods of using those compounds to treat phenylketonuria. [Background technology]

[0003] Phenyleketonuria (PKU) is an autosomal recessive disorder that affects approximately 1:10,000 people worldwide (approximately 1:15,000–1:20,000 in the United States). The prevalence varies by region. PKU occurs in patients with mutations in the gene encoding the phenylalanine hydroxylase (PAH) enzyme, which is responsible for converting phenylalanine to tyrosine. PAH is a tetrameric enzyme expressed in the liver that requires a BH4 cofactor for activity. Reduced or lost PAH activity leads to toxic accumulation of phenylalanine (Phe) in the blood and brain. High levels of Phe damage brain white matter and interfere with neurotransmitter production. If untreated, high levels of Phe can lead to mental retardation and reduced IQ in children, and neurocognitive and psychiatric problems in adults, such as executive function deficits (e.g., difficulties with attention, memory, flexible thinking, and organization / time management), psychological problems (e.g., depression, anxiety, and mood swings), mental and / or behavioral problems (e.g., attention deficit hyperactivity disorder, self-injury, schizophrenia, agoraphobia, and agitation), and neurological abnormalities (e.g., spasticity, tremors, gait disorders, and seizures).

[0004] The PKU phenotype can vary from mild hyperphenylalaninemia (HPA) to a more severe phenotype resulting in untreated blood Phe concentrations exceeding 1200 μM. US medical guidelines currently recommend maintaining blood Phe concentrations in the range of 120–360 μM in both adults and children under 12 years of age. European medical guidelines currently recommend maintaining blood Phe concentrations below 360 μM in children under 12 years of age and pregnant women, and below 600 μM in non-pregnant patients aged 12 years or older.

[0005] The standard of care for treating PKU is a Phe-restricted diet, which severely restricts natural protein intake. Such a diet is very strict and difficult to adhere to. Currently, two medications are approved to treat PKU, each with its own challenges. Kuvan (sapropterin dihydrochloride) is a synthetic BH4 cofactor approved for use in infants through adults in 2007. Kuvan is not effective in all PKU patients, and current guidelines suggest response testing in patients unless they are known to have two null mutations. Pegvaliase is an enzyme replacement therapy approved in 2018 for adults with blood Phe levels above 600 μM despite prior management with available treatment options. Pegvaliase typically involves injection of a purified PEGylated form of phenylalanine ammonia-lyase, which reduces Phe by converting Phe to ammonia and trans-cinnamic acid instead of tyrosine. One of the major challenges of enzyme replacement therapy is achieving and maintaining a therapeutically effective amount of protein in vivo due to rapid degradation or inactivation of the injected protein. The current approach to overcoming this problem is to perform multiple, expensive, high-dose injections.

[0006] There is a need for pharmaceuticals that allow patients to increase their intake of natural proteins. Summary of the Invention [Means for solving the problem]

[0007] In some embodiments, the present disclosure provides a compound of Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2; R 1 but, [ka] and x is 0 to 5, Each R a But independently, Halo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy, R 2 But C 1-4 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 But H or C 1-6 is alkyl, R 4 But H or C 1-6 Is it alkyl? or R 3 and R 4 together with the atoms to which they are bonded, C 3-6 forming a cycloalkyl, R 5 is H or D, R 5A is H or D, L is a bond, carbonyl, or optionally substituted C 1-6 Alkylene, optionally substituted C 1-6 Alkylenecarbonyl, optionally substituted C 2-6 Alkenylenecarbonyl, optionally substituted C 1-6 haloalkylenecarbonyl, or optionally substituted —C(O)NRb (C 1-6 alkylene)-, wherein the carbon atom of the carbonyl group is bonded to N in formula I; R b But H or C 1-6 It is alkyl.

[0008] In other aspects, the disclosure provides compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL, or IM, or a pharmaceutically acceptable salt thereof. [ka]

[0009] Also described are stereoisomers and mixtures of stereoisomers of compounds of Formula I, IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL, and IM, and pharmaceutical salts thereof.

[0010] In a further aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[0011] In yet another aspect, the disclosure provides methods for stabilizing a mutant PAH protein, comprising contacting the protein with one or more compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, the mutant PAH protein comprises at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, ​​I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein comprises at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.

[0012] In still a further aspect, the present disclosure provides a method for reducing phenylalanine levels in a subject suffering from phenylketonuria, comprising administering a therapeutically effective amount of one or more compounds described herein or pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition 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 belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the disclosure.

[0014] As used in the constructions herein, " [ka] " indicates the point of attachment of the particular depicted structure or substituent to the appropriate atom in the remainder of the molecule.

[0015] As used in this specification and the appended claims, the articles "a" and "an" 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.

[0016] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority or corresponding agency of the federal government of a country or a state government outside the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., humans.

[0017] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or salts formed with 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 or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, further include salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, fumarate, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0018] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent that facilitates and is compatible with administration of a drug.

[0019] The term "alkyl" when used alone or as part of a substituent group refers to an alkyl group containing 1 to 12 carbon atoms ("C 1-12 "), e.g., 1 to 6 carbon atoms ("C 1-6 "). 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, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), hexyl (C6) (e.g., n-hexyl), heptyl (C7) (e.g., n-heptyl), octyl (C8) (e.g., n-octyl), and the like. In some embodiments, an alkyl group is a C 1-6 alkyl, and in other embodiments, C 1-4 alkyl, and in other embodiments, C 1-3 It is alkyl.

[0020] 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 bonded to two other groups. For example, one embodiment of a C alkylene is the diradical -CHCH-. In some embodiments, an alkylene group is a C 1-6 alkylene, and in other embodiments, C 1-4 It is alkylene.

[0021] When a range of carbon atoms is used herein, e.g., C 1-6 , all ranges and individual numbers of carbon atoms are included. For example, "C 1-3 " is C 1-3 , C 1-2 , C 2-3 , C1, C2, and C3.

[0022] The term "cycloalkyl" when used alone or as part of a substituent group refers to a group having 3 to 10 carbon atoms ("C 3-10"), e.g., 3 to 7 carbon atoms ("C 3-7 "). Examples of cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), and the like. In some embodiments, cycloalkyl groups include C 3-4 cycloalkyl, and in other embodiments, C 3-6 cycloalkyl, and in other embodiments, C 3-8 The cycloalkyl is a cycloalkyl. The cycloalkyl can be unsubstituted or substituted. In some embodiments, the cycloalkyl is substituted with two substituents. In further embodiments, the cycloalkyl is substituted with one substituent. In yet other embodiments, the cycloalkyl is substituted with three substituents. In still further embodiments, the cycloalkyl is unsubstituted.

[0023] The term "aryl," when used alone or as part of a substituent, also refers to a monocyclic 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 are optionally substituted. The term "aryl" also includes a monocyclic 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 replaced such that the two adjacent carbon atoms and their respective substituents form a cycloalkyl or heterocyclyl ring. Examples of aryl groups include phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and the like. An aryl can be unsubstituted or substituted. In another embodiment, an optionally substituted phenyl has four substituents. In a further embodiment, an optionally substituted phenyl has three substituents. In yet another embodiment, an optionally substituted phenyl has two substituents. In yet a further embodiment, an optionally substituted phenyl has one substituent. In another embodiment, an optionally substituted phenyl is unsubstituted.

[0024] As used herein, the term "alkenyl" refers to an alkyl group having 2 to 12 carbon atoms ("C 2-12 " refers to a straight or branched chain group having at least one carbon-carbon double bond, wherein the group contains at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH2, C2 alkenyl), allyl (-CH2-CH=CH2, C3 alkenyl), propenyl (-CH=CHCH3, C3 alkenyl), isopropenyl (-C(CH3)=CH2, C3 alkenyl), butenyl (-CH=CHCH2CH3, C4 alkenyl), sec-butenyl (-C(CH3)=CHCH3, C4 alkenyl), iso-butenyl (-CH=C(CH3)2, C4 alkenyl), 2-butenyl (-CH2CH=CHCH3, C4 alkyl), pentenyl (-CH=CHCH2CH2CH3, C5 alkenyl), and the like. In some embodiments, an alkenyl group is a C 2-6 alkenyl groups, and in other embodiments, C 2-4 It is alkenyl.

[0025] As used herein, the term "alkynyl" refers to an alkyl group having 2 to 12 carbon atoms ("C 2-12 " refers to a straight or branched chain group having at least one carbon-carbon triple bond, wherein the group contains at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH, C2 alkynyl), propargyl (-CH2-C≡CH, C3 alkynyl), propynyl (-C≡CCH3, C3 alkynyl), butynyl (-C≡CCH2CH3, C4 alkynyl), pentynyl (-C≡CCH2CH2CH3, C5 alkynyl), and the like. In some embodiments, an alkynyl group is a C 2-6 alkynyl groups, and in other embodiments, C 2-4 It is alkynyl.

[0026] The term "carbonyl" when used alone or as part of another group refers to C(O) or C(=O).

[0027] The term "alkylcarbonyl," when used alone or as part of another group, refers to an alkyl group, as defined above, where at least one carbon is bonded to an oxo group. For example, one embodiment of a C alkylcarbonyl is -CHC(O)CH. In some embodiments, an alkylcarbonyl group is a C 1-6 It is an alkylcarbonyl group.

[0028] The term "alkenylenecarbonyl," when used alone or as part of another group, refers to the group -C(O)-(alkenylene), where alkenylene refers to an alkylene diradical, i.e., a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond that is bonded to two other groups. For example, one embodiment of -C(O)-C2 alkenylene is -C(O)-CH=CH-. In some embodiments, the alkenylene group of an alkenylenecarbonyl is C 2-6 alkenylene groups, and in other embodiments, alkenylene groups are C 2-4 It is alkenylene.

[0029] The terms "halo" or "halogen" when used alone or as part of another group refer to a fluorine, chlorine, bromine, or iodine atom.

[0030] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced with one or more halogen atoms, which can be the same or different. In some embodiments, the alkyl is substituted with at least one halogen. In other embodiments, the alkyl is substituted with one, two, or three F and / or Cl. Examples of haloalkyl groups include fluoromethyl (CHF), 1-fluoroethyl (CH(CH)F), 2-fluoroethyl, difluoromethyl (CHF), trifluoromethyl (CF), pentafluoroethyl, 1,1-difluoroethyl (C(CH)F), 2,2-difluoroethyl (CHCHF), 2,2,2-trifluoroethyl (CHCF), 2-fluoropropan-2-yl (C(CH)F), 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, trichloromethyl, and the like. In some embodiments, a haloalkyl group is selected from the group consisting of C 1-6 haloalkyl, and in other embodiments, C 1-4 haloalkyl, and in other embodiments, C 1-3 It is haloalkyl.

[0031] The term "haloalkylenecarbonyl," when used alone or as part of another group, refers to the group -C(O)-(haloalkylene), where haloalkylene refers to a haloalkyl diradical. For example, one embodiment of -C(O)-C1 haloalkylene is -C(O)-CF2-. In some embodiments, a haloalkylene group is 1-6 haloalkylene, and in other embodiments, C 1-4 haloalkylene, and in other embodiments, C 1-3 It is haloalkylene.

[0032] The term "cyanoalkyl," when used alone or as part of another group, refers to an alkyl, as defined herein, substituted with one or more CN. In some embodiments, the alkyl is substituted with at least one CN. In other embodiments, the alkyl is substituted with one, two, or three CN. In further embodiments, a cyanoalkyl group is a C 1-6 In yet other embodiments, the cyanoalkyl is C 1-4 Examples of cyanoalkyl groups include CHCN, CHCHCN, CH(CN)CH, CHCHCHCN, C(CH)CN, CHCH(CN)CH, CH(CN)CHCH, and the like.

[0033] The term "hydroxyalkyl," when used alone or as part of another group, refers to an alkyl group, as defined herein, in which one or more of the hydrogen atoms have been replaced with one or more hydroxyls (i.e., -OH). In some embodiments, the hydroxyalkyl contains one OH. In other 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, and 1,3-dihydroxyprop-2-yl. In some embodiments, the hydroxyalkyl group is selected from the group consisting of C 1-6 hydroxyalkyl, and in other embodiments, C 1-4 hydroxyalkyl, and in other embodiments, C 1-3 It is a hydroxyalkyl.

[0034] The term "cycloalkylsulfonyl," when used alone or as part of another group, refers to a cycloalkyl, as defined herein, attached to a sulfonyl, i.e., -SO-, where the sulfonyl group forms the point of attachment to the remainder of the molecule. In some embodiments, cycloalkylsulfonyl is C 3-8 cycloalkylsulfonyl, and in other embodiments, C 3-6 Examples of cycloalkylsulfonyl groups include -SO2-cyclopropyl, -SO2-cyclobutyl, -SO2-cyclopentyl, and the like.

[0035] The term "alkylsulfonyl," when used alone or as part of another group, refers to a sulfonyl, i.e., an alkyl, as defined herein, bonded to -SO-, where the sulfonyl group forms the point of attachment to the remainder of the molecule. In some embodiments, alkylsulfonyl is C 1-6 alkylsulfonyl, and in other embodiments, C 1-4 Examples of alkylsulfonyl groups include -SO2CH3, -SO2CH2CH3, and the like.

[0036] The term "alkylsulfonyl(alkylene)" used alone or as part of another group refers to an alkylene group, as defined herein, attached to the sulfonyl of an alkylsulfonyl group, as defined herein. Examples of alkylsulfonyl(alkylene) groups include -C(CH3)2SO2CH3, -CH2SO2CH3, -CH(CH3)SO2CH3, and the like.

[0037] The term "alkoxy," when used alone or as part of another group, refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxyl groups include methoxy (OCH), ethoxy (OCHCH), propoxy (e.g., -O n Pr, -O i Pr), or butoxy (e.g., -O n Bu, -O i Bu, -Os Bu, -O t In other embodiments, the alkoxy group is C 1-6 In a further embodiment, the alkoxy group is C 1-4 It is an alkoxy.

[0038] The term "alkoxy(alkylene)" used alone or as part of another group refers to an alkylene group, as defined herein, attached to an alkyl group, as defined herein. Examples of alkoxy(alkylene) groups include -CH2OCH3, -CH2CHOCH3, and the like.

[0039] The term "haloalkoxy," used alone or as part of another group, refers to an oxygen radical attached by a single bond to a haloalkyl group, where haloalkyl is defined above. Examples of haloalkoxy groups include fluoromethoxy (OCHF), 2-fluoroethoxy, difluoromethoxy (OCHF), trifluoromethoxy (OCF), pentafluoroethoxy, 1,1-difluoroethoxy (OC(CH)F), 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy (OCHCF), 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, trichloromethoxy groups, and the like. In some embodiments, a haloalkoxy group is selected from the group consisting of C 1-6 haloalkoxy, and in other embodiments, C 1-4 haloalkoxy, and in other embodiments, C 1-3 It is haloalkoxy.

[0040] The term "haloalkoxy(alkylene)" used alone or as part of another group refers to an alkylene group, as defined herein, attached to a haloalkoxy group, as defined herein. Examples of haloalkoxy(alkylene) groups include -CHOCF, and the like.

[0041] The term "heteroaryl," when used alone or as part of a substituent, refers to a monocyclic or bicyclic aromatic ring structure containing carbon atoms and up to four heteroatoms, each independently nitrogen, oxygen, or sulfur. The heteroaryl ring can contain a total of 5, 6, 9, or 10 ring atoms. In some embodiments, the heteroaryl ring is 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 or nitrogen atoms in the ring can be substituted. Examples of heteroaryl groups include thienyl, benzo[b]thienyl, furanyl, benzofuryl, pyranyl, thiophenyl, isobenzofuranyl, benzoxazinyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, quinoxalyl, phthalazinyl, naphthyridinyl, cinnolinyl, triaryl, and the like. Azolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, quinazolinyl, pteridinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrazolo[1,5-a]pyridinyl, benzisothiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzisoxazolyl, isothiazolyl, tetrahydropyrazolo[1,In some embodiments, heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furanyl, 3-furanyl, 4-furanyl), pyrrolyl (e.g., pyrrol-2-yl, pyrrol-3-yl), imidazolyl (e.g., imidazol-2-yl, imidazol-4-yl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), pyridyl (e.g., pyridin-1-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl (e.g., , isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), thiodiazolyl oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), indazolyl (e.g., indazol-3-yl), pyrazolo[1,5-a]pyridinyl (e.g., pyrazolo[1,5-a]pyridin-3-yl), imidazole[1,5-a]pyridinyl (e.g., imidazole[1,5-a]pyridin-1-yl), pyrrolo[1,2]pyridazinyl (e.g., pyrrolo[1,2]pyridazin-5-yl, pyrrolo[1,2]pyridazin-6-yl), benzo[d]thiazolyl (e.g., benzo[d]thiazol-3-yl, benzo[d]thiazol-2-yl), benzo[d]imidazolyl (e.g., benzo[d]imidazol-2-yl), benzo[d]oxazolyl (e.g., benzo[d]oxazol-2-yl), benzo[d]isoxazolyl (e.g., benzo[d]isoxazol-3-yl), benzo[d]isothiazolyl (e.g., benzo[d]isothiazol-3-yl), benzo[c]isoxazolyl (e.g., benzo[c]isoxazol-3-yl), quinolinyl (e.g., quinolin-3-yl), and pyridazinyl (e.g., pyridazin-3-yl, pyridazin-4-yl). The term "heteroaryl" also includes N-oxide. Heteroaryl can be unsubstituted or substituted. In some embodiments, the heteroaryl is substituted with two substituents. In further embodiments, the heteroaryl is substituted with one substituent. In still other embodiments, the heteroaryl is substituted with three substituents. In still further embodiments, the heteroaryl is unsubstituted. Substitution, if permitted by the substituent valence, can occur at any available carbon or heteroatom (e.g., nitrogen), or both.

[0042] In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms, wherein at least one carbon atom in the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In other embodiments, the heteroaryl is a 6-membered heteroaryl, e.g., the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms, wherein at least one carbon atom in the ring is replaced with a nitrogen atom. Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and the like.

[0043] The term "heterocyclyl," when used alone or as part of another group, refers to a cyclic group containing one, two, or three rings, e.g., a 3- to 14-membered heterocycle, that is non-aromatic, saturated, or partially saturated, having 3 to 14 ring members, e.g., containing one or two double bonds, and at least one carbon atom of one of the rings is replaced with a heteroatom. Each heteroatom is independently selected from oxygen, sulfur, sulfoxide, and sulfone and / or nitrogen atoms, and can be oxidized or quaternized. The term "heterocyclyl" also includes groups in which the ring -CH- is replaced with -C(O)-. The term "heterocyclyl" also includes groups fused with an optionally substituted aryl group, e.g., indolinyl or chroman-4-yl, and groups fused with an optionally substituted cycloalkyl group, e.g., 6-azaspiro[2.5]octanyl. In some embodiments, a heterocyclyl group is a C 4-6 Heterocyclyl is a 4-, 5-, or 6-membered ring group containing one ring and one or two oxygen and / or nitrogen atoms. In other embodiments, heterocyclyl is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 - 4-6Heterocyclyl. The heterocyclyl can be optionally attached to the rest of the molecule by any available carbon or nitrogen atom that results in a stable structure. Examples of heterocyclyl groups include azetidinyl, dioxanyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, aziridinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, thianyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, tetrahydropyranyl, and the like. In some embodiments, heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 6-azaspiro[2.5]octanyl. The heterocyclyl can be unsubstituted or substituted. In some embodiments, the heterocyclyl is substituted with two substituents. In further embodiments, the heterocyclyl is substituted with one substituent. In yet other embodiments, the heterocyclyl is substituted with three substituents. In yet further embodiments, the heterocyclyl is unsubstituted.

[0044] The term "(heterocyclyl)alkylene," when used alone or as part of another group, refers to an alkylene group, as defined herein, linked to an alkyl group, as defined herein.

[0045] The term "optionally substituted," when used herein to describe a chemical moiety as defined herein, means that the moiety may, but need not, be substituted with one or more suitable functional groups or other substituents provided herein. For example, the substituents may be halo, cyano, -NO, -N, -OH, -SH, C, or any combination thereof. 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy (alkylene), C 1-6Haloalkoxy, C 1-6 Haloalkoxy(alkylene), C 1-6 Alkyl carbonyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Archillencio, (CR v R x ) p NR y R z (R v and R x are independently H or C 1-6 alkyl, and R y and R z are independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy (alkylene), or C(O)OC1-6 alkyl, where p is 0, 1, 2, or 3), —C(O)NH2, —C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NHC 3-6 Cycloalkyl, -C(O)N(C 3-6 Cycloalkyl)2, -COOH, -C 1-6 Alkylene COOH 、 -C 3-6 CycloalkylCOOH, -C 1-6 AlkyleneCONH 2、 C 3-6 CycloalkylCONH2, -C 1-6 Alkylene CONHC 1-6 Alkyl 、 -C 1-6 Alkylene CON(C 1-6 alkyl) 2、 -C(O)OC 1-6 Alkyl, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)(C 1-6 alkyl), -S(O)C 1-6 Alkyl, -S(O)C 3-6 Cycloalkyl, C 1-6 Alkylsulfonyl, C3-8 Cycloalkylsulfonyl, C 1-6 In some embodiments, C in any of the substituents in this paragraph may be optionally substituted with one or more of alkylsulfonyl(alkylene), oxo(=O), 3- to 7-membered heterocyclyl, heterocyclyl(alkylene), aryl, aryl(alkylene), or heteroaryl groups. 1-6 The alkyl group is C 1-4 alkyl, and in other embodiments, C 1-3 In some embodiments, C in any of the substituents in this paragraph is alkyl. 1-6 The alkylene group is C 1-4 In some embodiments, C is alkylene. 1-6 Haloalkyl substituents include C 1-4 haloalkyl, and in other embodiments, C 1-3 In some embodiments, C is haloalkyl. 3-6 The cycloalkyl substituent is C 3-4 In some embodiments, C is a cycloalkyl substituent. 1-6 The alkoxy substituent is C 1-3 alkoxy, and in other embodiments, C 1-4 In some embodiments, C is alkoxy. 1-6 Haloalkoxy substituents are C 1-3 haloalkoxy, and in other embodiments, C 1-4 It is haloalkoxy.

[0046] In some embodiments, the substituent is C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, Halo, CN, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, OH, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted aryl, optionally substituted aryl(alkylene), optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), C 1-6 Hydroxyalkyl, C1-6 Haloalkoxy, C 1-6 Haloalkoxy(alkylene), C 1-6 Alkoxy, C 1-6 Alkoxy (alkylene), C 1-6 Deuterated alkoxy(alkylene), C 1-6 Alkyl carbonyl, C 3-8 Cycloalkylsulfonyl, C 1-6 Alkyl sulfonyl (alkylene), (CR v R x ) p NR y R z (R v and R x are independently H or C 1-6 alkyl, and R y and R z are independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy (alkylene), or C(O)OC1-6 alkyl, where p is 0, 1, 2, or 3, and C(O)NR y2 R z2 (R y2 and R z2 are independently H, C 1-6 Alkyl, or C 3-6 The alkyl group may be optionally substituted with one or more of the following:

[0047] 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 are known to those of skill 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 herein by reference.

[0048] The recitation of ranges of values ​​herein, unless otherwise indicated, is intended to serve as a shorthand method of referring to each individual value within that range, and each separate value is incorporated herein as if it were individually listed herein. The use of any and all examples and exemplary language (e.g., "such as") provided herein is intended to better explain the disclosure and is not limiting on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[0049] When used in conjunction with a numerical value or range of values, the term "about" means that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art.

[0050] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. 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 synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0051] Exemplary compounds of the present disclosure that contain chiral centers may be depicted herein as having a particular stereochemistry, although the absolute stereochemistry has not been obtained. The absolute configuration may be obtained using methods known in the art.

[0052] As used herein, the term "stereoisomers" refers to compounds that have identical chemical structure and bonding, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers or diastereomers.

[0053] 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., the configuration is depicted by an "R" or "S" in the chemical name) or structure (e.g., the configuration is depicted by a dashed line or wedge bond), the enrichment of the depicted configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. "Enrichment of the depicted configuration relative to the opposite configuration" is a mole percent and is determined by dividing the number of compounds having the depicted stereochemical configuration at the chiral center by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0054] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses one of the possible stereoisomers or geometric isomers without the other, or a mixture of the stereoisomers or geometric isomers encompassed.

[0055] It will be understood that certain compounds disclosed herein may exist in tautomeric forms. Such forms are included as part of the disclosure. When a compound herein is represented by a structural formula or designated by a chemical name herein, all other tautomeric forms that may exist for that compound are encompassed by the structural formula.

[0056] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, they are intended to include both E and Z geometric isomers.

[0057] In some embodiments, the compounds described herein are isotope-enriched compounds, e.g., isotopologues. The term "isotopically enriched" refers to an atom having an isotopic composition other than the isotopic composition of that atom abundant in nature. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the isotopic composition of that atom in nature. In an isotopologue, "isotopic enrichment" refers to the proportion of a particular isotope of a given atom incorporated into a molecule, instead of the atom's natural isotopic composition. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Because the naturally occurring distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. In one embodiment, one or more hydrogen atoms on the described compound can be replaced by deuterium.

[0058] Thus, as used herein, unless otherwise indicated, the term "isotopic enrichment factor" refers to the ratio between the isotopic composition of a specified isotope and the natural isotopic composition.

[0059] With respect to the compounds provided herein, certain atom positions may be designated as deuterium or as "D" or " 2When a position is designated as having "H," 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%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor of 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 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom, in certain embodiments. The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0060] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a compound or composition according to the present disclosure is provided. For treatment of a condition or pathology specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals such as dogs or cats, or domestic animals such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.

[0061] The term "therapeutically effective amount" or "effective amount" refers to the amount or dosage of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) sufficient to generally provide the desired therapeutic benefit in a subject in need of such treatment for a specified disease or disorder. Further, with respect to a compound of the present disclosure, a therapeutically effective amount refers to the amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease.

[0062] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (e.g., halting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving 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 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.

[0063] The terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of disease in a subject resulting from the administration of a prophylactic or therapeutic agent.

[0064] compound The present disclosure provides compounds of Formula I or a pharmaceutically acceptable salt thereof: [ka]

[0065] In Formula I, m is 1 or 2. In some embodiments, m is 1. In other embodiments, m is 2.

[0066] In Formula I, R 1 teeth, [ka] is.

[0067] R 1In the structure, x is 0-5. In some embodiments, x is 0. In other embodiments, x is 1. In further embodiments, x is 2. In still other embodiments, x is 3. In still further embodiments, x is 4. In other embodiments, x is 5.

[0068] In a further embodiment, R 1 teeth, [ka] and x is 0 or 1, for example: [ka] In other embodiments, R 1 teeth, [ka] In yet another embodiment, R 1 teeth, [ka] In yet another embodiment, R 1 teeth, [ka] In yet another embodiment, R 1 teeth, [ka] In still further embodiments, R 1 teeth, [ka] In other embodiments, R 1 teeth, [ka] is.

[0069] In some embodiments, the compound is a single enantiomer and R 1 In some embodiments, the compound is a single enantiomer and the R 1 The moiety is in the beta (β) configuration.

[0070] R 1 In the structure of a independently, halo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 In some embodiments, R a is halo, such as F, Cl, Br, or I. In other embodiments, R a is F, Br, or Cl. In yet other embodiments, R a is F. In a further embodiment, R a is Br. In yet another embodiment, R a is Cl. In still further embodiments, R a is I. In other embodiments, R a C such as methyl, ethyl, propyl, butyl, pentyl, or hexyl 1-6 In a further embodiment, R a is methyl, ethyl, or isopropyl. a is methyl. In a further embodiment, R a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc. 3-6 In still further embodiments, R a is cyclopropyl. In yet another embodiment, R a is C such as CF3, CHF2, CH2F, CH2CF3, C(CH3)2F, or C(CH3)F2 1-6 In yet another embodiment, R a is CF or CHF. In a further embodiment, R ais a C such as methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy 1-6 In yet another embodiment, R a is methoxy or ethoxy. In other embodiments, R a is C such as OCF3 or OCH2CF3 1-6 In yet another embodiment, one R a is a halo and the second R a is C 1-6 Alkoxy or C 1-6 It is alkyl.

[0071] In Formula I, R 2 is C 1-4 Alkyl, optionally substituted C 3-8 In some embodiments, R is cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 2 is an arbitrarily substituted C 3-8 In a further embodiment, R is cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 2 is the unsubstituted C 3-8 In other embodiments, R is cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. 2 is a substitution C 3-8 In some embodiments, R is cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl. 2 C such as methyl, ethyl, propyl, butyl, or tert-butyl 1-4 In another embodiment, R 2 is an optionally substituted C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. 3-8 In a further embodiment, R 2 is an optionally substituted heterocyclyl, such as azetidinyl. 2is optionally substituted aryl, such as phenyl. In still further embodiments, R 2 is an optionally substituted heteroaryl such as pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, furanyl, thiophenyl, pyrimidinyl, pyrazinyl, indazolyl, pyrazolo[1,5-a]pyridinyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, or benzo[d]isothiazolyl.

[0072] In Formula I, R 3 is H or C 1-6 In some embodiments, R 3 is H. In other embodiments, R 3 C such as methyl, ethyl, propyl, butyl, pentyl, or hexyl 1-6 In a further embodiment, R 3 is methyl. In yet another embodiment, R 3 is ethyl. In still further embodiments, R 3 is propyl. In other embodiments, R 3 is butyl. In a further embodiment, R 3 is pentyl. In yet another embodiment, R 3 is hexyl.

[0073] In Formula I, R 4 is H or C 1-6 In some embodiments, R 4 is H. In other embodiments, R 4 C such as methyl, ethyl, propyl, butyl, pentyl, or hexyl 1-6 In a further embodiment, R 4 is methyl. In yet another embodiment, R 4 is ethyl. In still further embodiments, R 4is propyl. In other embodiments, R 4 is butyl. In a further embodiment, R 4 is pentyl. In yet another embodiment, R 4 is hexyl.

[0074] Alternatively, R 3 and R 4 together with the atoms to which they are bonded, C 3-6 In some embodiments, R 3 and R 4 together form a cyclopropyl. In another embodiment, R 3 and R 4 together form a cyclobutyl. In a further embodiment, R 3 and R 4 together form cyclopentyl. In yet another embodiment, R 3 and R 4 together form cyclohexyl.

[0075] In some embodiments, R 3 and R 4 and R are both H. In other embodiments, R 3 is methyl and R 4 is H. In yet another embodiment, R 3 and R 4 Both of the are methyl.

[0076] In Formula I, R 5 is H or D. In some embodiments, R 5 is H. In a further embodiment, R 5 is D.

[0077] In Formula I, R 5A is H or D. In some embodiments, R 5A is H. In a further embodiment, R 5A is D.

[0078] In Formula I, L is a bond, carbonyl, optionally substituted C 1-6Alkylene, optionally substituted C 1-6 Alkylenecarbonyl, optionally substituted C 2-6 Alkenylenecarbonyl, optionally substituted C 1-6 haloalkylenecarbonyl, or optionally substituted —C(O)NR b (C 1-6 In some embodiments, L is a bond. In other embodiments, L is carbonyl (the carbon atom of the carbonyl group is bonded to N in Formula I). ​​In further embodiments, L is an optionally substituted C alkylene such as methylene, ethylene, propylene, butylene, pentylene, or hexylene. 1-6 In other embodiments, L is C alkylene. In still other embodiments, L is C alkylene. In further embodiments, L is C alkylene. In still other embodiments, L is C alkylene. In still further embodiments, L is C alkylene. In still further embodiments, L is C alkylene. In other embodiments, L is C alkylene. In still other embodiments, L is optionally substituted C alkylene. 1-6 In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is -C alkylene-C(O)-. In yet another embodiment, L is an optionally substituted C alkylene-C(O)-. 2-6In another embodiment, L is -C2 alkenylene-C(O)-. In a further embodiment, L is -C3 alkenylene-C(O)-. In yet another embodiment, L is -C4 alkenylene-C(O)-. In yet a further embodiment, L is -C5 alkenylene-C(O)-. In another embodiment, L is -C6 alkenylene-C(O)-. In another embodiment, L is an optionally substituted C 1-6 In still other embodiments, L is haloalkylenecarbonyl (the carbon atom of the carbonyl group is bonded to N in Formula I). ​​In still other embodiments, L is -C1 haloalkylene-C(O)-. In other embodiments, L is -C2 haloalkylene-C(O)-. In a further embodiment, L is -C3 haloalkylene-C(O)-. In still other embodiments, L is -C4 haloalkylene-C(O)-. In still further embodiments, L is -C5 haloalkylene-C(O)-. In other embodiments, L is -C6 haloalkylene-C(O)-. In a further embodiment, L is -C(O)NR b (C 1-6 In yet other embodiments, L is —C(O)NR b In other embodiments, L is -C(O)NR b In a further embodiment, L is -C(O)NR b In yet other embodiments, L is -C(O)NR b In yet a further embodiment, L is -C(O)NR b In other embodiments, L is -C(O)NR b It is a C6 alkylene.

[0079] In the structure of L, R b is H or C 1-6 In some embodiments, R b is H. In other embodiments, R bC such as methyl, ethyl, propyl, butyl, pentyl, or hexyl 1-6 In a further embodiment, R b is methyl. In yet another embodiment, R b is ethyl. In still further embodiments, R b is propyl. In other embodiments, R b is butyl. In a further embodiment, R b is pentyl. In yet another embodiment, R b is hexyl.

[0080] In some embodiments, L is a bond, —C(O)—, —C(O)CH—, —C(O)CHCH—, -C(O)CH2CH2CH2-, -C(O)CF2-, -C(O)CHF-, -C(O)C(CH3)2-, -C(O)CH=CH-, [ka] In still other embodiments, L is a bond, -C(O)-, -C(O)CH2- or -C(O)CF2.

[0081] In some embodiments, R 2 is cyclopentyl, cyclobutyl, cyclopropyl, azetidinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiadiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, thiophenyl, isoxazolyl, isothiazolyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, furanyl, or pyrazinyl, each of which is optionally substituted.

[0082] In a further embodiment, R 2is cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, azetidinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiadiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, thiophenyl, isoxazolyl, isothiazolyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]isothiazolyl, furanyl, pyrazinyl, or quinolinyl, each of which is optionally substituted.

[0083] In other embodiments, R 2 is cyclopentyl, cyclobutyl, cyclopropyl, azetidinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiadiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, thiophenyl, isoxazolyl, isothiazolyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, furanyl, or pyrazinyl, each of which is unsubstituted.

[0084] In yet other embodiments, R 2 is cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, azetidinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiadiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, thiophenyl, isoxazolyl, isothiazolyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]isothiazolyl, furanyl, pyrazinyl, or quinolinyl, each of which is unsubstituted.

[0085] In a further embodiment, R 2 is optionally substituted cyclopentyl. In a further embodiment, R 2 is optionally substituted cyclobutyl. In yet other embodiments, R 2 is optionally substituted cyclopropyl. In yet other embodiments, R 2 is optionally substituted cyclohexyl. In still further embodiments, R 2 is an optionally substituted azetidinyl. In other embodiments, R 2 is optionally substituted phenyl. In a further embodiment, R 2 is optionally substituted pyrazolyl. In yet other embodiments, R 2 is optionally substituted oxazolyl. In still further embodiments, R 2 is an optionally substituted thiazolyl. In other embodiments, R 2 is optionally substituted triazolyl. In a further embodiment, R 2 is optionally substituted oxadiazolyl. In yet other embodiments, R 2 is optionally substituted pyridinyl. In still further embodiments, R 2 is an optionally substituted pyrimidinyl. In other embodiments, R 2 is optionally substituted pyrazolo[1,5-a]pyridinyl. In a further embodiment, R 2 is optionally substituted indazolyl. In yet other embodiments, R 2 is optionally substituted thiadiazolyl. In other embodiments, R 2 is optionally substituted imidazole[1,5-a]pyridinyl. In a further embodiment, R 2 is optionally substituted pyrrolo[1,2]pyridazinyl. In yet other embodiments, R 2 is optionally substituted thiophenyl. In still further embodiments, R 2 is optionally substituted isoxazolyl. In a further embodiment, R 2is an optionally substituted isothiazolyl. In other embodiments, R 2 is optionally substituted benzo[d]thiazolyl. In a further embodiment, R 2 is optionally substituted benzo[d]imidazolyl. In yet other embodiments, R 2 is optionally substituted benzo[d]oxazolyl. In still further embodiments, R 2 is benzo[d]isoxazolyl. In yet other embodiments, R 2 is optionally substituted benzo[c]isoxazolyl. In still further embodiments, R 2 is optionally substituted benzo[d]isothiazolyl. In other embodiments, R 2 is optionally substituted furanyl. In yet other embodiments, R 2 is optionally substituted pyrazinyl. In still further embodiments, R 2 is an optionally substituted quinolinyl.

[0086] In other embodiments, R 2However, azetidin-1-yl, azetidin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, pyrazolo[1,5-a]pyridin-3-yl, indazol-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3,4-thiadiazol-2-yl, pyridin-1-yl, pyridine -2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, imidazol[1,5-a]pyridin-1-yl, pyrrolo[1,2]pyridazin-5-yl, pyrrolo[1,2]pyridazin-6-yl, thiophen-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]imidazol-2-yl, benzo[d]oxazol-2-yl, benzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, furan-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, or pyrazin-2-yl, each of which is optionally substituted.

[0087] In yet other embodiments, R 2azetidin-1-yl, azetidin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, pyrazolo[1,5-a]pyridin-3-yl, indazol-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3,4-thiadiazol-2-yl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, pyrimidin-2-yl, imidazol[1,5-a]pyridin-1-yl, pyrrolo[1,2]pyridazin-5-yl, pyrrolo[1,2]pyridazin-6-yl, thiophen-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]imidazol-2-yl, benzo[d]oxazol-2-yl, benzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, furan-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazin-2-yl, benzo[c]isoxazol-3-yl, or quinolin-3-yl, each of which is optionally substituted.

[0088] In a further embodiment, R 2 But C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, Halo, CN, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, OH, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkyl(alkylene), optionally substituted C3-8 Cycloalkenyl, optionally substituted aryl, optionally substituted aryl(alkylene), optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 Haloalkoxy(alkylene), C 1-6 Alkoxy, C 1-6 Alkoxy (alkylene), C 1-6 Deuterated alkoxy(alkylene), C 1-6 Alkyl carbonyl, C 3-8 Cycloalkylsulfonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkyl sulfonyl (alkylene), (CR v R x ) p NR y R z (R v and R x are independently H or C 1-6 alkyl, and R y and R z are independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy (alkylene), or C(O)OC1-6 alkyl, where p is 0, 1, 2, or 3, or C(O)NR y2 R z2 (R y2 and R z2 are independently H, C 1-6 Alkyl, or C 3-6 In other embodiments, R 2 is a C such as methyl, ethyl, propyl, isopropyl, or tert-butyl 1-6 In still further embodiments, R 2 is a C such as CH=CH2, CH=CHC(CH3)2OH, or CH=CH-cyclopropyl 2-6In a further embodiment, R 2 is optionally substituted with halo, such as Br, Cl, or F. In yet other embodiments, R 2 is optionally substituted with CN. In still further embodiments, R 2 is C such as C(CH3)2CN 1-6 In another embodiment, R 2 is C, such as CF3, CHF2, CH2F, CH(CH3)F, CH2CF3, C(CH3)2F, C(CH3)F2, or CH2CHF2. 1-6 In a further embodiment, R 2 is optionally substituted with OH. In yet another embodiment, R 2 is an optionally substituted C alkyl group, such as an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl. 3-8 In a further embodiment, R 2 is an optionally substituted C alkylene such as an optionally substituted cyclopropyl(alkylene) or an optionally substituted cyclobutyl(alkylene). 3-8 In another embodiment, R 2 is an optionally substituted C alkyl group such as an optionally substituted cyclohexenyl. 3-8 In still further embodiments, R 2 is optionally substituted with an optionally substituted aryl, such as an optionally substituted phenyl. In a further embodiment, R 2 is optionally substituted with an optionally substituted aryl(alkylene), such as an optionally substituted benzyl. In other embodiments, R 2 is optionally substituted with an optionally substituted heteroaryl, such an optionally substituted pyrazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl. 2is optionally substituted with an optionally substituted heteroaryl, such as an optionally substituted pyrazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, or an optionally substituted pyridazinyl. 2 is optionally substituted with an optionally substituted heterocyclyl, such as an optionally substituted azetidinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted pyrrolidinyl, an optionally substituted morpholinyl, or an optionally substituted 6-azaspiro[2.5]octan-6-yl. 2 is optionally substituted with an optionally substituted morpholinyl(alkylene), an optionally substituted piperidinyl(alkylene), an optionally substituted piperazinyl(alkylene), or an optionally substituted azetidinyl(alkylene). In yet other embodiments, R 2 is C(CH3)2OH, CH(CH3)OH, C(CH3)2CH2OH, CH2C(CH3)2OH, or CH(CH2CH3)OH, etc. 1-6 In still further embodiments, R 2 is C such as OCF3, OCH2CF3, or OCH2CH2CF3 1-6 In still further embodiments, R 2 is C such as CH2OCF3 1-6 In another embodiment, R 2 is C such as methoxy or ethoxy 1-6 In yet another embodiment, R 2 is C(CH3)2OCH3, CH2OCH3, or (CH2)2OCH3, etc. 1-6 In a further embodiment, R 2 is C such as CH2OCD3 1-6 In a further embodiment, R 2 is C(=O)CH3 or CH2C(=O)CH3 etc. 1-6In yet another embodiment, R 2 is cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl, etc. 3-8 In another embodiment, R 2 is C such as methylsulfonyl, ethylsulfonyl, or propylsulfonyl 1-6 In yet another embodiment, R 2 is C such as C(CH3)2SO2CH3 1-6 In still further embodiments, R 2 is (CR v R x ) p NR y R z optionally substituted with R v , R x , R y , R z and p is as defined above, such as NH, NHcyclopropyl, NHCH, N(CH), CHN(CH), (CH), N(CH), CHN(CH), CHN(CH), (CH), CHN(CH), C(CH), NH(CH), C(CH), N(CH), CHN(CH), cyclobutyl, or CHN(CH)(C(O)Otert-butyl). In some embodiments, p is 0. In other embodiments, p is 1. In further embodiments, p is 2. In still other embodiments, p is 3. In some embodiments, R v and R x are independently hydrogen or methyl. In other embodiments, R y and R z is independently hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, C(O)Omethyl, C(O)Oethyl, C(O)Opropyl, or C(O)Otert-butyl. 2 is C(O)NR y2 R z2 and R y2 and R z2is as defined above, such as C(O)N(CH) or C(O)NH cyclopropyl. y2 and R z2 is independently hydrogen, methyl, or cyclopropyl. In a further embodiment, R 2 is methyl, ethyl, propyl, isopropyl, tert-butyl, CH=CH2, CH=CHC(CH3)2OH, CH=CH-cyclopropyl, Br, Cl, F, CN, C(CH3)2CN, CF3, CHF2, CH2F, CH(CH3)F, CH2CF3, C(CH3)2F, C(CH3)F2, CH2CHF2, OH, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted cyclopropyl(alkylene), optionally substituted cyclobutyl(alkylene), optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridinyl, optionally substituted substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted azetidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted morpholinyl, optionally substituted 6-azaspiro[2.5]octan-6-yl, optionally substituted morpholinyl(alkylene), optionally substituted piperidinyl(alkylene), optionally substituted piperazinyl(alkylene), or optionally substituted azetidinyl(alkylene), C(CH3)2OH, CH(CH3)OH, C(CH3)2CH2OH, CH2C(CH3)2OH, CH(CH2CH3)OH, OCH2CH2CF3, OCF3, OCH2CF3, CH2OCF3, methoxy, ethoxy, C(CH3)2OCH3, CHOCH3, (CH2 )2OCH3, CH2OCD3, C(=O)CH3, CH2C(=O)CH3, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, C(CH3)2SO2CH3, NH2, NHcyclopropyl, NHCH3, N(CH3)2, CH2N(CH3)2, (CH2)2N(CH3)2, CH2N(CH3)(CH2CH3), C(CH3)2NH(CH3), C(CH3)2N(CH3)2, CH2N(CH3)cyclobutyl, CH2N(CH3)(C(O)Otert-butyl), C(O)N(CH3)2, or C(O)NHcyclopropyl.

[0089] In still further embodiments, R 2 teeth [ka] In other embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0090] In some embodiments, R 2 Ha, Halo, C 1-6 In yet another embodiment, R is a heterocyclyl optionally substituted with one or more of haloalkyl, or an optionally substituted heteroaryl. 2 teeth, [ka] In yet another embodiment, R 2 Ha, Halo, C 1-6 In a further embodiment, R is a heterocyclyl substituted with one or more of haloalkyl, or an optionally substituted heteroaryl. 2 teeth, [ka] In still further embodiments, R 2 but, [ka] is.

[0091] In some embodiments, R 2 Ha, Halo, C 1-6 Alkyl, C 1-6 C optionally substituted with one or more of haloalkyl, or OH 3-8 In another embodiment, R 2 is C optionally substituted with one or more of halo or OH 3-8 In yet another embodiment, R 2 represents unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, [ka] In a further embodiment, R 2 Ha, Halo, C 1-6 Alkyl, C 1-6 C substituted with one or more of haloalkyl, or OH 3-8 In still further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] is.

[0092] In some embodiments, R 2 is halo or C 1-6 In another embodiment, R is an aryl optionally substituted with one or more of alkoxy. 2 is unsubstituted phenyl, [ka] In yet another embodiment, R 2 is halo or C 1-6 In a further embodiment, R is aryl substituted with one or more of alkoxy. 2 teeth, [ka] is.

[0093] In some embodiments, R 2 is an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl. In other embodiments, the pyridinyl, pyrimidinyl, or pyrazinyl group is selected from the group consisting of halo, C 1-6 Haloalkyl, cyano, or NR y R z and R y and R z are independently H or C 1-6 It is alkyl.

[0094] In still further embodiments, R 2 is C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, or C 1-6 In another embodiment, R is a heteroaryl substituted with one or more of hydroxyalkyl. 2 is C 1-6 In yet another embodiment, R is heteroaryl substituted with one or more of alkyl. 2 is C 1-6 In a further embodiment, R is heteroaryl substituted with one or more of cyanoalkyl. 2 is C 1-6 In still further embodiments, R is heteroaryl substituted with one or more of haloalkyl. 2 is C 1-6 In yet another embodiment, R is heteroaryl substituted with one or more of fluoroalkyl. 2 is C 1-6In another embodiment, R is a heteroaryl substituted with one or more of hydroxyalkyl. 2 is heteroaryl substituted with one or more of methyl, ethyl, isopropyl, tert-butyl, C(CH3)2CN, CH(CH3)OH, C(CH3)2OH, C(CH3)2CH2OH, CH(CH2CH3)OH, CH2C(CH3)2OH, CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH(CH3)F, C(CH3)F2, or C(CH3)2F. In yet other embodiments, R 2 is heteroaryl substituted with one or more of methyl, isopropyl, tert-butyl, C(CH3)2CN, CH(CH3)OH, C(CH3)2OH, CHF2, CF3, CH2CF3, CH(CH3)F, or C(CH3)2F. In other embodiments, R 2 is heteroaryl substituted with methyl. In yet another embodiment, R 2 is heteroaryl substituted with isopropyl. In other embodiments, R 2 is heteroaryl substituted with tert-butyl. In yet another embodiment, R 2 is heteroaryl substituted with C(CH3)2CN. In still further embodiments, R 2 is heteroaryl substituted with CH(CH3)OH. In other embodiments, R 2 is heteroaryl substituted with C(CH3)2OH. In a further embodiment, R 2 is heteroaryl substituted with CHF2. In yet another embodiment, R 2 is heteroaryl substituted with CF. In a further embodiment, R 2 is heteroaryl substituted with CHCF. In yet another embodiment, R 2 is heteroaryl substituted with CH(CH)F. In other embodiments, R 2 is heteroaryl substituted with C(CH3)2F.

[0095] In other embodiments, R 2 is C 3-8Heteroaryl substituted with cycloalkyl, C 3-8 Cycloalkyl itself can be substituted with halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 1-6 In yet another embodiment, R 2 is an unsubstituted C such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-8 In a further embodiment, R is a heteroaryl substituted with cycloalkyl. 2 is heteroaryl substituted with cyclopropyl or cyclobutyl. 2 is a C cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-8 Heteroaryl substituted with cycloalkyl, C 3-8 Cycloalkyl itself can be substituted with halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 1-6 In some embodiments, the substituted C 3-8 In still further embodiments, the cycloalkyl is substituted with OH. 3-8 The cycloalkyl is substituted with one or more halo, such as F, Cl, or Br. In other embodiments, the substituted C 3-8 Cycloalkyl is a C alkyl group such as methyl, ethyl, or propyl. 1-6 In a further embodiment, the substituted C 3-8 Cycloalkyl is a C alkyl group such as CF, CHCF, or CHF. 1-6 In yet another embodiment, the substituted C 3-8 Cycloalkyl is a C alkoxy group such as methoxy, ethoxy, or propoxy. 1-6 In a further embodiment, the substituted C 3-8 Cycloalkyl is cyclopropyl or cyclobutyl, each of which is substituted with one or more of F, OH, or methyl. In other embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] and heteroaryl substituted with

[0096] In other embodiments, R 2 is a heteroaryl substituted with an aryl, the aryl itself being halo, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-8 In yet another embodiment, R 2 is heteroaryl substituted with unsubstituted phenyl. In a further embodiment, R 2 is a heteroaryl substituted with an aryl such as phenyl, and the aryl itself may be halo, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-8 In some embodiments, the substituted aryl is substituted with one or more of a cycloalkyl, such as F, Cl, or Br. In yet other embodiments, the substituted aryl is substituted with one or more of a C alkyl, such as CF, CHCF, or CHF. 1-6 In still further embodiments, the substituted aryl is substituted with a C haloalkyl, such as methyl, ethyl, or propyl. 1-6 In other embodiments, the substituted aryl is a C alkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-8 In yet other embodiments, the substituted aryl is phenyl substituted with one or more of F, methyl, or CF. In further embodiments, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] and heteroaryl substituted with

[0097] In still further embodiments, R 2 is heteroaryl substituted with an optionally substituted heteroaryl. In some embodiments, the optionally substituted heteroaryl is optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted pyrimidinyl. In still other embodiments, the optional substitutions on the heteroaryl are halo, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, or C 3-8 In other embodiments, the optionally substituted heteroaryl is substituted with one or more of halo, such as F, Cl, or Br. In yet other embodiments, the optionally substituted heteroaryl is substituted with one or more of C, such as CF, CHCF, CHCHF, or CHF. 1-6 In other embodiments, the optionally substituted heteroaryl is substituted with one or more of C haloalkyl, such as methyl, ethyl, propyl, or isopropyl. 1-6 In yet other embodiments, the optionally substituted heteroaryl is substituted with one or more C alkyl, such as methoxy, ethoxy, or propoxy. 1-6 In other embodiments, the optionally substituted heteroaryl is substituted with one or more of C alkoxy, such as OCF3. 1-6 In yet other embodiments, the optionally substituted heteroaryl is substituted with one or more of a C alkoxy, such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-8 In other embodiments, the optionally substituted heteroaryl is substituted with one or more of C cycloalkyl, such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl.3-8 In yet other embodiments, the optionally substituted heteroaryl is substituted with one or more of F, CF, CHCHF, CHF, methyl, methoxy, cyclobutyl, or cyclopropylsulfonyl.

[0098] In yet other embodiments, R 2 is heteroaryl substituted with pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, pyrazin-5-yl, imidazol-4-yl, or imidazol-5-yl, each of which may be optionally substituted. 2 is substituted with pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, pyrazin-5-yl, imidazol-4-yl, imidazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, each of which is optionally substituted. 2 is substituted with an optionally substituted pyrazol-1-yl. In other embodiments, R 2 is substituted with an optionally substituted pyrazol-3-yl. 2 is substituted with an optionally substituted pyrazol-4-yl. 2 is substituted with an optionally substituted pyridin-2-yl. 2 is substituted with an optionally substituted pyridin-3-yl. 2 is substituted with an optionally substituted pyridin-4-yl. 2is substituted with an optionally substituted imidazol-4-yl. 2 is substituted with an optionally substituted imidazol-5-yl. 2 is substituted with an optionally substituted pyrimidin-2-yl. 2 is substituted with an optionally substituted pyrimidin-4-yl. 2 is substituted with an optionally substituted pyrimidin-5-yl. 2 is substituted with an optionally substituted pyrazin-2-yl. 2 is substituted with an optionally substituted pyridazin-3-yl. 2 is substituted with an optionally substituted pyridazin-4-yl.

[0099] In some embodiments, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] and heteroaryl substituted with

[0100] In some embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] and heteroaryl substituted with

[0101] In other embodiments, R 2 is heterocyclyl or heteroaryl substituted with heterocyclyl(alkylene), where the heterocyclyl and heterocyclyl(alkylene) groups themselves are not substituted with halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C(O)O(C 1-6 alkyl), or C 3-8 In yet another embodiment, R 2 is an unsubstituted heterocyclyl group such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 6-azaspiro[2.5]octan-6-yl, or a heteroaryl substituted with an unsubstituted heterocyclyl(alkylene) group such as azetidinyl(alkylene), pyrrolidinyl(alkylene), piperidinyl(alkylene), piperazinyl(alkylene), or morpholinyl(alkylene). In further embodiments, R 2 is heterocyclyl such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, or heteroaryl substituted with heterocyclyl(alkylene) such as azetidinyl(alkylene), pyrrolidinyl(alkylene), piperidinyl(alkylene), piperazinyl(alkylene), or morpholinyl(alkylene), wherein the heterocyclyl and heterocyclyl(alkylene) groups themselves may each be selected from halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C(O)O(C 1-6 alkyl), or C 3-8In further embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more of halo, such as F, Cl, or Br. In still further embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more of OH. In yet other embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more of C alkyl, such as CF, CHCF, or CHF. 1-6 In still further embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more C haloalkyl, such as methyl, ethyl, or propyl. 1-6 In still further embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more of C(CH3)2OH, or CH(CH3)OH. 1-6 In other embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more C hydroxyalkyl groups such as methoxy, ethoxy, or propoxy. 1-6 In yet other embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more C(O)O(C methyl, C(O)Oethyl, C(O)Opropyl, or C(O)Otert-butyl. 1-6 In further embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more of C cyclopropyl, cyclobutyl, or cyclopentyl. 3-8 In yet other embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more of F, OH, or methyl. R 2 In still other embodiments, where R is heteroaryl, 2 teeth, [ka] is replaced by R 2 In still further embodiments, where R is heteroaryl, 2teeth, [ka] is replaced by

[0102] In a further embodiment, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In a further embodiment, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In a further embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In a further embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In a further embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In a further embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0103] R 2 In these structures for R 6 and R 7 are each independently H, CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy (alkylene), C 1-6 Haloalkoxy, C 1-6 Haloalkoxy(alkylene), C 1-6 Deuterated alkoxy (alkylene), halo, (CR v R x ) p NR y R z , C(O)NR y2 R z2 , C 1-6 Alkylcarbonyl, optionally substituted C 3-8Cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted (C 3-8 (cycloalkyl)alkylene, optionally substituted (aryl)alkylene, optionally substituted (heterocyclyl)alkylene, or C 1-6 alkylsulfonyl, and R 8 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy (alkylene), C 1-6 Alkyl carbonyl, C 1-6 Hydroxyalkyl, (CR v R x ) p NR y R z 、 Optionally substituted C 3-8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted (C 3-8 cycloalkyl)alkylene, and R v and R x are independently H or C 1-6 Alkyl, R y and R z are independently H, C 1-6 Alkyl, C 1-6 Alkoxy (alkylene), or C 3-6 is cycloalkyl, and R y2 and R z2 are independently H, C 1-6 Alkyl, or C 3-6 cycloalkyl, and p is 0, 1, 2, or 3. In some embodiments, R 6 , R 7 , and R 8 is H.

[0104] In other embodiments, R 6 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Cyanoalkyl, or C 1-6 In a further embodiment, R 6 C such as methyl, ethyl, isopropyl, or tert-butyl 1-6 In still further embodiments, R 6 is C such as CF3, CHF2, CH2F, CH2CF3, CH(CH3)F, C(CH3)F2, or C(CH3)2F 1-6 In a further embodiment, R 6 is C such as C(CH3)2CN 1-6 In another embodiment, R 6 is C such as C(CH3)2OH, CH(CH3)OH, CH(CH2CH3)OH, CH2C(CH3)2OH, or C(CH3)2CH2OH 1-6 In a further embodiment, R 6 are methyl, isopropyl, tert-butyl, CF3, CHF2, C(CH3)F 2、 C(CH3)2F, C(CH3)2OH, or CH(CH3)OH.

[0105] In other embodiments, R 6 Halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl 、 or C 1-6 C optionally substituted with one or more of alkoxy 3-6 In a further embodiment, R 6 Halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 1-6 In still further embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with one or more of alkoxy. 6 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other embodiments, R 6 is C substituted with one or more halo, such as F, Cl, or Br 3-6 In yet another embodiment, R 6is a C substituted with one or more OH 3-6 In still further embodiments, R 6 CF 3、 One or more C such as CH2CF3 or CHF2 1-6 Haloalkyl-substituted C 3-6 In a further embodiment, R 6 is one or more C groups such as methyl, ethyl, or propyl. 1-6 Alkyl-substituted C 3-6 In still further embodiments, R 6 is one or more C groups such as methoxy, ethoxy, or propoxy. 1-6 Alkoxy-substituted C 3-6 In another embodiment, R 6 is cyclopropyl, cyclobutyl, or cyclohexyl, each of which is optionally substituted with one or more of F, OH, or methyl. In other embodiments, R 6 teeth, [ka] In other embodiments, R 6 teeth, [ka] is.

[0106] In a further embodiment, R 6 Ha, Halo, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-6 In another embodiment, R is an aryl optionally substituted with one or more of cycloalkyl. 6 Ha, Halo, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-6 In yet another embodiment, R is phenyl optionally substituted with one or more of cycloalkyl. 6 is aryl optionally substituted with one or more halo, such as F, Cl, or Br. In yet other embodiments, R 6is C such as CF3, CH2CF3, or CHF2 1-6 In another embodiment, R is an aryl optionally substituted with one or more of haloalkyl. 6 is C such as methyl, ethyl, or propyl 1-6 In yet another embodiment, R is an aryl optionally substituted with one or more of alkyl. 6 is a C such as cyclopropyl, cyclobutyl, or cyclopentyl 3-6 In another embodiment, R is an aryl optionally substituted with one or more of cycloalkyl. 6 is aryl (e.g., phenyl) optionally substituted with F, methyl, or CF. In other embodiments, R 6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] is.

[0107] In yet other embodiments, R 6 Ha, Halo, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, or C 3-6 In yet another embodiment, R is heteroaryl optionally substituted with one or more of cycloalkylsulfonyl. 6 is pyridinyl, pyrazolyl, pyrazinyl, imidazolyl, or pyrimidinyl, each of which is optionally substituted. In yet other embodiments, R 6 is pyridinyl, pyrazolyl, pyrazinyl, pyridazinyl, imidazolyl, or pyrimidinyl, each of which is optionally substituted. 6is an optionally substituted pyrazinyl, such as pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, or pyrazin-5-yl. 6 is an optionally substituted pyrazolyl, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl. 6 is an optionally substituted pyridinyl, such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. 6 is an optionally substituted pyridazinyl, such as pyridazin-3-yl or pyridazin-4-yl. 6 is optionally substituted imidazolyl, such as imidazol-4-yl or imidazol-5-yl. In a further embodiment, R 6 is an optionally substituted pyrimidinyl, such as pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl. 6 is pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, pyrazin-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, imidazol-4-yl, imidazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl, each of which is optionally substituted. 6 is pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, pyrazin-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, imidazol-4-yl, imidazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl, each of which is optionally substituted. 6is unsubstituted pyridin-2-yl, unsubstituted pyridin-3-yl, unsubstituted pyridin-4-yl, unsubstituted pyrimidin-2-yl, unsubstituted pyrimidin-4-yl, unsubstituted pyrimidin-5-yl, or unsubstituted pyrazin-2-yl. 6 is unsubstituted pyridin-2-yl, unsubstituted pyridin-3-yl, unsubstituted pyridin-4-yl, unsubstituted pyrimidin-2-yl, unsubstituted pyrimidin-4-yl, unsubstituted pyrimidin-5-yl, unsubstituted pyrazin-2-yl, or pyridazin-3-yl. 6 is optionally substituted with one or more halo, such as F, Cl, or Br. In yet other embodiments, R 6 is one or more C, such as CF3, CH2CF3, or CHF2 1-6 In another embodiment, R 6 is one or more C groups such as methyl, ethyl, propyl, or isopropyl. 1-6 In yet another embodiment, R 6 is one or more C such as methoxy, ethoxy, or propoxy 1-6 In still further embodiments, R 6 is one or more C 1-6 In a further embodiment, R 6 is one or more C groups such as cyclopropyl, cyclobutyl, or cyclopentyl 3-6 In still further embodiments, R 6 is one or more C groups such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl 3-6 In yet another embodiment, R 6 is heteroaryl optionally substituted with one or more of F, CF3, CH2CF3, CHF2, methyl, methoxy, OCF3, cyclobutyl, or cyclopropylsulfonyl.

[0108] In other embodiments, R 6is a 5-membered heteroaryl optionally substituted with one or more of CF, CHCF, CHF, methyl, cyclobutyl, or cyclopropylsulfonyl. 6 teeth, [ka] In yet a further embodiment, R 6 teeth, [ka] In other embodiments, R 6 teeth, [ka] In yet a further embodiment, R 6 teeth, [ka] In yet a further embodiment, R 6 teeth, [ka] In a further embodiment, R 6 teeth, [ka] In still further embodiments, R 6 teeth, [ka] is.

[0109] In other embodiments, R 6 is a 6-membered heteroaryl optionally substituted with one or more of F, CF, methoxy, OCF, or methyl. In yet other embodiments, R 6 teeth, [ka] In yet a further embodiment, R6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] is.

[0110] In yet other embodiments, R 6 are heterocyclyl or heterocyclyl(alkylene), each of which is selected from halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C(O)O(C 1-6 alkyl), or C 3-6 In a further embodiment, R 6 is optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl. 6 is an optionally substituted azetidinyl. In yet other embodiments, R 6 is optionally substituted pyrrolidinyl. In a further embodiment, R 6 is optionally substituted piperidinyl. In yet other embodiments, R 6 is an optionally substituted piperazinyl. In still further embodiments, R 6 is optionally substituted morpholinyl. In other embodiments, R 6 is an optionally substituted morpholinyl(alkylene), an optionally substituted piperidinyl(alkylene), an optionally substituted piperazinyl(alkylene), or an optionally substituted azetidinyl(alkylene). In further embodiments, R 6 is unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. 6is an unsubstituted morpholinyl(alkylene), piperidinyl(alkylene), piperazinyl(alkylene), or azetidinyl(alkylene). 6 is unsubstituted morpholinyl or morpholinyl(alkylene). In other embodiments, heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more halo, such as F, Cl, or Br. In still other embodiments, heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more OH. In further embodiments, heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more C alkylene groups, such as CF3, CH2CF3, or CHF2. 1-6 In still further embodiments, the heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more C alkyl groups, such as methyl, ethyl, or propyl. 1-6 In further embodiments, heterocyclyl and heterocyclyl(alkylene) groups may be substituted with one or more C(CH3)2OH. 1-6 In still further embodiments, the heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more C hydroxyalkyl groups, such as methoxy, ethoxy, or propoxy. 1-6 In other embodiments, heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more C(O)O(C methyl, C(O)Oethyl, C(O)Opropyl, or C(O)Otert-butyl. 1-6 In still further embodiments, heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more C alkyl groups, such as one or more cyclopropyl, cyclobutyl, or cyclopentyl. 3-6 In yet another embodiment, R 6 is heterocyclyl and heterocyclyl(alkylene), each optionally substituted with one or more of F, OH, C(CH)(OH), methyl, C(O)O(tert-butyl), or cyclopropyl.

[0111] In a further embodiment, R6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] In a further embodiment, R 6 teeth, [ka] In still further embodiments, R 6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] In other embodiments, R 6 teeth, [ka] In still further embodiments, R 6 teeth, [ka] is.

[0112] In a further embodiment, R 6 are H, CN, and C 1-6 Alkoxy, C 1-6 Alkoxy (alkylene), C 1-6 Haloalkoxy, C 1-6 Haloalkoxy(alkylene), C 1-6 Deuterated alkoxy (alkylene), halo, (CR v R x ) p NR y R z , C(O)NR y2 R z2 , C 1-6Alkylcarbonyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted (C 3-6 (cycloalkyl)alkylene, optionally substituted (aryl)alkylene, or C 1-6 In another embodiment, R 6 is H. In a further embodiment, R 6 is CN. In yet another embodiment, R 6 C such as methoxy 1-6 In yet another embodiment, R 6 is C, such as CH2OCH3, C(CH3)2OCH3, or (CH2)2OCH3 1-6 In yet another embodiment, R 6 is C such as OCF3, OCHF2, OCH2F, or O(CH2)2CF3 1-6 In another embodiment, R 6 is C such as CH2OCF3 1-6 In yet another embodiment, R 6 is C such as CH2OCD3 1-6 In a further embodiment, R 6 is halo, such as F, Br, or Cl. In still further embodiments, R 6 is (CR) such as NH2, N(CH3)2, NHCH2CF3, NHCH2CH2OCH3, NH(cyclopropyl), CH2N(CH3)2, (CH2)2N(CH3)2, C(CH3)2NHCH3, C(CH3)2N(CH3)2, CH2NH(cyclopropyl), or CH2CH2NH(cyclopropyl). v R x ) p NR y R z In other embodiments, R 6 is C(O)NR such as C(O)N(CH3)2 or C(O)NH(cyclopropyl). y2 R z2 In yet another embodiment, R 6is C such as C(O)CH3 1-6 In a further embodiment, R 6 is an optionally substituted C such as CH=CH2, CH=CH-cyclopropyl, or CH=CHC(CH3)2OH. 2-6 In yet another embodiment, R is alkenyl. 6 teeth, [ka] Any substitution of C such as 3-6 In yet another embodiment, R 6 is optionally substituted (C) such as CH-cyclopropyl, CHCH-cyclopropyl, or C(CH)OH-cyclopropyl. 3-6 In a further embodiment, R 6 is an optionally substituted (aryl)alkylene, such as benzyl. In other embodiments, C is an alkyl group such as C(CH)SOCH. 1-6 Alkylsulfonyl(alkylene). In yet other embodiments, R 6 is H, CH2OCH3, Cl, NH(cyclopropyl), or C(O)N(CH3)2.

[0113] In some embodiments, R 7 are H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, C 3-8 In yet other embodiments, R is cycloalkyl, aryl, or heteroaryl. 7 is H. In still further embodiments, R 7 is CN. In other embodiments, R 7 is C such as methyl, ethyl, or propyl 1-6 In a further embodiment, R 7 is methyl. In yet another embodiment, R 7 is C such as CHF2, CH2F, C(CH3)F2, CH2CHF2, or CF3 1-6 In still further embodiments, R 7is CHF2 or CF3. In a further embodiment, R 7 is halo, such as F, Br, or Cl. In yet other embodiments, R 7 is Br or Cl. In still further embodiments, R 7 is a C such as cyclopropyl, cyclobutyl, or cyclopentyl 3-6 In another embodiment, R 7 is cyclopropyl. In a further embodiment, R 7 is aryl. In yet other embodiments, R 7 is phenyl. In still further embodiments, R 7 is heteroaryl. In other embodiments, R 7 is pyridinyl. In a further embodiment, R 7 is H, CN, methyl, CF, CHF, CHF, CF(CH), CHCHF, Br, Cl, cyclopropyl, phenyl, or pyridinyl. 7 is H, CN, methyl, CHF2, CF3, Br, Cl, cyclopropyl, phenyl, or pyridinyl.

[0114] R 2 In some embodiments of 8 is H. In other embodiments, R 8 C such as methyl, ethyl, isopropyl, or tert-butyl 1-6 In a further embodiment, R 8 is C such as CF3, CHF2, CH2F, CH2CF3, CH2CHF2, C(CH3)2F, or C(CH3)F2 1-6 In still further embodiments, R 8 is C such as CH2CH2OCH3 1-6 In another embodiment, R 8 is C such as CH2C(=O)CH3 1-6 In yet another embodiment, R 8 is C such as CH2C(CH3)2OH 1-6In a further embodiment, R 8 is (CR such as (CH2)2N(CH3)2 v R x ) p NR y R z In yet another embodiment, R 8 is an optionally substituted C alkyl group, such as an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl. 3-8 In another embodiment, R 8 is optionally substituted aryl, such as optionally substituted phenyl. In a further embodiment, R 8 is an optionally substituted heteroaryl, such as an optionally substituted pyridinyl. In still further embodiments, R 8 is an optionally substituted heteroaryl, such as an optionally substituted pyridinyl. 8 is arbitrarily substituted (C 3-8 cycloalkyl) alkylene, for example, [ka] In still further embodiments, R 8 is H, methyl, isopropyl, CHF2, CH2CF3, CF3, cyclopropyl, or [ka] is.

[0115] In some embodiments, R v and R x One or both of R v and R x One or both of the groups may be C, such as methyl, ethyl, propyl, or butyl. 1-6 In yet another embodiment, R v and R x In some embodiments, one or both of R y and Rz One or both of R y and R z One or both of the groups may be C, such as methyl, ethyl, propyl, or butyl. 1-6 In yet another embodiment, R y and R z One or both of the following may be C, such as CH2OCH3: 1-6 In a further embodiment, R y and R z One or both of the groups may be a C cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 In some embodiments, R y2 and R z2 One or both of R y2 and R z2 One or both of the groups may be C, such as methyl, ethyl, propyl, or butyl. 1-6 In a further embodiment, R y2 and R z2 One or both of the groups may be a C cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 In a further embodiment, p is 0. In another embodiment, p is 1. In a further embodiment, p is 2. In yet another embodiment, p is 3.

[0116] In some embodiments, R 2 teeth, [ka] and R 6 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy(alkylene), optionally substituted C 3-6 cycloalkyl, or optionally substituted heteroaryl; R 7are H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, C 3-6 In a further embodiment, R is cycloalkyl, aryl, or heteroaryl. 6 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted heteroaryl; R 7 are H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, halo, or C 3-6 In another embodiment, R 6 is H. In a further embodiment, R 6 is C 1-6 In still further embodiments, R 6 is methyl, isopropyl, or tert-butyl. 6 is C 1-6 In still further embodiments, R 6 is CF2H, C(CH3)2F, CH(CH3)F, or CF3. In other embodiments, R 6 is C 1-6 In a further embodiment, R 6 is C(CH3)2CN. In yet another embodiment, R 6 is C 1-6 In still further embodiments, R 6 is C(CH3)2OH, CH2C(CH3)2OH, CH(CH2CH3)OH, C(CH3)2(CH2OH), or CH(CH3)OH. In other embodiments, R 6 is C 1-6 In yet another embodiment, R 6 is methoxy or ethoxy. In yet another embodiment, R 6 is C 1-6 In a further embodiment, R 6is CH2OCH3 or (CH2)2OCH3. In other embodiments, R 6 is an arbitrarily substituted C 3-6 In yet another embodiment, optionally substituted C 3-6 The cycloalkyl is substituted with one or more OH. In a further embodiment, R 6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] In other embodiments, R 6 is optionally substituted heteroaryl. In yet other embodiments, R 6 is optionally substituted pyridinyl, optionally substituted pyrazolyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted imidazolyl. In yet other embodiments, the optionally substituted heteroaryl is selected from the group consisting of one or more C substituted aryl groups, such as methyl, ethyl, or isopropyl. 1-6 In a further embodiment, R 6 teeth, [ka] In still further embodiments, R 6 teeth, [ka] In other embodiments, R 6 is H, methyl, tert-butyl, C(CH3)2F, C(CH3)2CN, C(CH3)2OH, CH(CH3)OH, CH2OCH3, cyclopropyl, [ka] In a further embodiment, R 6is H, tert-butyl, C(CH3)2F, C(CH3)2CN, C(CH3)2OH, CH(CH3)OH, [ka] In yet another embodiment, R 7 is H. In still further embodiments, R 7 is CN. In other embodiments, R 7 is C 1-6 In a further embodiment, R 7 is methyl. In yet another embodiment, R 7 is C 1-6 In still further embodiments, R 7 is CF2H, CHF2, CH2F, C(CH3)F2, or CF3. In other embodiments, R 7 is CHF2 or CF3. In a further embodiment, R 7 is halo. In yet other embodiments, R 7 is Br or Cl. In still further embodiments, R 7 is C 3-6 In another embodiment, R 7 is cyclopropyl. In a further embodiment, R 7 is aryl. In yet other embodiments, R 7 is phenyl. In still further embodiments, R 7 is heteroaryl. In other embodiments, R 7 is pyridinyl. In yet another embodiment, R 7 is H, CN, methyl, CHF, CF, Br, Cl, cyclopropyl, phenyl, or pyridinyl. 7 is H, CN, methyl, CHF2, CF3, Br, Cl, or cyclopropyl.

[0117] In other embodiments, R 2 teeth, [ka] and R6 are H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy(alkylene), optionally substituted C 3-6 cycloalkyl, optionally substituted heteroaryl, and R 7 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, or C 3-6 In yet another embodiment, R 6 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 hydroxyalkyl, and R 7 is H. In a further embodiment, R 6 is H. In other embodiments, R 6 is CN. In a further embodiment, R 6 is C 1-6 In still further embodiments, R 6 is methyl, isopropyl, or tert-butyl. 6 is C 1-6 In still further embodiments, R 6 is CHF, C(CH)F, C(CH)F, or CF. In yet other embodiments, R 6 is C 1-6 In still further embodiments, R 6 is C(CH3)2OH. In other embodiments, R 6 is C 1-6 In still further embodiments, R 6 is methoxy or ethoxy. In yet another embodiment, R 6 is C 1-6 In a further embodiment, R 6 is CH2OCH3. In other embodiments, R 6 is an arbitrarily substituted C 3-6In still further embodiments, R 6 teeth, [ka] In other embodiments, R 6 is optionally substituted heteroaryl. In yet other embodiments, R 6 is optionally substituted pyridinyl or optionally substituted pyrazolyl. In a further embodiment, R 6 teeth, [ka] In other embodiments, R 6 is H, tert-butyl, C(CH3)2F, C(CH3)F2, C(CH3)2OH, CH2OCH3, [ka] In a further embodiment, R 6 is H or C(CH3)2F. In yet other embodiments, R 7 is H. In other embodiments, R 7 is C 1-6 In a further embodiment, R 7 is methyl. In yet another embodiment, R 7 is C 1-6 In still further embodiments, R 7 is CF2H or CF3. In a further embodiment, R 7 is halo. In yet other embodiments, R 7 is Br or Cl. In still further embodiments, R 7 is C 3-6 In another embodiment, R 7 is cyclopropyl. In still further embodiments, R 7 is H, methyl, CF2H, CF3, Br, Cl, or cyclopropyl.

[0118] In a further embodiment, R 2 teeth [ka] and R 6 and R 7 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, optionally substituted C 3-6 In other embodiments, R 6 and R 7 are each H. In a further embodiment, R 6 or R 7 One of them is C, such as methyl. 1-6 In yet another embodiment, R 6 or R 7 One of them is C such as CF3. 1-6 In yet another embodiment, R 6 or R 7 In still further embodiments, one of R 6 or R 7 one of which is an optionally substituted C such as unsubstituted cyclopropyl 3-6 In another embodiment, R 6 or R 7 In yet other embodiments, one of R 6 is methyl, CF, Cl, cyclopropyl, or phenyl, and R 7 is H. In yet another embodiment, R 7 is methyl, CF, Cl, cyclopropyl, or phenyl, and R 6 is H.

[0119] In still further embodiments, R 2 teeth, [ka] and R 6 is H, C 1-6 In other embodiments, R is alkyl, halo, or optionally substituted aryl. 6is H. In a further embodiment, R 6 C such as methyl, ethyl, isopropyl, or tert-butyl 1-6 In another embodiment, R 6 is methyl or ethyl. In another embodiment, R 6 is halo, such as F, Br, or Cl. In a further embodiment, R 6 is Br. In other embodiments, R 6 is optionally substituted aryl. In a further embodiment, R 6 is phenyl. In yet another embodiment, R 6 is H, methyl, ethyl, Br, or phenyl. In yet other embodiments, R 6 is H, methyl, or phenyl.

[0120] In yet other embodiments, R 2 teeth, [ka] and R 6 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C(O)NR y2 R z2 , (CR v R x ) p NR y R z , optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R v and R x are independently H or C 1-6 alkyl, and R y and R z are independently H, C 1-6 Alkyl, C 1-6 Alkoxy (alkylene), or C 3-6 is cycloalkyl, and R y2 and R z2 are independently H, C 1-6Alkyl, or C 3-6 cycloalkyl, and p is 0, 1, 2, or 3. In a further embodiment, R 6 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, optionally substituted C 3-6 In some embodiments, R is cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. 6 is H. In a further embodiment, R 6 is C 1-6 In another embodiment, R 6 is methyl, ethyl, isopropyl, or tert-butyl. 6 is methyl, isopropyl, or tert-butyl. In other embodiments, R 6 is C 1-6 In a further embodiment, R 6 is CHF, CF, or C(CH)F. In still further embodiments, R 6 is CF, CHF, C(CH)F, or C(CH)F. In yet other embodiments, R 6 is C 1-6 In still further embodiments, R 6 is C(CH3)2OH or CH(CH3)OH. In yet other embodiments, R 6 is C(O)NR y2 R z2 In still further embodiments, R 6 is C(O)N(CH) or C(O)NH(cyclopropyl). In other embodiments, R 6 is (CR v R x ) p NR y R z In a further embodiment, R 6 is NH2, N(CH3)2, NHCH2CF3, NHCH2CH2OCH 3、NH(cyclopropyl), CHN(CH), CHNH(cyclopropyl), or CHCHNH(cyclopropyl). In yet other embodiments, R 6 is an arbitrarily substituted C 3-6 In yet another embodiment, optionally substituted C 3-6 Cycloalkyl can be substituted with halo, such as F, or C, such as methyl. 1-6 In still further embodiments, R 6 teeth, [ka] In other embodiments, R 6 is optionally substituted aryl. In yet other embodiments, the optionally substituted aryl is selected from halo, such as F, C, such as methyl, 1-6 Alkyl or C such as CF3 1-6 In a further embodiment, R 6 teeth, [ka] In yet another embodiment, R 6 is an optionally substituted heterocyclyl. In a further embodiment, the optionally substituted heterocyclyl is halo, such as F, or C, such as methyl. 1-6 In still further embodiments, R 6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] In other embodiments, R 6is an optionally substituted heteroaryl, such as an optionally substituted pyrazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, or an optionally substituted pyrazinyl. In a further embodiment, the optionally substituted heteroaryl is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 34 -C 35 -C 40 -C 41 -C 42 -C 43 -C 44 -C 45 -C 46 -C 47 -C 48 -C 49 -C 50 -C 51 -C 52 -C 53 -C 54 -C 55 -C 56 -C 57 -C 58 -C 59 -C 60 -C 61 -C 62 -C 63 -C 64 -C 65 -C 66 -C 67 -C 68 -C 69 -C 70 -C 71 -C 72 -C 73 -C 74 -C 75 -C 76 -C 77 -C 78 -C 79 -C 80 -C 81 -C 82 -C 83 -C 84 -C 85 -C 86 -C 87 -C 88 -C 89 -C 90 -C 91 -C 92 -C 93 -C 94 -C 95 -C 96 1-6 C such as alkyl, CF3, CH2CF3, or CHF2 1-6 haloalkyl, halo such as F, C such as methoxy, ethoxy, or propoxy 1-6 C such as alkoxy, cyclopropyl or cyclobutyl 3-6 cycloalkyl, or C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl 3-6 In yet another embodiment, R 6 teeth, [ka] In yet another embodiment, R 6 teeth, [ka] In a further embodiment, R 6 are methyl, isopropyl, tert-butyl, CHF2, C(CH3)2F, C(CH3)2OH, CH(CH3)OH, C(O)N(CH3)2, NH(cyclopropyl), [ka] phenyl, [ka] In still further embodiments, R 6 are methyl, isopropyl, tert-butyl, CF3, CHF2, C(CH3)F2, C(CH3)2F, C(CH3)2OH, [ka] is.

[0121] In still further embodiments, R 2 teeth, [ka] and R 6 and R 7 are independently H, halo, and C 1-6 Alkyl, or C 1-6 haloalkyl, and R 8 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 In yet other embodiments, R is cycloalkyl, optionally substituted aryl, or heteroaryl. 6 and R 7 are independently H, halo, and C 1-6 Alkyl, C 1-6 Haloalkyl, or NR y R z and R y and R z are independently H or C 1-6 alkyl, and R 8 is H, C 1-6 Alkyl, C 1-6 Alkyl, C 3-6 In another embodiment, R 6 and R 7 In yet another embodiment, one or both of R 6 or R 7 In a further embodiment, one of R 6 or R 7 In still further embodiments, one of R 6 or R 7 In yet another embodiment, one of R 6 or R 7 One of them is C 1-6 In still further embodiments, R 6 or R 7 In another embodiment, one of R 6 or R 7 One of them is C 1-6In a further embodiment, R 6 or R 7 is CHF, CHCF, CFH, or CF. In other embodiments, R 6 or R 7 In a further embodiment, one of R 6 or R 7 One of them is NR y R z and R y and R z are independently H or NH2, etc. 1-6 In yet another embodiment, R 6 or R 7 is Cl, Br, methyl, CHF, or CF. In further embodiments, R 6 or R 7 is Cl, methyl, CHF, or NH. In other embodiments, R 6 or R 7 is methyl, Cl, CHF, or CF. In some embodiments, R 8 is H. In other embodiments, R 8 is C 1-6 In a further embodiment, R 8 is methyl, ethyl, isopropyl, or tert-butyl. 8 is methyl or isopropyl. In yet other embodiments, R 8 is C 1-6 In still further embodiments, R 8 is CHF2, CH2CF3, CF2H, CH2CHF2, or CF3. In still further embodiments, R 8 is CHF2, CH2CF3, or CF3. In other embodiments, R 8 is C 3-6 In a further embodiment, R 8 is cyclopropyl. In yet another embodiment, R 8 is optionally substituted aryl. In still further embodiments, R 8is phenyl or fluorophenyl. In another embodiment, R 8 is heteroaryl. In a further embodiment, R 8 is pyridinyl. In yet another embodiment, R 8 is H, methyl, isopropyl, tert-butyl, CHF, CHCF, CHCHF, CHC(=O)CH, CHC(CH)OH, (CH)N(CH), cyclopropyl, fluorophenyl, pyridinyl, CH-cyclopropyl, or CH-cyclobutyl. 8 are methyl, isopropyl, CHF2, CH2CF3, CF3, cyclopropyl, and pyridinyl.

[0122] In a further embodiment, R 2 teeth, [ka] and R 6 is H, C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, or C 3-6 is cycloalkyl, and R 8 is H, C 1-6 Alkyl, or C 1-6 In still further embodiments, R 6 is H, C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, or C 3-6 is cycloalkyl, and R 8 is H or C 1-6 In another embodiment, R 6 is H. In yet another embodiment, R 6 is C such as methyl 1-6 In yet another embodiment, R 6 is halo, such as Cl or Br. In a further embodiment, R 6 is Cl. In other embodiments, R 6 is C such as CHF2 or CF3 1-6 In yet another embodiment, R 6is C such as cyclopropyl 3-6 In still further embodiments, R 6 is H, methyl, Cl, CHF, CF, or cyclopropyl. 8 is H. In other embodiments, R 8 is C such as methyl, ethyl, or isopropyl 1-6 In yet another embodiment, R 8 is C such as CF3 or CHF2 1-6 In another embodiment, R 8 is methyl.

[0123] In yet other embodiments, R 2 teeth, [ka] In these structures, W is S or NR 15 and W 1 is S, O, or NR 15 and R 10 , R 11 , R 12 , R 13 , and R 14 are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy (alkylene), C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 Haloalkoxy(alkylene), C 2-6 Alkenyl, CN, halo, (CR v R x ) p NR y R z , C(O)NR y2 R z2 , optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), optionally substituted aryl, or optionally substituted heteroaryl; R vand R x are independently H or C 1-6 alkyl, and R y and R z are independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy (alkylene), or C(O)OC alkyl, R y2 and R z2 are independently H, C 1-6 Alkyl, or C 3-6 cycloalkyl, p is 0, 1, 2, or 3, and R 15 is H or C 1-6 It is alkyl.

[0124] In some embodiments, W is S. In other embodiments, W is NR 15 In some embodiments, W 1 is S. In another embodiment, W 1 is O. In a further embodiment, W 1 is NR 15 In some embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 is H. In a further embodiment, R 10 , R 11 , R 12 , and R 13 is H. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In yet another embodiment, R 10, R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 2-6 In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 In yet another embodiment, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 In still further embodiments, at least one of R 10 , R 11 , R 12 , R13 , and R 14 At least one of the (CR v R x ) p NR y R z In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the y2 R z2 In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 3-8 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 In yet other embodiments, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 In still further embodiments, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is optionally substituted aryl. 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is optionally substituted heteroaryl. v and R x One or both of R v and R x One or both of 1-6In some embodiments, R y and R z One or both of R y and R z One or both of 1-6 In a further embodiment, R y and R z One or both of 3-6 In yet another embodiment, R y and R z One or both of 1-6 In still further embodiments, R y and R z One or both of 1-6 In a further embodiment, R y and R z One or both of R is C(O)OC alkyl. y2 and R z2 One or both of R y2 and R z2 One or both of 1-6 In a further embodiment, R y2 and R z2 One or both of 3-6 In some embodiments, p is 0. In other embodiments, p is 1. In further embodiments, p is 2. In yet other embodiments, p is 3. In some embodiments, R 15 is H. In other embodiments, R 15 is C 1-6 It is alkyl.

[0125] In still further embodiments, R 2 teeth, [ka] and R 10 , R 11 , R 12 , R 13 , and R 14are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 alkoxy(alkylene), halo, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), optionally substituted heteroaryl, or (CR v R x ) p NR y R z In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 are each independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 alkoxy(alkylene), optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), optionally substituted heteroaryl, or (CR v R x ) p NR y R z In some embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 is H. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the groups is a C such as methyl or ethyl. 1-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the C groups, such as methyl 1-6 In a further embodiment, R 10 , R 11 , R 12 , R13 , and R 14 At least one of the C 1-6 haloalkyl, or C(CH3)2F. In still further embodiments, R 10 , R 11 , R 12 , R 13 , and / or R 14 At least one of the groups is C, such as cyclopropyl. 3-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the C groups, such as methoxy 1-6 In another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the groups is a C group such as CH2OCH3 or (CH2)2OCH3. 1-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is halo, such as F, Br, or Cl. 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is an optionally substituted aryl, such as unsubstituted phenyl. 10 , R 11 , R 12 , R 13 , and R 14 At least one of the [ka] In yet another embodiment, R 10 , R 11 , R 12 , R13 , and R 14 At least one of the [ka] In other embodiments, the optionally substituted heteroaryl is [ka] In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 In still further embodiments, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the [ka] In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the [ka] In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of R is an optionally substituted heteroaryl, such as an optionally substituted pyridinyl, an optionally substituted pyrazinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazolyl. 10 , R 11 , R 12 , R 13 , and R 14 At least one of the [ka] In still further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the groups is (CR), such as NH, NH(CH), N(CH), CHN(CH), or CHCHN(CH). v R x ) p NR y R z In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the groups is (CR), such as N(CH), CHN(CH), or CHCHN(CH). v R x ) p NR y R z In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 are each independently H, methyl, C(CH3)2F, cyclopropyl, methoxy, CH2OCH3, (CH2)2OCH3, Br, F, Cl, phenyl, [ka] N(CH), CHN(CH), or CHCHN(CH). In yet other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 are each independently H, methyl, cyclopropyl, methoxy, CH2OCH3, (CH2)2OCH3, [ka] N(CH), CHN(CH), or CHCHN(CH). In other embodiments, R10 , R 13 , and R 14 are each hydrogen. In a further embodiment, R 10 , R 13 , and R 14 are each hydrogen, and R 11 is a halo.

[0126] In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 at least one of which is halo, such as F, Cl, or Br; C, such as CF3, CH2CF3, or CHF2; 1-6 Haloalkyl; C such as methyl, ethyl, or propyl 1-6 Alkyl; OH; C such as C(CH3)2OH 1-6 Hydroxyalkyl; C such as methoxy, ethoxy, or propoxy 1-6 alkoxy; or C such as cyclopropyl, cyclobutyl, or cyclopentyl 3-6 In another embodiment, the heterocyclyl or heterocyclyl(alkylene) is substituted with one or more methyl, OH, or F.

[0127] In a further embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 at least one of which is halo, such as F, Cl, or Br; C, such as CF3, CH2CF3, or CHF2; 1-6 Haloalkyl; C such as methyl, ethyl, propyl, or isopropyl 1-6 Alkyl; C such as methoxy, ethoxy, or propoxy 1-6 Alkoxy; C such as OCF3 1-6 Haloalkoxy; C such as cyclopropyl, cyclobutyl, or cyclopentyl 3-6cycloalkyl; or C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl 3-6 In yet another embodiment, the substituted heteroaryl is substituted with one or more of F, CF, CHF, or methyl. In a further embodiment, the optionally substituted heteroaryl is pyrazolyl substituted with one methyl.

[0128] In other embodiments, R 2 teeth, [ka] and R 10 , R 11 , R 12 , and R 13 are each independently H, C 1-6 alkyl or halo, R 15 is H or C 1-6 In a further embodiment, R 10 , R 11 , R 12 , and R 13 is H. In other embodiments, R 10 , R 11 , R 12 , and R 13 At least one of the 1-6 In a further embodiment, R 10 , R 11 , R 12 , and R 13 In yet other embodiments, at least one of R 10 , R 11 , R 12 , and R 13 At least one of R is Br. 15 is H. In other embodiments, R 15 is C 1-6 In a further embodiment, R 15 is methyl. In yet another embodiment, R 15 is H or methyl.

[0129] In a further embodiment, R 2 teeth, [ka] and R 10 , R 11 , R 12 , R 13 , and R 14 are each independently H, halo, or C 1-6 In some embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In some embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 is H. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 In a further embodiment, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 It is alkyl.

[0130] In yet other embodiments, R 2 teeth, [ka] and R 10 , R 11 , R 12 , R 13 , and R 14 are each independently H, halo, or C1-6 In some embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 is H. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 In a further embodiment, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 In yet another embodiment, at least one of R 10 , R 11 , R 12 , R 13 , and R 14 At least one of the 1-6 It is alkyl.

[0131] In still further embodiments, R 2 teeth, [ka] and R 10 , R 11 , R 12 , and R 13 are each independently H, C 1-6 In some embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In a further embodiment, R 2 teeth, [ka] In some embodiments, R10 , R 11 , R 12 , and R 13 is H. In other embodiments, R 10 , R 11 , R 12 , and R 13 In a further embodiment, at least one of R 10 , R 11 , R 12 , and R 13 At least one of R is F. In yet other embodiments, R 10 , R 11 , R 12 , and R 13 At least one of the 1-6 In still further embodiments, R 10 , R 11 , R 12 , and R 13 In yet other embodiments, at least one of R 10 , R 11 , R 12 , and R 13 are each independently H, methyl, or F.

[0132] In other embodiments, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is H. In yet another embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0133] In a further embodiment, R 2 teeth [ka] and R 6 is defined herein, and R 7 is CH3. In other embodiments, R 2 teeth [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0134] In yet other embodiments, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is cyclopropyl. In a further embodiment, R 2 teeth, [ka] In still further embodiments, R 2 teeth, [ka] is.

[0135] In still further embodiments, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is CHF2. In another embodiment, R 2 teeth, [ka] In yet another embodiment, R 2teeth, [ka] is.

[0136] In other embodiments, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is CF. In yet another embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0137] In a further embodiment, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is CN. In still further embodiments, R 2 teeth, [ka] is.

[0138] In yet other embodiments, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is Br or Cl. In a further embodiment, R 2 teeth, [ka] is.

[0139] In still further embodiments, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is phenyl or pyridinyl. In another embodiment, R 2 teeth, [ka] is.

[0140] In a further embodiment, R 2 teeth, [ka] and R 6 is defined herein, and R 7 is H. In yet another embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0141] In other embodiments, R 2 teeth, [ka] and R 6 ~R 8 is defined herein. In yet another embodiment, R 2 teeth [ka] In yet another embodiment, R2 teeth, [ka] is.

[0142] In a further embodiment, R 2 teeth, [ka] and R 6 ~R 8 is defined herein. In still further embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0143] In other embodiments, R 2 teeth, [ka] and R 6 is optionally substituted heterocyclyl. In yet other embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0144] In a further embodiment, R 2 teeth, [ka] and R 6is optionally substituted heteroaryl. In still further embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] [ka] is.

[0145] In other embodiments, R 2 teeth, [ka] and R 6 is optionally substituted aryl. In yet other embodiments, R 2 teeth, [ka] is.

[0146] In a further embodiment, R 2 teeth, [ka] and R 6 is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In still further embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0147] In other embodiments, R 2 teeth, [ka] and R 6 is an arbitrarily substituted C 3-8 In yet another embodiment, R 2 teeth, [ka] is.

[0148] In yet other embodiments, R 2 teeth, [ka] and R 6 is C(O)NR y2 R z2 or (CR v R x ) p NR y R z and R y2 , R z2 ,p,R v , R x , R y , and R z is defined herein. In other embodiments, R 2 teeth, [ka] is.

[0149] In other embodiments, R 2 teeth, [ka] and R 6 is H, C 1-6 In yet another embodiment, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0150] In a further embodiment, R 2 teeth, [ka] and R 6 is C 1-6 In still further embodiments, R 2 teeth, [ka] is.

[0151] In other embodiments, R 2 teeth, [ka] and R 8 is C 1-6 alkyl, and R 6 is defined herein. In yet another embodiment, R 2 teeth [ka] is.

[0152] In a further embodiment, R 2 teeth, [ka] and R 10 ~R 14 is defined herein. In still further embodiments, R 2 teeth, [ka] In yet another embodiment, R 2 teeth, [ka] is.

[0153] In other embodiments, R 2 teeth, [ka] and R 13 is H and R 10 , R 11 , R 12 , R 14 , and R 15 is defined herein. In yet another embodiment, R 2 teeth, [ka] is.

[0154] In some embodiments, the compound of formula I is a compound of formula IA or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 , L, and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0155] In another embodiment, the compound of formula IB is a compound of formula IB or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In a further embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0156] In a further embodiment, the compound of formula I is a compound of formula IC or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0157] In yet other embodiments, the compound of formula I is a compound of formula ID, or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0158] In still further embodiments, the compound of formula I is a compound of formula IE or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment, the compound of formula I is a compound of formula IF, or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In yet other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0160] In a further embodiment, the compound of formula I is a compound of formula IG or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In a further embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0161] In yet other embodiments, the compound of formula I is a compound of formula IH, or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0162] In still further embodiments, the compound of formula I is a compound of formula II or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0163] In another embodiment, the compound of formula I is a compound of formula IJ, or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In yet other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0164] In a further embodiment, the compound of formula I is a compound of formula IK or a pharmaceutically acceptable salt thereof: [ka] for example, [ka] In the formula, R 1 , R 2 , R 5 and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0165] In yet other embodiments, the compound of formula I is a compound of formula IL, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 5, L, and m are defined herein. In a further embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0166] In still further embodiments, the compound of formula I is a compound of formula IM or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 5 , L, and m are defined herein. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compounds of the present disclosure are any one or more of the compounds in Table 1, and pharmaceutically acceptable salts and / or isotopologues thereof. Compounds having Formula I are further disclosed in the Examples and are included in the present disclosure, including pharmaceutically acceptable salts and neutral forms thereof.

[0168] The present disclosure further provides the R-enantiomer, S-enantiomer, or racemic mixture of any of the compounds described herein. In some embodiments, the compound is an S-enantiomer. In other embodiments, the compound is an R-enantiomer. In further embodiments, the compound is racemic.

[0169] In another embodiment, the compounds of the present disclosure are enantiomerically enriched, e.g., the enantiomeric excess or "ee" of the compound is about 5% or greater, as measured by chiral HPLC. In some embodiments, the ee is greater than about 10%. In other embodiments, the ee is greater than about 20%. In further embodiments, the ee is greater than about 30%. In still other embodiments, the ee is greater than about 40%. In still further embodiments, the ee is greater than about 50%. In other embodiments, the ee is greater than about 60%. In further embodiments, the ee is greater than about 70%. In still other embodiments, the ee is greater than about 80%. In still further embodiments, the ee is greater than about 85%. In other embodiments, the ee is greater than about 90%. In further embodiments, the ee is greater than about 91%. In still other embodiments, the ee is greater than about 92%. In still further embodiments, the ee is greater than about 93%. In other embodiments, the ee is greater than about 94%. In further embodiments, ee is greater than about 95%. In yet other embodiments, ee is greater than about 96%. In still further embodiments, ee is greater than about 97%. In other embodiments, ee is greater than about 98%. In further embodiments, ee is greater than about 99%.

[0170] The present disclosure encompasses the preparation and use of salts of the disclosed compounds. Salts of the disclosed compounds can be prepared during the final isolation and purification of the compounds, or separately by reacting the compounds with an appropriate acid or base.

[0171] Treatment method The compounds of the present disclosure have several uses, as described herein. In some embodiments, the compounds of the present disclosure are useful in methods for stabilizing mutant PAH proteins. These methods include contacting the protein with one or more compounds described herein or pharmaceutically acceptable salts thereof. The compounds of the present disclosure can provide better Phe control and reduce the severity of phenylketonuria in patients whose disease is not well-controlled by diet alone. Accordingly, patients administered a compound of the present disclosure may have a better quality of life, e.g., a more normal lifestyle and / or no or fewer dietary restrictions, compared to phenylketonuric patients who do not receive a compound of the present disclosure. In some embodiments, patients administered a compound of the present disclosure may experience increased executive function, decreased anxiety symptoms, and / or decreased attention-deficit hyperactivity disorder symptoms.

[0172] As used herein, the term "variant PAH gene" refers to the complete DNA sequence of a PAH that differs in one or more ways from the standard accepted sequence ("basic gene") published in any one of a variety of curated databases. As an example, the sequence described by GenBank Accession No. NG_008690.2 describes the basic gene.

[0173] As used herein, the term "mutant PAH protein" refers to a PAH protein that contains at least one mutation in its amino acid sequence compared to that encoded by a reference. The reference human PAH protein is described by Genbank accession number NP_000268 and contains 452 amino acids. PAH protein mutations can be identified using methods known in the art. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, ​​I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation. In still other embodiments, the mutant PAH protein comprises at least one R408W, R243Q, R408Q, V388M, or L348V mutation. In still other embodiments, the mutant PAH protein comprises at least one R408W mutation. In a further embodiment, the mutant PAH protein comprises at least two R408W mutations. In a further embodiment, the mutant PAH protein comprises at least one R261Q mutation. In still other embodiments, the mutant PAH protein comprises at least one R243Q mutation. In still other embodiments, the mutant PAH protein comprises at least one Y414C mutation. In yet further embodiments, the mutant PAH protein comprises at least one L48S mutation. In other embodiments, the mutant PAH protein comprises at least one A403V mutation. In a further embodiment, the mutant PAH protein comprises at least one I65T mutation. In still further embodiments, the mutant PAH protein comprises at least one R241C mutation. In yet other embodiments, the mutant PAH protein comprises at least one L348V mutation. In further embodiments, the mutant PAH protein comprises at least one R408Q mutation. In other embodiments, the mutant PAH protein comprises at least one V388M mutation. In other embodiments, the mutant PAH protein comprises at least one F39L mutation.In still further embodiments, the mutant PAH protein comprises at least one A300S mutation. In still further embodiments, the mutant PAH protein comprises at least one L48S mutation.

[0174] In other embodiments, the present disclosure provides methods for stabilizing the activity of a mutant phenylalanine hydroxylase (PAH) protein compared to a wild-type PAH. Such methods include contacting the phenylalanine hydroxylase with one or more compounds described herein or a pharmaceutically acceptable salt thereof. As used herein, the term "stabilizing" refers to adjusting the activity or amount of a PAH enzyme so that it catalyzes the hydroxylation of the aromatic side chain of phenylalanine at a rate more similar to the PAH catalytic rate of a control population having a wild-type PAH, i.e., not having a mutant PAH gene mutation, compared to a baseline PAH catalytic rate. In some aspects, the term "stabilizing" refers to adjusting the activity of a PAH in a subject so that it catalyzes the hydroxylation of the aromatic side chain of phenylalanine at a flux more similar to the PAH catalytic flux of a control subject population not having a mutant PAH gene mutation. In some embodiments, "stabilizing" the activity of a PAH includes increasing the level of the PAH enzyme compared to baseline. Increasing the accumulation of stabilized active PAH protein can reduce toxic Phe levels in a subject compared to the subject's baseline level of dietary Phe prior to administration of a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure.

[0175] In some embodiments, the present disclosure provides methods for reducing blood phenylalanine concentrations in a subject suffering from phenylketonuria to a concentration of about 600 μM or less. In other embodiments, blood Phe concentrations are reduced to a concentration of about 360 μM or less. In other embodiments, the present disclosure provides methods for reducing blood Phe concentrations compared to an untreated baseline. In some embodiments, the subject's blood Phe concentration compared to an untreated baseline is reduced by a percentage, including but not limited to, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In other embodiments, the subject's blood Phe concentration compared to an untreated baseline is reduced by at least about 10%. In further embodiments, the subject's blood Phe concentration compared to an untreated baseline is reduced by at least about 20%. In yet other embodiments, the subject's blood Phe concentration compared to an untreated baseline is reduced by at least about 30%. In still further embodiments, the subject's blood Phe concentration compared to untreated baseline is reduced by at least about 40%. In other embodiments, the subject's blood Phe concentration compared to untreated baseline is reduced by at least about 50%. In further embodiments, the subject's blood Phe concentration compared to untreated baseline is reduced by at least about 60%. In yet other embodiments, the subject's blood Phe concentration compared to untreated baseline is reduced by at least about 70%. In still further embodiments, the subject's blood Phe concentration compared to untreated baseline is reduced by at least about 80%. In other embodiments, the subject's blood Phe concentration compared to untreated baseline is reduced by at least about 90%. A subject's Phe concentration can be determined by blood testing; methods for measuring such levels are known in the art. In some embodiments, the reduction in Phe concentration achieved using the disclosed compounds is achieved in conjunction with the subject actively managing their dietary Phe intake. In other embodiments, the reduction in Phe concentration is achieved in conjunction with the subject maintaining a Phe-restricted diet.

[0176] In some embodiments, a subject is treated with a compound of the present disclosure, or a pharmaceutical composition comprising a compound of the present disclosure, wherein the compound is administered in an amount sufficient to stabilize PAH protein, or to reduce blood phenylalanine levels in the subject, or a combination thereof in the subject.

[0177] In further embodiments, the subject is a human patient, such as a human adult over 18 years of age in need of treatment. In still further embodiments, the human patient is a human child under 18 years of age. In still further embodiments, the human patient is a human child between 12 and 18 years of age. In yet other embodiments, the human patient is a human child under 12 years of age. In any of the embodiments, the subject has phenylketonuria (PKU), optionally classical PKU or severe PKU. In some embodiments, the subject has a blood Phe concentration greater than about 600 μM prior to administration of a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure. In other embodiments, the subject's blood Phe concentration prior to administration is greater than about 700 μM. In further embodiments, the subject's blood Phe concentration prior to administration is greater than about 800 μM. In still further embodiments, the subject's blood Phe concentration prior to administration is greater than about 900 μM. In still other embodiments, the subject's blood Phe concentration prior to administration is greater than about 1000 μM. In further embodiments, the subject's blood Phe concentration prior to administration is greater than about 1100 μM, hi other embodiments, the subject's blood Phe concentration prior to administration is greater than about 1200 μM.

[0178] The methods of the present invention also include administering an additional therapeutic agent to a subject in addition to a compound of the present disclosure. In some embodiments, the additional therapeutic agent is selected from drugs known to be useful in stabilizing mutant PAH proteins and / or reducing blood Phe levels. The additional therapeutic agent is different from the compound of the present disclosure. In some embodiments, the additional therapeutic agent is sapropterin or sepiapterin. In other embodiments, the additional therapeutic agent is a nutritional supplement. Nutritional supplements that can be used include those containing amino acids and other nutrients. In a further embodiment, the nutritional supplement contains large neutral amino acids such as leucine, tyrosine, tryptophan, methionine, histidine, isoleucine, valine, and threonine. In another embodiment, the nutritional supplement contains tyrosine. In a further embodiment, the nutritional supplement contains casein glycomacropeptide, i.e., a milk peptide that does not naturally contain Phe in its pure form. In another embodiment, the additional therapeutic agent is an enzyme substrate or enzyme cofactor. In yet another embodiment, the enzyme substrate or cofactor is tetrahydrobiopterin. In other embodiments, the additional therapeutic agent is a biopterin analog. In further embodiments, the additional therapeutic agent is a biologic, synthetic biology, microbiota, or probiotic. In yet other embodiments, the biologic, synthetic biology, microbiota, or probiotic comprises a genetically modified phenylalanine ammonia-lyase (PAL) gene, such as, for example, E. coli Nissle PAL. Examples of genetically modified E. coli Nissle PAL biologics include SYNB1934 and SYNB1618. In yet further embodiments, the additional therapeutic agent is an inhibitor of an amino acid transporter. In some embodiments, the amino acid transporter is B 0 AT1 (also known as SLC6A19), and the additional therapeutic agent is an SLC6A19 inhibitor. Examples of SLC6A19 inhibitors include nimezuride, benztropine, NSC63912, NSC22789, cinromide, CB3, E62, and JNT-517.

[0179] The compound of the present disclosure and the additional therapeutic agent may be administered simultaneously or sequentially to achieve the desired effect. Further, the compound of the present disclosure and the additional therapeutic agent may be administered in a single composition or in two separate compositions.

[0180] The additional therapeutic agent is administered in an amount that provides its desired therapeutic effect. Effective dosage ranges for each additional therapeutic agent are known in the art, and the additional therapeutic agent is administered to an individual in need thereof within such established ranges.

[0181] The compound of the present disclosure and the additional therapeutic agent can be administered as a single unit dose or as separate multi-unit doses, with the compound of the present disclosure being administered before the additional therapeutic agent, or vice versa. One or more doses of the compound of the present disclosure and / or one or more doses of the additional therapeutic agent can be administered.

[0182] The compounds of the present disclosure may also be administered sequentially or simultaneously with non-pharmacological techniques. In some embodiments, the patient uses non-pharmacological techniques to maintain lower Phe levels. In other embodiments, the non-pharmacological technique is administering a diet low in Phe. One of skill in the art would be able to determine the type of diet that will maintain an appropriate level of Phe. In some embodiments, a phenylamine intake of about 200 to about 500 mg / day of Phe (for patients under 10 years of age) or less than about 600 mg / day (for patients over 10 years of age). In other embodiments, the diet may include limiting or eliminating one or more foods high in Phe, such as soy, egg whites, shrimp, chicken breast, spirulina, watercress, fish, nuts, crayfish, lobster, tuna, turkey, beans, and low-fat cottage cheese.

[0183] An example of a dosage range is about 0.001 to about 100 mg of compound per kg of subject body weight per day, in single or divided dose units (e.g., BID, TID, QID). For a 70 kg human, a suitable dosage is about 0.05 to about 7 g / day.

[0184] In some embodiments, a therapeutically effective amount of one or more compounds described herein is an amount that is effective to stabilize a mutant PAH protein described herein. In other embodiments, a therapeutically effective amount of one or more compounds described herein is an amount that is effective to reduce blood phenylalanine levels.

[0185] Unless otherwise specified, amounts of compounds described herein are provided on a free base basis, i.e., the amount indicates the amount of compound administered excluding, for example, solvent or counterion (such as a pharmaceutically acceptable salt).

[0186] Pharmaceutical Composition The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier and / or excipient.

[0187] The method of the present disclosure can be achieved by administering the compound of the present disclosure as a raw compound or as a pharmaceutical composition. The administration of the pharmaceutical composition of the present disclosure or the raw compound can be carried out at any time determined by the attending physician. Typically, the pharmaceutical composition does not contain toxic, carcinogenic, or mutagenic compounds that would cause adverse reactions when administered.

[0188] Pharmaceutical compositions include those in which the compounds of the present disclosure are administered in an effective amount to achieve its intended purpose, with the exact formulation, route of administration, and dosage being determined by the individual physician.

[0189] The compounds of the present disclosure can be administered by any suitable route, for example, orally, bucally, by inhalation, sublingually, rectally, vaginally, intracisternally or intrathecally via lumbar puncture, transurethrally, intranasally, transdermally, i.e., transdermally, or parenterally (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at a specific site). Parenteral administration can be accomplished using a needle and syringe or using high pressure techniques.

[0190] The additional therapeutically active agents described above, one or more of which may be used in combination with the compounds of the present disclosure, are prepared and administered as described in the art.

[0191] The compounds of the present disclosure may be administered in admixture with a pharmaceutical carrier 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 conventional manner using one or more physiologically acceptable carriers containing excipients and / or adjuvants that facilitate processing of the compounds of the present disclosure.

[0192] The administration of the compounds or pharmaceutical compositions of the present disclosure can be achieved by any method that allows the compound to be delivered to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or delivery by inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0193] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the pharmacokinetics of the compound, and the discretion of the prescribing physician. The desired dose can be administered as a single dose or as multiple doses administered at appropriate intervals, e.g., once, twice, three times, four or more times daily in subdoses. 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 about 0.01 to 2000 mg of a compound disclosed herein per day are exemplary dosage forms that may be used. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician. In some cases, dosage levels below the lower limit of the aforementioned range may be more than appropriate, while in other cases, even larger doses may be employed without causing any adverse side effects, for example, by dividing such a larger dose into several smaller doses for administration throughout the day.

[0194] In some embodiments, the compounds of the present disclosure are administered in a single dose.

[0195] Typically, such administration is by solid oral dosage form such as a tablet or capsule. However, other routes may be used if desired. A single dose of the compound may also be used to treat acute conditions.

[0196] In some embodiments, the compounds of the present disclosure may be administered in multiple doses. Administration may be once, twice, three times, four times, five times, six times, or more than six times daily. In another embodiment, the compounds described herein and another therapeutic agent are administered from about once per day to about six times per day. Administration of the compounds disclosed herein may be continued as needed. In some embodiments, the compounds are administered chronically, for example, to treat chronic effects.

[0197] An effective amount of a compound of the present disclosure may be administered by any of the accepted modes of administration for therapeutic agents having similar utilities, including rectal, buccal, intranasal, and transdermal routes, either in single or multiple doses, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0198] The pharmaceutical composition may be in a form suitable for oral administration, for example, as a tablet, capsule, pill, powder, sustained-release formulation, solution, or suspension; parenteral injection as a sterile solution; topical administration as a suspension or emulsion, ointment, or cream; or rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition will contain one or more conventional pharmaceutical carriers or excipients and a compound disclosed herein as an active ingredient. In addition, it may contain other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0199] Exemplary parenteral dosage forms include solutions or suspensions of compounds of the present disclosure in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[0200] Pharmaceutical composition for oral administration In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising a compound of the present disclosure and a pharmaceutical excipient suitable for oral administration.

[0201] In some embodiments, the present disclosure provides a solid pharmaceutical composition for oral administration comprising (i) an effective amount of a compound of the present disclosure, optionally (ii) an effective amount of a second therapeutic agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises (iv) an effective amount of a third therapeutic agent.

[0202] In some embodiments, the pharmaceutical composition may be suitable for oral ingestion. Pharmaceutical compositions containing the compounds of the present disclosure suitable for oral administration may be presented as individual dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or in granules, granules in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, a solution, or a suspension. Such dosage forms may be prepared by any method of pharmacy, but all methods include the step of bringing the compounds of the present disclosure into association with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately mixing the compounds of the present disclosure with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with excipients, including but not limited to binders, lubricants, inert diluents, and / or surface-active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0203] The present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can accelerate the degradation of some compounds. For example, water may be added (e.g., 5%) in pharmaceutical arts as a means of simulating long-term storage to determine properties such as shelf life or the stability of a formulation over time. Anhydrous pharmaceutical compositions and dosage forms containing compounds of the present disclosure may be prepared using anhydrous or low-moisture containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms containing compounds of the present disclosure that contain lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, such that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0204] The compounds of the present disclosure can be combined in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms, depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, for example, for oral liquid preparations (suspensions, solutions, and elixirs) or aerosols, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used as carriers; or, in some embodiments, for oral solid preparations, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used, although lactose is not used. For example, suitable carriers include powders, capsules, and tablets containing solid oral preparations. If necessary, tablets can be coated by standard aqueous or non-aqueous techniques.

[0205] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0206] 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, pregelatinized starch, and mixtures thereof.

[0207] Disintegrants can be used in the compositions of the present disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Excessive disintegrant can produce tablets that may disintegrate in the bottle. Too little can be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant, but not too little to adversely alter the release of the active ingredient, can be used to form a dosage form of the compounds disclosed herein. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0208] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present 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 oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added in an amount of less than about 2 weight percent of the pharmaceutical composition.

[0209] 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 substances or dyes, and, if desired, emulsifying and / or suspending agents, along with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0210] Tablets may be uncoated or may be coated with known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Oral preparations may also be hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules, in which the active ingredient is mixed with an aqueous medium or an oily medium such as peanut oil, liquid paraffin, or olive oil.

[0211] Surfactants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0212] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values ​​are more lipophilic or hydrophobic and more soluble in oil, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions.

[0213] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, and 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 of about 10 or less. However, the HLB value of a surfactant is merely a rough guide that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0214] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactate, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0215] Within the above group, examples of ionic surfactants include lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl cylate salts, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0216] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactate, stearoyl lactate, stearoyl hydroxybenzo ... The ionized forms may be cucinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristic acid, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0217] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid 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 polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylene sterols, derivatives, and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters and hydrophilic esterification products of polyols comprising at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0218] Other hydrophilic nonionic surfactants include, but are not limited to, 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 / Caprylic Glyceride, PEG-8 Caprate / Caprylic Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Plant Sterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, PO Examples of suitable sucrose monoesters include E-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, polyglyceryl-10-oleate, Tween® 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0219] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, low-alcohol fatty acid 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, mono- and diglyceride lactic acid derivatives, glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and the hydrophobic transesterification product of polyols with at least one member of the group consisting of sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0220] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the disclosed compound and minimize precipitation of the disclosed compound. This may be important for compositions for parenteral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0221] Examples of suitable solubilizing agents include, but are not limited to, alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transacetol, dimethyl isosorbide, polyethylene glycol (PEG), polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000 such as tetrahydrofuryl alcohol PEG ether (glycofuryl) or methoxy PEG, polyethylene glycol 660 amides and other nitrogen-containing compounds such as 12-hydroxystearate, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0222] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, glycofurol, transcatechol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG having an average molecular weight of about 100 to about 8000 g / mol, glycofurol, and propylene glycol.

[0223] 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 can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize drug concentration, it may be advantageous to include an amount of solubilizer that is much greater than the bioacceptable amount, and the excess solubilizer is removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. Thus, when present, the solubilizer may be present in a weight ratio of less than about 10% by weight, less than about 25% by weight, less than about 50% by weight, less than about 100% by weight, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If necessary, very small amounts of solubilizer, such as less than about 5%, less than about 2%, less than about 1%, or even less, may also be used. Typically, the solubilizer may be present in an amount of about 1% to less than about 100% by weight, more typically about 5% to less than about 25% by weight.

[0224] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, without limitation, detackifying agents, antifoaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscosity adjusting agents, tonicity agents, flavoring agents, coloring agents, odorants, emulsifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0225] Injectable pharmaceutical composition In some embodiments, the present disclosure provides an injectable pharmaceutical composition comprising a compound described herein and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the agents in the composition are as described herein.

[0226] Forms in which the compositions of the present disclosure may be incorporated for administration by injection include aqueous or oily suspensions or emulsions. Such compositions may include elixirs containing sesame oil, corn oil, cottonseed oil, peanut oil, mannitol or dextrose, sterile water, and similar pharmaceutical vehicles.

[0227] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0228] Sterile injectable solution is prepared by incorporating the compound of the present disclosure in the amount required in suitable solvent with various other components as listed above, if necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle, which comprises basic dispersion medium and other necessary components from the above-listed list.For the sterile powder used to prepare sterile injectable solution, some desired preparation methods are vacuum drying and freeze-drying technology, which obtains the powder of active ingredient plus any additional desired components from the solution that has been previously sterilized and filtered.

[0229] Other pharmaceutical compositions Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for topical, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, 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 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 herein by reference in their entireties.

[0230] Synthesis of Compounds of the Present Disclosure The compounds of the present disclosure can be prepared by the methods illustrated in the general schemes, procedures, and examples described herein, and by related methods known in the art. For example, compounds of Formula I can be prepared by the general methods shown in general Schemes 1-11.

[0231] General Scheme 1: Preparation of Compounds of Formula I [ka]

[0232] Compounds of Formula I were obtained through the reactions illustrated in General Scheme 1. An amine of Formula 1.1 or 1.2 and an aldehyde of Formula 1.3 were first reacted under Pictet-Spengler reaction conditions to give the core amine of Formula 1.4. To the extent that an imine by-product is formed during the Pictet-Spengler reaction, the imine by-product can be converted to the core amine of Formula 1.4 by reaction with sodium borohydride in an alcohol solvent (e.g., methanol or ethanol). Various L and R groups can then be added to give the core amine of Formula 1.4. 2 The group was introduced by using either a nucleophilic substitution reaction (Method A1), a Buchwald or other similar cross-coupling reaction (Method A2), a reductive animation reaction (Method B), or an amide coupling reaction (Methods C, D, E, and F). In Method A1, R 2 An aryl or heteroaryl halide (where X is Br, Cl, or F) is coupled with the core amine of formula 1.4 using a nucleophilic substitution reaction under basic conditions such as DIPEA to give compounds of formula 1.6. 2 An aryl or heteroaryl halide (where X is Br, Cl, or I) is coupled with the core amine of formula 1.4 using art-known Buchwald coupling or cross-coupling conditions, such as using a palladium catalyst (e.g., CPhos-Pd-G3, Pd(OAc)2, Pd(dppf)Cl2) and a base such as Cs2CO3, to provide compounds of formula 1.6. In Method B, R 2 An aryl or heteroaryl aldehyde is coupled with a core amine of formula 1.4 under reductive animation reaction conditions using a hydride such as sodium triacetoxyborohydride to give compounds of formula 1.8. 2A carboxylic acid or its basic salt (i.e., Li, K, or Na) is coupled with the core amine of formula 1.4 using acid coupling conditions known in the art, such as using one of the following reagents—HOBt, EDCI, HATU, T3P—with a base such as DIPEA (Hunig's base), pyridine, or TEA, to provide a compound of formula 1.11, where L 2 is a bond, optionally substituted C 1-6 Alkylene, optionally substituted C 2-6 Alkenylene or optionally substituted C 1-6 Alternatively, in Method D, R in Formula 1.10 is 2 The acid chloride is coupled with the core amine of formula 1.4 under basic conditions to give compounds of formula 1.11, where L 2 is a bond, optionally C 1-6 Alkylene, optionally substituted C 2-6 Alkenylene or optionally substituted C 1-6 In Method E, R in Formula 1.12 is 2 The acid chloride is coupled with the core amine of formula 1.4 under basic conditions to give compounds of formula 1.14, where L 3 is a bond or an optionally substituted C 1-6 In Method F, R in Formula 1.13 is 2 The amine is coupled with the core amine of formula 1.4 and carbonyldiimidazole under basic conditions to give compounds of formula 1.14, where L 3 is a bond or an optionally substituted C 1-6 It is alkylene.

[0233] General Scheme 2: Preparation of deuterated core amine intermediates of formula 2.2 [ka]

[0234] R 5Compounds of Formula I, where is D, are prepared according to General Scheme 2. An amine of Formula 1.1 or 1.2 and an aldehyde of Formula 1.3 are reacted under Pictet-Spengler reaction conditions to give a compound of Formula 2.1 or a mixture of compounds of Formula 2.1 and an imine by-product of Formula 2.1a. The compound of Formula 2.1 or a mixture of compounds of Formula 2.1 and 2.1a is then reacted with sodium borohydride in deuterated methanol to give the deuterated core amine of Formula 2.2. The deuterated core amine intermediate of Formula 2.2 can then be further purified via methods A, B, C, D, E, and F described in General Scheme 1 to afford various L and R groups. 2 can be further attached to a group to provide a compound of formula I, wherein R 5 is D.

[0235] General Scheme 3: Oxazolyl R 2 Preparation of the acid intermediate [ka]

[0236] R 6 and / or R 7 Oxazolyl R containing substitution at position 2Carboxylic acid intermediates were prepared according to general Scheme 3. Carboxylic acids of formula 3.1 were reacted with oxalyl chloride and catalytic N,N-dimethylformamide to give acid chlorides of formula 3.2. The acid chlorides of formula 3.2 were then reacted with enamines of formula 3.3 to give enamides of formula 3.4. The enamides of formula 3.4 then underwent divalent iodine-mediated cyclization after reaction with [bis(trifluoroacetoxy)iodo]benzene and boron trifluoride diethyl etherate to give oxazoles of formula 3.5. Hydrolysis of esters of oxazole formula 3.5 using a base such as LiOH, KOH, or NaOH in THF / water gave compounds of formula 3.6. Alternatively, basic salts (i.e., Li, K, or Na) of carboxylic acids of formula 3.6 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acid or its base salt can then be used without further purification in the coupling reaction illustrated in General Scheme 1, Method C.

[0237] General Scheme 4: Oxazolyl R 2 Preparation of the acid intermediate [ka]

[0238] R 6 and / or R 7 Oxazolyl R containing substitution at position 2 Carboxylic acid intermediates were prepared according to general Scheme 4. β-ketoesters of formula 4.1 were halogenated with a chlorinating agent such as SOCl or a brominating agent such as NBS to give compounds of formula 4.2, where X 1is Br or Cl). Reaction of compounds of formula 4.2 with urea gave amine oxazole compounds of formula 4.3. Additionally, reaction of compounds of formula 4.2 with amides of formula 4.5 gave oxazole compounds of formula 4.6. Subjecting the amine in compounds of formula 4.3 to Sandmeyer reaction conditions gave compounds of formula 4.4 (where X is Cl, Br, or F) and compounds of formula 4.10. Alternatively, compounds of formula 4.10 can be obtained by deprotonating compounds of formula 4.8 with a base such as LiHMDS, followed by reaction in a nucleophilic substitution reaction with a reagent of formula 4.9 (where Y is a suitable leaving group such as Br, Cl, mesylate, or tosylate) to give compounds of formula 4.10. Hydrolysis of the esters of compounds of formulas 4.6 and 4.10 with a base such as LiOH, KOH, or NaOH in THF / water gives compounds of formulas 4.7 and 4.11. Alternatively, the base salts (i.e., Li, K, or Na) of the carboxylic acids of formulas 4.7 and 4.11 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acid or its base salt can then be used without further purification in the coupling reaction described in General Scheme 1, Method C.

[0239] General Scheme 5: Thiadiazolyl and Oxazolyl R 2 Synthesis of acid intermediates [ka]

[0240] R 6 and / or R 7 Oxazolyl and thiazolyl R containing substitution at position 2Carboxylic acid intermediates were prepared according to general Scheme 5. In Method A, halides of formula 5.1 were reacted with heteroaryl or aryl compounds of formula 5.2 in either a Suzuki coupling (Y is a boronic acid or ester) or a Stille coupling (Y is SnR) to give compounds of formula 5.3. In Method B, compounds of formula 5.3 were obtained by reacting compounds of formula 5.4 with heteroaryl or aryl halide compounds of formula 5.5 in a cross-coupling reaction using a metal catalyst such as the Buchwald or Ullmann catalyst. In Method C, halides of formula 5.1 can also be reacted with amines of formula 5.7 or heterocyclic amines such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine, and bases such as TEA in a substitution reaction to give compounds of formula 5.8. Hydrolysis of the esters of compounds of formula 5.3 and 5.8 using a base such as LiOH, KOH, or NaOH in THF / water provides compounds of formula 5.6 and 5.9. Alternatively, the base salts (i.e., Li, K, or Na) of the carboxylic acids of formula 5.6 and 5.9 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acids or their base salts can then be used without further purification in the coupling reactions described in General Scheme 1, Method C.

[0241] General Scheme 6: Thiadiazolyl and Oxazolyl R 2 Synthesis of acid intermediates [ka]

[0242] Oxazolyl and thiazolyl R containing hydroxyalkyl and haloalkyl substitution 2Carboxylic acid intermediates were prepared according to general Scheme 6. In Method A, a halide of formula 6.1 was reacted with tributyl(1-ethoxyvinyl)stannane in a Stille coupling, followed by hydrolysis with an acid / water such as TFA, to give compounds of formula 6.3. An alkyl group ("R") was then added to the ketone in compounds of formula 6.3 using RMgBr or RLi or through reduction of the ketone with NaBR to give compounds of formula 6.4. In Method B, compounds of formula 6.4 can also be obtained starting from compounds of formula 6.1 through a Grignard addition reaction with a ketone of formula 6.2 (where R is alkyl) or cyclobutanone and a RMgCl such as iPrMgCl. The hydroxyl substituent in compounds of formula 6.4 was converted to a fluorine substituent using a fluorinating agent such as BAST to give compounds of formula 6.6. Hydrolysis of the esters of compounds of formula 6.4 and 6.6 with a base such as LiOH, KOH, or NaOH in THF / water provides compounds of formula 6.5 and 6.7. Alternatively, the basic salts (i.e., Li, K, or Na) of the carboxylic acids of formula 6.5 and 6.7 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acids or their basic salts can then be used without further purification in the coupling reactions described in General Scheme 1, Method C.

[0243] General Scheme 7: Pyrazolo[1,5-a]pyridinyl R 2 Synthesis of acid intermediates [ka]

[0244] Substituted pyrazolo[1,5-a]pyridinyl R 2 Carboxylic acid intermediates were prepared according to general Scheme 7. In Method A, halides of formula 7.1 (wherein X 1is Br or Cl) is reacted with amines of formula 7.2 or heterocyclic amines such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine in a C-N cross-coupling reaction using a metal catalyst such as Buchwald's or Ullmann's catalyst to give compounds of formula 7.3. 1 where X is Br or Cl) can also be reacted with heteroaryls or aryls of formula 7.5 in either Suzuki couplings (where Y is a boronic acid or ester) or Stille couplings (where Y is SnR3) to give compounds of formula 7.6. In Method C, halides of formula 7.1 (where X is Br or Cl) can be reacted with heteroaryls or aryls of formula 7.5 in either Suzuki couplings (where Y is a boronic acid or ester) or Stille couplings (where Y is SnR3) to give compounds of formula 7.6. 1 where X is Cl, Br, or Cl) was reacted with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane in a Suzuki coupling to give compounds of formula 7.8. The olefin in compounds of formula 7.8 then underwent oxidative cleavage to give compounds of formula 7.9. In Method D, the aldehyde in compounds of formula 7.9 was reduced to an alcohol with a hydride such as NaBH4 in an alcoholic solvent such as methanol or ethanol to give compounds of formula 7.13. The alcohol in compounds of formula 7.13 was alkylated with sodium hydride and an alkyl halide ("R") of formula 7.14 (where X is Cl, Br, or F) to give compounds of formula 7.15. In Method E, compounds of formula 7.9 were reacted with amines of formula 7.10 under reductive animation conditions to give compounds of formula 7.11. Hydrolysis of the esters of compounds of formulas 7.3, 7.6, 7.11, and 7.15 with a base such as LiOH, KOH, or NaOH in THF / water provides compounds of formulas 7.4, 7.7, 7.12, and 7.16. Alternatively, the base salts (i.e., Li, K, or Na) of the carboxylic acids of formulas 7.4, 7.7, 7.12, and 7.16 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acids or their base salts can then be used without further purification in the coupling reactions described in General Scheme 1, Method C.

[0245] General Scheme 8: Pyrazolo[1,5-a]pyridinyl R 2 Synthesis of acid intermediates [ka]

[0246] Disubstituted pyrazolo[1,5-a]pyridinyl R 2 Carboxylic acid intermediates were prepared according to general Scheme 8. The starting reagent 3-bromo-4-chloropyridine was reacted with ethyl (E)-N-((mesitylsulfonyl)oxy)acetimidate to give the N-aminopyridinium salt 8.1. Cycloaddition of the N-aminopyridinium salt 8.1 with ethyl propiolate and a base such as KCO gave ethyl 6-bromo-5-chloropyrazolo[1,5-a]pyridine-3-carboxylate 8.2. Compound 8.2 was reacted in a C-N cross-coupling reaction with an amine of formula 8.4 or a heterocyclic amine such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine using a metal catalyst such as the Buchwald or Ullmann catalyst to give compounds of formula 8.5. Hydrolysis of the esters of compounds of formula 8.2 and 8.5 using a base such as LiOH, KOH, or NaOH in THF / water gave compounds of formula 8.3 and 8.6. Alternatively, the basic salts (i.e., Li, K, or Na) of the carboxylic acids of formulas 8.3 and 8.6 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acid or its basic salt can then be used without further purification in the coupling reaction described in General Scheme 1, Method C.

[0247] General Scheme 9: 1,3,4-Oxadiazolyl R 2 Synthesis of acid intermediates [ka]

[0248] Heteroaryl and aryl substituted oxadiazolyl R 2Carboxylic acid intermediates were prepared according to general Scheme 9. In Method A, heteroaryl and aryl esters of formula 9.1 were reacted with hydrazine hydrate to give hydrazines of formula 9.2. Compounds of formula 9.2 were then reacted with ethyl 2-chloro-2-oxoacetate to give compounds of formula 9.3, followed by intramolecular cyclization with p-toluenesulfonyl chloride and a base such as TEA to give 1,3,4-oxadiazoles of formula 9.4. Alternatively, compounds of formula 9.4 can be made using Method B. In Method B, 2-hydrazinyl-2-oxoethyl acetate was reacted with 1,1'-thiocarbonyldiimidazole to form the 1,3,4-oxadiazole, which was then alkylated with methyl iodide and a base such as TEA to give ethyl 5-(methylthio)-1,3,4-oxadiazole-2-carboxylate. Ethyl 5-(methylthio)-1,3,4-oxadiazole-2-carboxylate reacts with heteroaryl or arylboronic acids or esters of formula 9.5 in a desulfuric C-C cross-coupling reaction (also known as Liebekind-Slogl cross-coupling) to give compounds of formula 9.4. Hydrolysis of the ester of compounds of formula 9.4 using a base such as LiOH, KOH, or NaOH in THF / water gives compounds of formula 9.6. Alternatively, a basic salt (i.e., Li, K, or Na) of the carboxylic acid of formula 9.6 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acid or its basic salt can then be used without further purification in the coupling reactions described in General Scheme 1, Method C.

[0249] General Scheme 10: 1,3,4-Oxadiazolyl R 2 Synthesis of acid intermediates [ka]

[0250] Substituted 1,3,4-oxadiazolyl R 2Carboxylic acid intermediates were prepared according to general Scheme 10. The starting reagent, ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate, was subjected to Sandmeyer reaction conditions to give ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (compound 10.1). Reaction of the bromo in compound 10.1 with an amine of formula 10.2 or a heterocyclic amine such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine, and a base such as TEA, gave compounds of formula 10.3. Hydrolysis of the ester of compound 10.3 using a base such as LiOH, KOH, or NaOH in THF / water gave compounds of formula 10.4. Alternatively, the basic salt (i.e., Li, K, or Na) of the carboxylic acid of formula 10.4 can be obtained after the hydrolysis reaction by isolating the product at basic pH. The carboxylic acid or its base salt can then be used without further purification in the coupling reaction illustrated in General Scheme 1, Method C.

[0251] General Scheme 11: Preparation of deuterated core amine intermediates of formulas 11.6 and 11.7 [ka]

[0252] R 5A Compounds of Formula I, where R is D, are prepared according to General Scheme 11. Amines of Formula 2.1, prepared according to General Scheme 2, are protected with the BOC protecting group or other suitable nitrogen protecting group to give compounds of Formula 11.1. The amines of Formula 11.1 are then protected with the dimethylsulfamoyl protecting group to give a mixture of compounds of Formulas 11.2 and 11.3, which are separated during purification. Deuterium is then transferred to R by deprotonating the compound of Formula 11.2 with butyllithium, followed by the addition of DO to give compounds of Formulas 11.4 and 11.5. 5A Deprotection of the nitrogen protecting group with acid afforded the deuterated core amine intermediate of formula 11.6. The deuterated core amine intermediate of formula 11.6 was then converted to various L and R groups via methods A, B, C, D, E, and F as illustrated in General Scheme 1.2 can be further attached to a group to provide a compound of formula I, wherein R 5A is D.

[0253] The present disclosure will be more fully understood by reference to the following examples. The examples provided herein are illustrative but should not be construed as limiting the scope of the disclosure. [Example]

[0254] In some embodiments, the present disclosure provides specific examples of compounds of Formula I, and pharmaceutically acceptable salts and / or isotopologues thereof, as set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

Table 1-133

Table 1-136

Table 1-137

Table 1-138

Table 1-139

Table 1-141

Table 1-145

Table 1-147

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-161

Table 1-166

Table 1-171

Table 1-176

Table 1-177

Table 1-178

Table 1-179

Table 1-186

Table 1-191

Table 1-193

Table 1-196

Table 1-197

Table 1-199

Table 1-200

Table 1-201

Table 1-202

Table 1-203

Table 1-205

Table 1-207

Table 1-209

Table 1-211

Table 1-212

Table 1-213

[0255] In further embodiments, the compound of Formula I is one or more of the compounds of Table 1 that are S-enantiomers, or a pharmaceutically acceptable salt thereof.

[0256] In still further embodiments, the compound of Formula I is selected from the group consisting of Examples 605, 626, 640, 670, 688, 708, 710, 726, 728, 733, 748, 760, 762, 764, 791, 836, 840, 906, 922, 938, 942, 944, 946, 948, 950, 952, 954, 957, 958, 960, 962, 964, 966, 969, 971, 972, 975, 976, 979, 980, 982, 984, 988, 1381, 1438, 1461, 1506, 1531, 1548, 1589, 1607, 1613, 1628, 1652, 1657, 1728, 1737, 1757, 1807, 1809, 1823, 1843, 1849, 1850, 1943, 1953, 1986, 2218, 2221, and 2223, or a pharmaceutically acceptable salt thereof. In still other embodiments, the compound of Formula I is selected from the group consisting of Examples 640, 670, 688, 708, 710, 726, 728, 733, 748, 760, 762, 764, 836, 840, 906, 922, 938, 942, 944, 946, 948, 950, 952, 954, 957, 960, 962, 969, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 103 72, 975, 976, 979, 980, 984, 988, 1438, 1461, 1506, 1548, 1628, 1652, 1657, 1728, 1737, 1757, 1809, 1849, 1850, 1953, 1986, 2218, and 2221, or a pharmaceutically acceptable salt thereof. In still other embodiments, the compound of Formula I is one or more of Examples 640, 670, 688, 708, 710, 726, 728, 733, 748, 760, 762, 764, 836, 840, 906, 922, 938, 942, 944, 946, 948, 950, 952, 954, 957, 960, 962, 969, 971, 972, 975, 976, 979, 980, 984, 988, 1438, 1461, 1506, 1548, 1628, 1652, 1657, 1728, 1986, and 2218, or a pharmaceutically acceptable salt thereof.

[0257] List of Abbreviations and Terms: [Table A]

[0258] Solvents and Reagents: [Table B-1] [Table B-2] [Table B-3]

[0259] General Experiment

[0260] In the following examples, reagents and solvents were purchased from commercial sources (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, etc.) and used without further purification unless otherwise indicated. Flash chromatography was performed on a CombiFlash® Rf 150 (ISCO) column with 200-300 mesh silica gel particles. HPLC was performed on an Agilent 1100 Liquid Chromatography column (Agilent, USA) and a Shimadzu LC20 / 20A column (Shimadzu, Japan). Supercritical fluid chromatography was performed on a Waters Prep SFC 150 AP / 80Q / 200 / 350 system (Waters, USA). Analytical and preparative thin-layer chromatography plates (TLC) were HSGF 254 (0.15-0.2 mm thick, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AV-400 NMR or Bruker AVIII 500 MHz NMR (Bruker, Switzerland). Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were obtained with electrospray ionization (ESI) on a Waters LCT TOF mass spectrometer (Waters, USA). LC-MS was performed on an Agilent Prime-6125B / Agilent LC1260-MS6150 / Agilent LC1260-MS6125B / Agilent LC1200-MS6110 (Agilent, USA) and a Shimadzu LC20-MS2020.Microwave reactions were carried out on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).

[0261] Intermediate (1-(1H-imidazol-5-yl)cyclopropyl)methanamine hydrochloride [ka]

[0262] Step 1: Preparation of 2-(3-tritirimidazol-4-yl)acetonitrile (B2)

[0263] B2 was prepared starting from 2-(1H-imidazol-5-yl)acetonitrile (B1) according to literature procedures, see for example WO2008 / 003766 (page 19).

[0264] Step 2: Preparation of 1-(3-tritylimidazol-4-yl)cyclopropanecarbonitrile (B3)

[0265] To a solution of 2-(3-trityrimidazol-4-yl)acetonitrile (B2) (10 g, 28.6 mmol) in THF (200 mL) was added LDA (2 M, 42.9 mL, 3 equiv.) dropwise at −78 °C. After the addition was complete, the reaction mixture was stirred at −20 °C to −10 °C for 1 h. The reaction mixture was then cooled to −78 °C, and 1,2-dibromoethane (10.75 g, 57.2 mmol, 4.32 mL, 2 equiv.) was added dropwise at −78 °C. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for an additional 2 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. The reaction mixture was quenched with saturated NH4Cl solution (200 mL) and stirred at room temperature for 0.5 h. The aqueous portion was extracted with EtOAc (100 mL × 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue (combined with two other reactions carried out using 10 g of B2) was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® Silica Flash Column, eluent of 0-40% EtOAc / PE, gradient @ 40 mL / min) to give B3 (23.4 g, 72% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.30-7.52 (m, 10H), 7.09 (dd, 6H), 6.84 (d, 1H), 1.51-1.66 (m, 2H), 1.29-1.46 (m, 2H).

[0266] Step 3: Preparation of 1-(3-tritirimidazol-4-yl)cyclopropyl]methanamine (B4)

[0267] A mixture of 1-(3-trityrimidazol-4-yl)cyclopropanecarbonitrile (B3) (19 g, 50.6 mmol), Raney-Ni (4.60 g, 53.7 mmol, 1.06 equiv.), and NH3.HO (591 mg, 5.06 mmol, 650 μL, 30% purity, 0.1 equiv.) in MeOH (200 mL) was degassed and purged with H2 three times. The reaction mixture was then stirred at 45 °C under an atmosphere of H2 (45 psi) for 16 h. The progress of the reaction was monitored using TLC (DCM:MeOH = 10:1). The reaction mixture was filtered, and additional Raney-Ni (4.60 g, 53.7 mmol, 1.06 equiv.) was added. The reaction mixture was stirred at 45 °C under an atmosphere of H2 (45 psi) for an additional 24 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to give B4 (18 g), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 7.33-7.44(m,9H),7.18-7.25(m,1H),7.04-7.13(m,6H),6.64-6.71(m,1H),3.17(br s, 2H), 2.58-2.74 (m, 2H), 0.60-0.82 (m, 4H).

[0268] Step 4: Preparation of [1-(1H-imidazol-5-yl)cyclopropyl]methanamine hydrochloride (B5)

[0269] To a solution of [1-(3-trityrimidazol-4-yl)cyclopropyl]methanamine (B4) (18 g, 47.4 mmol) in MeOH (100 mL) was added HCl / MeOH (4 M, 100 mL, 8.4 equiv.). The reaction mixture was stirred at 60° C. for 16 h. LC-MS was used to follow the progress of the reaction. The reaction mixture was concentrated to dryness, and the residue was triturated with EtOAc (40 mL) and stirred for 15 min. The precipitate was collected by filtration and then dried in vacuo to give B5 (8.5 g, diHCl salt). 1H NMR (400MHz, DMSO-d6) δ 14.73 (br s, 1H), 9.04 (s, 1H), 8.27 (br s, 2H), 7.51 (s, 1H), 2.98-3.22 (m, 2H), 0.90-1.23 (m, 4H).

[0270] Intermediate 2-(1H-imidazol-5-yl)-2-methylpropan-1-amine hydrochloride [ka]

[0271] Step 1: Preparation of (2-methyl-2-(3-tritirimidazol-4-yl)propanenitrile (B6)

[0272] To a solution of 2-(3-tritirimidazol-4-yl)acetonitrile (B2) (12 g, 34.3 mmol) in THF (400 mL) was added LiHMDS (1 M, 96.2 mL, 2.8 equiv.) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 15 minutes, and then MeI (14.62 g, 103 mmol, 6.41 mL, 3 equiv.) was added. The reaction mixture was stirred at −78° C. for 1 hour and then warmed to room temperature for 18 hours. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated NH4Cl solution (15 mL), followed by the addition of HO (60 mL). The aqueous portion was extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The residue (combined with the residue from another reaction carried out using 2 g of B2) was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® Silica Flash Column, eluent of 0-80% EtOAc / PE, gradient @ 60 mL / min) to give B6 (14 g, 92% yield). 1 H NMR (400MHz, CDCl3) δ 7.41(d,1H),7.32-7.39(m,9H),7.08-7.16(m,6H),6.81(d,1H),1.69(s,6H).

[0273] Step 2: Preparation of (2-methyl-2-(3-tritirimidazol-4-yl)propan-1-amine (B7)

[0274] To a solution of 2-methyl-2-(3-trityrimidazol-4-yl)propanenitrile (B6) (14 g, 37.1 mmol) in MeOH (350 mL) was added Raney-Ni (2 g, 23.3 mmol, 0.63 equiv.) under N. The reaction mixture was degassed under vacuum and purged with H several times. The reaction mixture was stirred under H (50 psi) at 40 °C for 36 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness to give B7 (12 g, 85% yield). 1 LCMS:m / z 382.2[M+H] + .

[0275] Step 3: Preparation of 2-(1H-imidazol-5-yl)-2-methyl-propan-1-amine (B8)

[0276] To a solution of 2-methyl-2-(3-trityrimidazol-4-yl)propan-1-amine (B7) (14 g, 36.7 mmol) in MeOH (150 mL) was added HCl / MeOH (4 M, 150 mL, 16.4 equiv.) and the reaction mixture was stirred at 50° C. for 18 h. TLC (EtOAc) was used to follow the reaction progress. The reaction mixture was concentrated to dryness and 200 mL of EtOAc was added. The mixture was stirred at 60° C. for 1 h. The precipitate was collected by filtration, rinsed with EtOAc, and then dried in vacuo to give B8 (7.0 g, 90% yield, diHCl salt). 1 H NMR (400MHz, CD3OD) δ 8.96 (s, 1H), 7.52 (s, 1H), 3.20-3.27 (m, 2H), 1.49 (s, 6H).

[0277] Intermediate 2-(1H-imidazol-5-yl)propan-1-amine hydrochloride [ka]

[0278] Step 1: Preparation of 2-(3-tritylimidazol-4-yl)propanenitrile (B9)

[0279] To a solution of 2-(3-trityrimidazol-4-yl)acetonitrile (B2) (15 g, 42.9 mmol) in THF (120 mL) was added LiHMDS (1 M, 51.5 mL, 1.2 equiv.) dropwise at −78° C. After the addition, the reaction mixture was stirred for 0.5 h, and then MeI (10.97 g, 77.3 mmol, 4.81 mL, 1.8 equiv.) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 2 h. TLC (PE: EtOAc = 2:1) was used to monitor the reaction progress. The reaction mixture was quenched by the addition of saturated NH4Cl solution (120 mL) and stirred for 15 min. The aqueous portion was extracted with EtOAc (400 mL), and the organic layer was washed with water (100 mL) and brine (60 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue (combined with the residue from another reaction carried out using 15 g of B2) was purified by column chromatography on silica gel (PE: EtOAc = 20: 1 to 2: 1) to give B9 (33.5 g, 75% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.38-7.45(m,10H),7.06-7.13(m,6H),6.82-6.92(m,1H),4.12-4.23(m,1H),1.48(d,3H).

[0280] Step 2: Preparation of 2-(3-tritirimidazol-4-yl)propan-1-amine (B10)

[0281] A mixture of 2-(3-tritirimidazol-4-yl)propanenitrile (B9) (16.5 g, 45.4 mmol), Raney-Ni (4.08 g, 47.7 mmol, 1.05 equiv.), and NH3.HO (910 mg, 7.79 mmol, 1 mL, 30% purity) in MeOH (300 mL) was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred at 45 °C under an atmosphere of H2 (45 psi) for 16 h. TLC (PE: EtOAc = 2:1) was used to monitor the reaction progress. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness to give B10 (33 g), which was used without further purification. 1 H NMR (400MHz, CD3OD) δ 7.36-7.44 (m, 10H), 7.13-7.20 (m, 6H), 6.72 (br s, 1H), 2.57-2.92 (m, 3H), 1.21 (br d, 3H).

[0282] Step 3: Preparation of 2-(1H-imidazol-5-yl)propan-1-amine (B11)

[0283] To a solution of 2-(3-tritirimidazol-4-yl)propan-1-amine (B10) (23 g, 62.6 mmol) in MeOH (100 mL) was added HCl / MeOH (4 M, 100 mL). The mixture was stirred at room temperature for 12 h. TLC (EtOAc) was used to follow the reaction progress. The reaction mixture (combined with the reaction mixture from another reaction carried out using 23 g of B10) was concentrated to dryness. HO (40 mL) was added to the residue, and the aqueous layer was washed with EtOAc (50 mL). The aqueous layer was lyophilized to give B11 (21 g, 2HCl). 1 H NMR (400MHz, CD3OD) δ 8.96(d,1H),7.56(s,1H),3.43-3.51(m,1H),3.17-3.32(m,2H),1.29-1.53(m,3H).

[0284] Intermediates 2-[(2R)-2-(1H-imidazol-5-yl)propyl]isoindoline-1,3-dione and 2-[(2S)-2-(1H-imidazol-5-yl)propyl]isoindoline-1,3-dione [ka]

[0285] Step 1: Preparation of 2-[2-(1H-imidazol-5-yl)propyl]isoindoline-1,3-dione (B13)

[0286] To a solution of 2-(1H-imidazol-5-yl)propan-1-amine (B11) (10 g, 50.5 mmol, 2HCl) and phthalic anhydride (7.85 g, 53.0 mmol, 1.05 equiv.) in i-PrOH (400 mL) was added EtN (15.32 g, 151 mmol, 21.1 mL, 3 equiv.). The reaction mixture was stirred at 100° C. under a N atmosphere for 18 h. After cooling, the reaction mixture was concentrated to dryness. Water (200 mL) was then added, and the mixture was stirred at room temperature for 10 min. The precipitate was collected by filtration, rinsed with water (100 mL), and dried in vacuo to give B13 (13 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 7.71-7.89(m,4H),7.49(s,1H),6.79(s,1H),3.70-3.76(m,1H),3.60-3.65(m,1H),3.15-3.23(m,1H),1.16(d,3H).

[0287] Step 2: SFC separation

[0288] The compound 2-[2-(1H-imidazol-5-yl)propyl]isoindoline-1,3-dione (13 g) was separated by SFC separation (column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm), mobile phase: [0.1% NH3HO ETOH], B%: 40%-40%, min) to give Enantiomer 1 (4.8 g, 37% yield, Rt = 3.953 min) and Enantiomer 2 (5.2 g, 40% yield, Rt = 4.652 min).

[0289] Enantiomer 1: 2-[(2R)-2-(1H-imidazol-5-yl)propyl]isoindoline-1,3-dione (B13A). 1 H NMR(400MHz,CD3OD)δ 7.73-7.89(m,4H),7.56(d,1H),6.82(s,1H),3.84-3.93(m,1H),3.70-3.82(m,1H),3.36-3.39(m,1H),1.31(d,3H);SFC:98.4%ee.

[0290] Enantiomer 2: 2-[(2S)-2-(1H-imidazol-5-yl)propyl]isoindoline-1,3-dione (B13B). 1 H NMR(400MHz,CD3OD)δ 7.77-7.88(m,4H),7.55(d,1H),6.82(s,1H),3.84-3.97(m,1H),3.72-3.82(m,1H),3.36-3.42(m,1H),1.31(d,3H);SFC:99.1%ee.

[0291] Intermediate pyrazolo[1,5-a]pyridine-2-carbaldehyde [ka]

[0292] Step 1: Preparation of N-methoxy-N-methyl-pyrazolo[1,5-a]pyridine-2-carboxamide (C2)

[0293] To a solution of pyrazolo[1,5-a]pyridine-2-carboxylic acid (C1) (12.5 g, 77.1 mmol) and N-methoxymethanamine (9.42 g, 96.6 mmol, 1.25 equiv., HCl) in DMF (200 mL) was added EDCI (22.17 g, 116 mmol, 1.5 equiv.), DIPEA (29.89 g, 231 mmol, 40.3 mL, 3 equiv.), and HOBt (15.63 g, 116 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored using TLC (PE: EtOAc = 1:1). The reaction mixture was combined with the reaction mixture from a separate reaction carried out using 12.5 g of C1 and concentrated to dryness. The residue was dissolved in DCM (200 mL), and the organic layer was washed with saturated Na2CO3 solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 to 1:1) to give the given C2 (30.5 g, 96% yield). 1 H NMR(400MHz, CDCl3)δ 8.47-8.54(m,1H),7.59(d,1H),7.16(ddd,1H),7.02(s,1H),6.86(td,1H),3.81(s,3H),3.51(s,3H).

[0294] Step 2: Preparation of pyrazolo[1,5-a]pyridine-2-carbaldehyde (C3)

[0295] To a solution of N-methoxy-N-methyl-pyrazolo[1,5-a]pyridine-2-carboxamide (C2) (15 g, 73.1 mmol) in THF (150 mL) was added DIBAL-H (1 M, 146.2 mL, 2 equiv.) dropwise under N2 at −78 °C, and the reaction mixture was then stirred under N2 at −78 °C for 2 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. The reaction mixture was combined with the reaction mixture from another reaction carried out using 15 g of C2 and quenched by the slow addition of saturated NH4Cl solution (200 mL) and stirred for 15 min. 1 M HCl solution was added until a clear solution was observed. The aqueous portion was extracted with EtOAc (250 mL × 3), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20: 1 to 1: 1) to give the given C3 (14.2 g). 1 H NMR (400MHz, DMSO-d6) δ 10.14 (s, 1H), 8.81 (dd, 1H), 7.84 (d, 1H), 7.34 (t, 1H), 7.10-7.15 (m, 2H).

[0296] The intermediate 3-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C3, starting from 3-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid.

[0297] The intermediate 3-bromopyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C3, starting from 3-bromopyrazolo[1,5-a]pyridine-2-carboxylic acid.

[0298] The intermediate 4-chloropyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C3, starting from 4-chloropyrazolo[1,5-a]pyridine-2-carboxylic acid.

[0299] The intermediate 6-bromopyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C3, starting from 6-bromopyrazolo[1,5-a]pyridine-2-carboxylic acid.

[0300] The intermediate 6-chloropyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C3, starting from 6-chloropyrazolo[1,5-a]pyridine-2-carboxylic acid.

[0301] The intermediate 7-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C3, starting from 7-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid.

[0302] Intermediate 4-Fluoropyrazolo[1,5-a]pyridine-2-carbaldehyde [ka]

[0303] Step 1: Preparation of 3-(3-fluoro-2-pyridyl)prop-2-yn-1yl acetate (C5)

[0304] A mixture of 2-bromo-3-fluoropyridine (C4) (30 g, 170 mmol), prop-2-yn-1yl acetate (23.41 g, 239 mmol, 1.4 equiv.), Pd(PPh3)2Cl2 (5.98 g, 8.52 mmol, 0.05 equiv.), CuI (1.62 g, 8.52 mmol, 0.05 equiv.), and TEA (51.75 g, 511 mmol, 71.2 mL, 3 equiv.) in dioxane (300 mL) was degassed and purged with N2 three times, and the reaction mixture was stirred under N2 atmosphere at 50 °C for 6 h. The reaction progress was monitored using TLC (PE: EtOAc = 5:1). The reaction mixture was concentrated to dryness. EtOAc (600 mL) was added to the residue, and the organic portion was washed with water (300 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® Silica Flash Column, eluent of 0-20% EtOAc / PE, gradient @ 120 mL / min) to give C5 (23.4 g, 71% yield). 1 H NMR (400MHz, CDCl3) δ 8.43 (d, 1H), 7.46 (td, 1H), 7.32 (dt, 1H), 4.99 (s, 2H), 2.16 (s, 3H).

[0305] Step 2: Preparation of 3-(3-fluoro-2-pyridyl)prop-2-yn-1-ol (C6)

[0306] To a solution of 3-(3-fluoro-2-pyridyl)prop-2-ynyl acetate (C5) (23.4 g, 121 mmol) in THF (300 mL) and HO (150 mL) was added LiOH. HO (5.34 g, 127 mmol, 1.05 equiv) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. TLC (PE: EtOAc = 1:1) was used to check the reaction progress. EtOAc (600 mL) was added to the reaction mixture, and the organic layer was washed with HO (400 mL) and brine (400 mL), dried over NaSO, filtered, and concentrated to dryness to give C6 (17.5 g), which was used without further purification. 1H NMR (400MHz, DMSO-d6) δ 8.34-8.53(m,1H),7.72-7.88(m,1H),7.50(dt,1H),5.54(t,1H),4.38(d,2H).

[0307] Step 3: Preparation of 1-amino-3-fluoro-2-(3-hydroxyprop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (C7)

[0308] To a mixture of HO (35 mL, 1.94 mol, 17.3 equiv) and TFA (308.0 g, 2.70 mol, 200 mL, 24.0 equiv), (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethaneimidate (33.70 g, 118 mmol, 1.05 equiv) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with ice water (40 mL). The precipitate was filtered and washed with water (20 mL × 2). The precipitate was then dissolved in DCM (200 mL), dried over NaSO, and filtered. To the filtrate was added 3-(3-fluoro-2-pyridyl)prop-2-yn-1-ol (C6) (17 g, 112 mmol, 1 equiv) at 0 °C. The reaction mixture was allowed to warm to room temperature for 16 h. The reaction progress was checked using TLC (PE: EtOAc = 1:1). TBME (400 mL) was slowly added to the reaction mixture, and the precipitate was collected by filtration. The precipitate was rinsed with TBME (200 mL × 2) to give C7 (26 g), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.66-8.88(m,3H),8.32(t,1H),8.01(dt,1H),6.75(s,2H),4.58(s,2H),3.17(s,1H),2.49(s,6H),2.17(s,3H).

[0309] Step 4: Preparation of (4-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol (C8)

[0310] To a solution of 1-amino-3-fluoro-2-(3-hydroxyprop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (C7) (26 g, 71.0 mmol) in MeOH (250 mL) was added NaOMe (5.4 M, 26.3 mL, 2 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (PE: EtOAc = 1:1). The reaction mixture was quenched by the addition of ice-cold HO (200 mL), concentrated to remove most of the MeOH, and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (400 mL), dried over NaSO, filtered, and concentrated to dryness to give C8 (7.5 g), which was used without further purification. 1 H NMR (400MHz, CDCl3) δ 8.27 (d, 1H), 6.62-6.88 (m, 3H), 4.94 (s, 2H).

[0311] Step 5: Preparation of 4-fluoropyrazolo[1,5-a]pyridine-2-carbaldehyde (C9)

[0312] To a solution of (4-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol (C8) (7.5 g, 45.1 mmol) in MeCN (150 mL) was added IBX (15.17 g, 54.2 mmol, 1.2 equiv). The reaction mixture was stirred at 80 °C for 3 h. The reaction progress was monitored using TLC (PE: EtOAc = 5:1). The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0-4% EtOAc / PE, gradient @ 40 mL / min) to give C9 (4 g, 54% yield). 1 H NMR (400MHz, CDCl3) δ 10.22 (s, 1H), 8.33-8.41 (m, 1H), 7.20 (d, 1H), 6.85-6.98 (m, 2H).

[0313] The intermediate 4-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-3-methylpyridine.

[0314] The intermediate 4-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-3-(trifluoromethyl)pyridine.

[0315] The intermediate 4-methoxypyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-3-methoxypyridine.

[0316] The intermediate 5-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-4-methylpyridine.

[0317] The intermediate 5-fluoropyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-4-fluoropyridine.

[0318] The intermediate 5-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 4-(trifluoromethyl)pyridine.

[0319] The intermediate 6-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-5-methylpyridine.

[0320] The intermediate 6-fluoropyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-5-fluoropyridine.

[0321] The intermediate 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared following the general procedure described above for C9, starting from 2-bromo-5-(trifluoromethyl)pyridine.

[0322] Intermediate 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde [ka]

[0323] Step 1: Preparation of 1-amino-2-(trifluoromethyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (C11)

[0324] To a mixture of TFA (215.60 g, 1.89 mol, 140 mL, 27.8 equiv.) and HO (20.00 g, 1.11 mol, 20.0 mL, 16.3 equiv.), ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethanimidate (21.34 g, 74.8 mmol, 1.1 equiv.) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of ice water (100 mL), and the precipitate was filtered and rinsed with water (50 mL × 2). The precipitate was then dissolved in DCM (140 mL), dried over NaSO, and filtered. To the filtrate was added 2-(trifluoromethyl)pyridine (C10) (10 g, 68.0 mmol, 7.87 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. TBME (100 mL) was slowly added to the reaction mixture, and the precipitate was collected, rinsed with TBME (40 mL × 3), and then dried in vacuo to give C11 (8.5 g, 35% yield), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 9.06(d,1H),8.40-8.60(m,2H),8.20-8.26(m,1H),8.12(s,2H),6.60(s,2H),2.34(s,6H),2.02(s,3H).

[0325] Step 2: Preparation of dimethyl 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate (C12)

[0326] To a mixture of 1-amino-2-(trifluoromethyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (C11) (8.5 g, 23.5 mmol) and K2CO3 (6.49 g, 46.9 mmol, 2 equiv.) in DMF (100 mL) was added dimethyl but-2-ynedioate (6.66 g, 46.9 mmol, 2 equiv.) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction progress was monitored by TLC (PE: EtOAc = 1:1). Water (200 mL) was added, and the solution was stirred for 30 min. The resulting precipitate was collected by vacuum filtration, rinsed with water, and dried. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® Silica Flash Column, eluent of 0-40% EtOAc:PE @ 60 mL / min) to give C12 (2.85 g, 40% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.40 (d, 1H), 7.74-7.96 (m, 2H), 3.85-3.96 (m, 6H).

[0327] Step 3: Preparation of 2-(methoxycarbonyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (C13)

[0328] To a solution of dimethyl 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate (C12) (2.85 g, 9.43 mmol) in THF (20 mL) was added LiOH.HO (1.58 g, 37.7 mmol, 4 equiv.) in HO (20 mL), and the reaction mixture was stirred at room temperature for 16 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. The reaction mixture was concentrated in vacuo to remove most of the THF, and the aqueous phase was adjusted to pH ∼2 with 4 M HCl. The precipitate was collected by filtration and then dried in vacuo to give C13 (2.25 g), which was used without further purification.1 H NMR (400MHz, DMSO-d6) δ 8.43 (d, 1H), 7.85 (d, 1H), 7.71-7.76 (m, 1H).

[0329] Step 4: Preparation of 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid (C14)

[0330] A mixture of 2-(methoxycarbonyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (C13) (2.25 g, 8.21 mmol) in H2SO4 (41.40 g, 422 mmol, 22.5 mL, 51.4 equiv.) and HO (11.25 g, 624 mmol, 11.3 mL, 76.1 equiv.) was stirred at 90 °C for 16 h. LC-MS was used to monitor the reaction progress. The reaction mixture was cooled to room temperature, and water (60 mL) was added. The precipitate was collected by filtration and then dried in vacuo to give C14 (1.7 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.14 (d, 1H), 7.71 (d, 1H), 7.41-7.49 (m, 1H), 7.32 (s, 1H).

[0331] Step 5: Preparation of N-methoxy-N-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide (C15)

[0332] To a solution of 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid (C14) (8.00 g, 34.8 mmol) and N-methoxymethanamine (10.17 g, 104 mmol, 3 equiv., HCl) in DMF (80 mL) was added HOBt (7.05 g, 52.1 mmol, 1.5 equiv.), EDCI (10.00 g, 52.1 mmol, 1.5 equiv.), and DIPEA (13.48 g, 104 mmol, 18.2 mL, 3 equiv.). The mixture was stirred at room temperature for 16 h. TLC (DCM:MeOH = 10:1) was used to monitor the reaction progress. DCM (150 mL) was added, and the organic portion was washed with saturated Na2CO3 solution (100 mL × 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® Silica Flash Column, eluent of 0-10% MeOH:DCM @ 60 mL / min) to give C15 (6 g, 60% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.11(d,1H),7.67(d,1H),7.37-7.49(m,1H),7.21(s,1H),3.77(s,3H),2.50-2.52(m,3H);LCMS:m / z 274.1[M+H] + .

[0333] Step 6: Preparation of 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde (C16)

[0334] To a solution of N-methoxy-N-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide (C15) (6 g, 22.0 mmol) in THF (60 mL) was added DIBAL-H (1 M, 65.9 mL, 3 equiv.) dropwise at −78° C. under N , and the reaction mixture was then stirred at −78° C. under N for 2 h. TLC (PE: EtOAc = 5:1) was used to monitor the reaction progress. The reaction mixture was quenched by the addition of saturated NH Cl solution (150 mL), followed by the addition of 4 M HCl solution (80 mL). The aqueous portion was extracted with EtOAc (100 mL × 2), and the combined organic layers were washed with water (80 mL) and brine (80 mL). The organic layers were dried over Na SO , filtered, and evaporated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0-30% EtOAc:PE @ 40 mL / min) to give C16 (3.95 g, 68% yield). 1 H NMR (400MHz, DMSO-d6) δ 10.20 (s, 1H), 8.20 (d, 1H), 7.79 (d, 1H), 7.49 (dd, 1H), 7.40 (s, 1H).

[0335] The intermediate 7-chloropyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared starting from 2-chloropyridine following the general procedure described above for C16.

[0336] The intermediate 5-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared starting from 4-(trifluoromethyl)pyridine following the general procedure described above for C16.

[0337] Intermediate 7-Fluoropyrazolo[1,5-a]pyridine-2-carbaldehyde [ka]

[0338] Step 1: Preparation of ethyl 7-fluoropyrazolo[1,5-a]pyridine-2-carboxylate (C18)

[0339] To a solution of ethyl 7-bromopyrazolo[1,5-a]pyridine-2-carboxylate (C17) (1 g, 3.72 mmol) in DMA (8 mL) was added CsF (1.69 g, 11.2 mmol, 411 μL, 3 equiv.), and the reaction mixture was stirred at 150 °C for 1 h under microwave irradiation. LCMS was used to monitor the reaction progress. DCM (60 mL) was added to the reaction mixture, and the organic portion was washed with water (30 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 to 4 / 1) to give C18 (450 mg, 29% yield). 1 H NMR(400MHz,CDCl3)δ 7.48(d,1H),7.18-7.26(m,2H),6.64(ddd,1H),4.52(q,2H),1.48(t,3H);LCMS:m / z 208.8[M+H] + .

[0340] Step 2: Preparation of (7-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol (C19)

[0341] To a solution of ethyl 7-fluoropyrazolo[1,5-a]pyridine-2-carboxylate (C18) (450 mg, 2.16 mmol) in THF (4 mL) and EtOH (2 mL) was added LiBH (260 mg, 11.9 mmol, 5.5 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. LCMS was used to follow the reaction progress. The reaction mixture was quenched by the addition of saturated NH Cl solution (10 mL), and the aqueous portion was extracted with EtOAc (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na SO , filtered, and concentrated to dryness to give C19 (360 mg), which was used without further purification. LCMS: m / z 167.0 [M+H] + .

[0342] Step 3: Preparation of 7-fluoropyrazolo[1,5-a]pyridine-2-carbaldehyde (C20)

[0343] To a solution of (7-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol (C19) (360 mg, 2.17 mmol) in MeCN (5 mL) was added IBX (971 mg, 3.47 mmol, 1.6 equiv.), and the reaction mixture was stirred at 80° C. for 1 h. LCMS was used to monitor the reaction progress. The reaction mixture was filtered and concentrated to dryness to give C20 (355 mg), which was used without further purification. 1 H NMR(400MHz,CDCl3)δ 10.26-10.46(m,1H),7.52(dd,1H),7.22-7.28(m,1H),7.16(d,1H),6.69(ddd,1H);LCMS:m / z 165.0[M+H] + .

[0344] Intermediate 4-(difluoromethyl)oxazole-5-carboxylic acid according to general scheme 4 [ka]

[0345] Step 1: Preparation of ethyl 2-bromo-4,4-difluoro-3-oxo-butanoate (E1)

[0346] To a solution of ethyl 4,4-difluoro-3-oxobutanoate (20 g, 120 mmol) in DCM (240 mL) were added TsOH (4.15 g, 24.1 mmol, 0.2 equiv.) and NBS (22.50 g, 126 mmol, 1.05 equiv.) in portions at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction progress was checked using TLC (PE: EtOAc = 5:1). DCM (100 mL) was added, and the organic portion was washed with saturated Na2CO3 solution (100 mL) and brine (150 mL), dried over Na2SO4, filtered, and concentrated to dryness to give E1 (34 g), which was used without further purification. 1H NMR (400MHz, DMSO-d6) δ 5.81-6.16 (m, 1H), 4.34-4.41 (m, 1H), 4.12-4.20 (m, 2H), 1.17-1.23 (m, 3H).

[0347] Step 2: Preparation of ethyl 2-amino-4-(difluoromethyl)oxazole-5-carboxylate (E2)

[0348] A mixture of E1 (37 g, 151 mmol) and urea (45.34 g, 755 mmol, 40.5 mL, 5 equiv) in DMF (30 mL) was stirred at 120° C. for 12 h. LC-MS was used to check the reaction progress. The reaction mixture was cooled to room temperature and poured into 100 mL of water. The reaction mixture was stirred at 0° C. for 15 min, and the precipitate was collected by filtration, rinsed with water (50 mL), and dried in vacuo to give E2 (15.5 g, 63% yield for steps 1 and 2). LCMS: m / z 207.2 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ 7.86 (s, 2H), 6.84-7.44 (m, 1H), 4.27 (q, 2H), 1.28 (t, 3H).

[0349] Step 3: Preparation of ethyl 4-(difluoromethyl)oxazole-5-carboxylate (E3)

[0350] To a solution of ethyl 2-amino-4-(difluoromethyl)oxazole-5-carboxylate (20 g, 97.0 mmol) in THF (300 mL) was added t-BuONO (30.01 g, 291 mmol, 34.6 mL, 3 equiv.) dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. DCM (300 mL) was added, and the organic portion was washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 10 / 1) to give E3 (12.7 g, 69% yield). 1H NMR (400MHz, CDCl3) δ 8.05 (s, 1H), 6.93-7.27 (m, 1H), 4.44 (q, 2H), 1.40 (t, 3H).

[0351] Step 5: Preparation of 4-(difluoromethyl)oxazole-5-carboxylic acid (E4)

[0352] To a solution of ethyl 4-(difluoromethyl)oxazole-5-carboxylate (12.7 g, 66.5 mmol) in THF (100 mL) and HO (20 mL) was added LiOH.HO (3.07 g, 73.1 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to remove the THF. Water (80 mL) was added, and the aqueous portion was extracted with TBME (50 mL). The aqueous layer was then adjusted to pH ∼6 by the addition of 0.5 M HCl. The aqueous layer was concentrated to dryness to give E4 (11 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.30 (s, 1H), 7.34-7.76 (m, 1H).

[0353] Intermediate ethyl 2-bromo-4-(difluoromethyl)oxazole-5-carboxylate according to general scheme 4 [ka]

[0354] Preparation of ethyl 2-bromo-4-(difluoromethyl)oxazole-5-carboxylate (E5)

[0355] To a solution of ethyl 2-amino-4-(difluoromethyl)oxazole-5-carboxylate (E2) (25 g, 121 mmol) in MeCN (200 mL) was added CuBr (40.63 g, 182 mmol, 8.5 mL, 1.5 equiv) at 0 °C. The mixture turned dark green and was further stirred at room temperature for 15 min. t-BuONO (18.76 g, 182 mmol, 21.6 mL, 1.5 equiv) was added at 0 °C. The reaction was stirred at room temperature for 2 h, then heated to 50 °C and stirred for 12 h. TLC (EtOAc:PE = 5:1) was used to monitor the reaction progress. The reaction mixture was filtered. DCM (200 mL) was added to the filtrate, and the organic layer was washed with water (100 mL) and brine (100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® Silica Flash Column, eluent of 0-20% EtOAc / PE gradient @ 100 mL / min) to give E5 (19 g, 58% yield). 1 H NMR (400MHz, CDCl3) δ 7.02(t,1H),4.39(q,2H),1.35(t,3H).

[0356] General Scheme 6, Method A to prepare intermediate 4-(difluoromethyl)-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylic acid [ka]

[0357] Step 1: Preparation of ethyl 2-acetyl-4-(difluoromethyl)oxazole-5-carboxylate (E6)

[0358] To a solution of ethyl 2-bromo-4-(difluoromethyl)oxazole-5-carboxylate (E5) (10 g, 37.0 mmol) in toluene (150 mL) was added Pd(PPh)Cl (2.60 g, 3.70 mmol, 0.1 equiv.) and tributyl(1-ethoxyvinyl)stannane (17.39 g, 48.1 mmol, 16.3 mL, 1.3 equiv.). The mixture was stirred at 85 °C under a N atmosphere for 12 h. The reaction progress was checked using TLC (PE: EtOAc). 100 mL of EtOAc was added to the reaction mixture, and the organic portion was washed with saturated KF solution (150 mL) and brine (100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was dissolved in THF (60 mL), treated with 4 M HCl (60 mL), and then stirred at 40 °C for 12 h. The reaction progress was checked by TLC (petroleum ether: EtOAc = 10:1). EtOAc (100 mL) was added to the reaction mixture, and the organic portion was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, 0-20% EtOAc / PE gradient eluent @ 40 mL / min) to give E6 (7.1 g, 82% yield). 1 H NMR (400MHz, CDCl3) δ 7.00-7.36 (m, 1H), 4.48 (q, 2H), 2.66-2.86 (m, 3H), 1.43 (t, 3H).

[0359] Step 2: Preparation of ethyl 4-(difluoromethyl)-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylate (E7)

[0360] To a solution of E6 (2.5 g, 10.7 mmol) in THF (120 mL) was added MeMgBr (3 M, 7.15 mL, 2 equiv.) at −78° C. The mixture was stirred at −78° C. for 1 h. The reaction progress was checked by TLC (PE: EtOAc = 2:1). The reaction mixture was quenched by the addition of saturated NH4Cl solution (50 mL), followed by the addition of water (100 mL). The aqueous portion was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0-12% EtOAc / PE gradient @ 40 mL / min) to give E7 (3.2 g, 60% yield). 1 H NMR (400 MHz, CDCl) δ 6.94-7.29 (m, 1H), 4.46 (q, 2H), 2.86 (s, 1H), 1.72 (s, 6H), 1.44 (t, 3H). Starting material E6 (300 mg) was also recovered.

[0361] Step 3: Preparation of 4-(difluoromethyl)-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylic acid (E8)

[0362] To a solution of E7 (3.9 g, 15.7 mmol) in THF (40 mL) and HO (40 mL) was added LiOH.HO (690 mg, 16.4 mmol, 1.05 equiv). The mixture was stirred at room temperature for 1 h. The reaction progress was checked using TLC (PE: EtOAc = 5:1). The reaction mixture was concentrated to remove THF. The aqueous mixture was then adjusted to pH 3 by the addition of 1 M HCl and then lyophilized in vacuo to give E8 (4 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 7.35-7.71 (m, 1H), 5.68 (br s, 1H), 1.50 (s, 6H).

[0363] Intermediate 2-(1-hydroxycyclobutyl)-4-(trifluoromethyl)oxazole-5-carboxylic acid [ka]

[0364] Step 1: Preparation of ethyl 4-(trifluoromethyl)oxazole-5-carboxylate (E10)

[0365] To a solution of ethyl 2-amino-4-(trifluoromethyl)oxazole-5-carboxylate (2.00 g, 8.92 mmol) in THF (60 mL) was added t-BuONO (1.84 g, 17.9 mmol, 2.12 mL, 2 equiv.). The reaction mixture was stirred at 55 °C for 24 h. EtOAc (120 mL) was added to the reaction mixture, and the organic portion was washed with water (100 mL) and brine (100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 to 8 / 1) to give E10 (1.2 g, 64% yield). 1 H NMR (400MHz, CDCl3) δ 7.96 (s, 1H), 4.39 (q, 2H), 1.34 (t, 3H).

[0366] Step 2: Preparation of ethyl 2-(1-hydroxycyclobutyl)-4-(trifluoromethyl)oxazole-5-carboxylate (E11)

[0367] To a solution of ethyl 4-(trifluoromethyl)oxazole-5-carboxylate (1.2 g, 5.74 mmol) in THF (30 mL) was added LiHMDS (1 M, 8.61 mL, 1.5 equiv.) at −78 °C, and the reaction mixture was stirred at −78 °C for 0.5 h. Cyclobutanone (1.21 g, 17.2 mmol, 1.29 mL, 3 equiv.) in THF (5 mL) was added to the reaction mixture, and the mixture was stirred at −78 °C for 2 h under a N atmosphere. The reaction mixture was quenched by the addition of saturated NH Cl solution (30 mL), and the aqueous portion was extracted with EtOAc (100 mL). The organic layer was washed with water (70 mL) and brine (70 mL), dried over Na SO , filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO , PE / EtOAc = 1 / 0 to 10 / 1) to give E11 (600 mg, 37% yield). 1 H NMR (400MHz, CDCl3) δ 4.29(q,2H),2.78-2.94(m,1H),2.52-2.65(m,2H),2.24-2.38(m,2H),1.78-1.98(m,3H),1.26(t,3H).

[0368] Step 3: Preparation of 2-(1-hydroxycyclobutyl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (E12)

[0369] To a solution of ethyl 2-(1-hydroxycyclobutyl)-4-(trifluoromethyl)oxazole-5-carboxylate (600 mg, 2.15 mmol) in HO (2 mL) and THF (10 mL) was added LiOH.HO (99.2 mg, 2.36 mmol, 1.1 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to remove the THF. Water (10 mL) was added, and the aqueous portion was extracted with TBME (30 mL). The aqueous layer was then adjusted to pH 6 by the addition of 0.5 M HCl and concentrated to dryness to give E12 (540 mg), which was used without further purification. 1 H NMR (400MHz, CD3OD) δ 2.54-2.67 (m, 2H), 2.19-2.34 (m, 2H), 1.81-1.95 (m, 1H), 1.66-1.80 (m, 1H).

[0370] Intermediate ethyl 4-bromo-2-(2-hydroxypropan-2-yl)oxazole-5-carboxylate according to general scheme 6 [ka]

[0371] Step 1: Preparation of ethyl 4-bromooxazole-5-carboxylate (E14)

[0372] Ethyl oxazole-5-carboxylate (E13) (500 mg, 3.54 mmol) was added in THF (2.50 mL) and DMF (2.50 mL) at about 10° C. The reaction mixture was cooled to −80° C., and LiHMDS (1 M, 4.61 mL, 1.30 equiv.) was added dropwise at about −80° C. The reaction mixture was stirred at about −80° C. for 0.5 h. Br2 (736 mg, 4.61 mmol, 1.3 equiv.) was then added dropwise at about −80° C. The reaction mixture was stirred at about −80° C. for 0.5 h. LC-MS was used to check the reaction progress. The reaction mixture was combined with 19 other reactions carried out using 500 mg of E13. The combined reaction mixture was poured into saturated citric acid at about −10° C. The aqueous portion was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 to 0 / 1) to give E14 (3.00 g, 19% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.70(s,1H),4.29-4.34(m,2H),1.29(t,3H);LCMS:m / z 219.9&221.9(M+H) + .

[0373] Step 2: Preparation of ethyl 4-bromo-2-iodooxazole-5-carboxylate (E15)

[0374] Ethyl 4-bromooxazole-5-carboxylate (E14) (3.15 g, 14.3 mmol, 1.00 equiv.) was added in THF (15.0 mL) at room temperature. LiHMDS (1 M, 17.2 mL, 1.20 equiv.) was added dropwise at about −80° C. Then, I2 (5.45 g, 21.5 mmol, 1.50 equiv.) in THF (15.0 mL) was added dropwise at about −80° C. The reaction mixture was stirred at about −80° C. for 1 hour. The reaction progress was checked using TLC (PE / EtOAc). The reaction mixture was poured into saturated citric acid (30 mL) at about −10° C. The aqueous layer was extracted with ethyl acetate (30 mL × 3). 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 (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) to give E15 (1.10 g, yield 22%). 1 H NMR (400MHz, DMSO-d6) δ: 4.29-4.35 (m, 2H), 1.30 (t, 3H). LCMS:m / z 345.8&347.9(M+H) + .

[0375] Step 3: Preparation of ethyl 4-bromo-2-(2-hydroxypropan-2-yl)oxazole-5-carboxylate (E16)

[0376] Ethyl 4-bromo-2-iodooxazole-5-carboxylate (E15) (1.10 g, 3.18 mmol) was added in THF (10 mL) under N at about 10°C. The mixture was degassed under high vacuum and purged with N three times. The mixture was cooled to -80°C, and iPr-MgCl.LiCl (1.3 M, 2.45 mL, 1 equiv.) was added dropwise at about -80°C. The reaction mixture was stirred at about -80°C for 0.5 h, and then acetone (222 mg, 3.82 mmol, 1.20 equiv.) was added dropwise at about -80°C. The mixture was stirred at about -80°C for 0.5 h. TLC (PE / EtOAc = 5 / 1) was used to check the reaction progress. The reaction mixture was poured into saturated citric acid solution (5 mL) at about -10°C. The aqueous portion was extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) and further purified by preparative HPLC (column: Phenomenex luna C18 80 × 40 mm × 3 μm, mobile phase: [water (0.04% HCl)-ACN], B%: 18% to 45%, 7 min) to give E16 (140 mg, 16% yield). 1 H NMR (400MHz, DMSO-d6) δ: 5.93 (s, 1H), 4.30-4.37 (m, 2H), 1.50 (s, 6H), 1.32 (t, 3H). LCMS:m / z 277.9&279.9(M+H) + .

[0377] Intermediate ethyl 4-chloro-2-(2-hydroxypropan-2-yl)oxazole-5-carboxylate according to general scheme 6 [ka]

[0378] Step 1: Preparation of ethyl 4-chlorooxazole-5-carboxylate (E17)

[0379] Ethyl oxazole-5-carboxylate (E13) (10.0 g, 70.9 mmol) was added to DMF (50 mL) at about 10° C. The reaction mixture was cooled to −80° C., and LiHMDS (1 M, 92.1 mL, 1.3 equiv.) was added dropwise at about −80° C. The reaction mixture was stirred at about −80° C. for 0.5 h, and then NCS (12.3 g, 92.1 mmol, 1.3 equiv.) in THF (50 mL) was added dropwise at about −80° C. The mixture was stirred at about −80° C. for 0.5 h. TLC (PE / EtOAc = 5 / 1) was used to check the reaction progress. The reaction mixture was combined for workup with seven other reactions carried out using 10 g of E13 each. The combined reaction mixture was poured into saturated citric acid solution (100 mL) at about −10° C. The aqueous portion was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 to 0 / 1) to give E17 (18.0 g, 18% yield). 1 H NMR(400MHz,CDCl3)δ 7.94(s,1H),4.44(q,2H),1.42(t,3H);LCMS:m / z 176.0(M+H) + .

[0380] Step 2: Preparation of ethyl 4-chloro-2-iodooxazole-5-carboxylate (E18)

[0381] Three reactions were carried out in parallel. Ethyl 4-chlorooxazole-5-carboxylate (E17) (6.00 g, 34.2 mmol) was dissolved in THF (30 mL) at room temperature. LiHMDS (1 M, 41.0 mL, 1.2 equiv.) was added dropwise at about −80° C., followed by the dropwise addition of I2 (13.0 g, 51.3 mmol, 1.5 equiv.) in THF (30 mL) at about −80° C. The reaction mixture was stirred at about −80° C. for 1 h. The reaction progress was checked using TLC (PE / EtOAc = 5 / 1). The three parallel reactions were combined together for workup. The combined reaction mixture was poured into saturated citric acid solution (100 mL) at about −5° C. The aqueous portion was extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) to give E18 (10.0 g, yield 32%). 1 H NMR(400MHz,DMSO-d6)δ 4.20-4.27(m,2H),1.21(t,3H);LCMS:m / z 301.9(M+H) + .

[0382] Step 3: Preparation of ethyl 4-chloro-2-(2-hydroxypropan-2-yl)oxazole-5-carboxylate (E19)

[0383] Two parallel reactions were carried out. Compound E18 (5.00 g, 16.6 mmol) was added to THF (50 mL) at about 10° C. under N2. The suspension was degassed under high vacuum and purged with N2 three times. The mixture was cooled to −80° C., and iPr-MgCl.LiCl (1.3 M, 12.8 mL, 1 equiv.) was added dropwise at about −80° C. The mixture was stirred at about −80° C. for 0.5 hours, and then acetone (1.16 g, 19.9 mmol, 1.2 equiv.) was added dropwise at about −80° C. The mixture was stirred at about −80° C. for 0.5 hours. TLC (PE / EtOAc = 5 / 1) was used to check the reaction progress. The two parallel reactions were combined together for workup. The combined reaction mixture was poured into saturated citric acid solution (50 mL) at about −10° C. The aqueous portion was extracted with ethyl acetate (50 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 column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) and further purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm), mobile phase: [water (0.05% HCl)-ACN], B%: 20% to 50%, 23 min) to give E19 (1.80 g, 23% yield). 1 H NMR(400MHz,DMSO-d6)δ:5.92(s,1H),4.32-4.37(m,2H),1.51(s,6H),1.31(t,3H);LCMS:m / z 234.0(M+H) + .

[0384] Intermediate 4-(difluoromethyl)-2-(2-cyanopropan-2-yl)oxazole-5-carboxylic acid [ka]

[0385] Step 1: Preparation of 2-cyano-2-methyl-propanoyl chloride (E20)

[0386] To a solution of 2-cyano-2-methyl-propanoic acid (2 g, 17.7 mmol) and DMF (129 mg, 1.77 mmol, 136 μL, 0.1 equiv) in DCM (20 mL) was added oxalyl chloride (2.69 g, 21.2 mmol, 1.86 mL, 1.2 equiv) dropwise at 0° C., and the reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness to give E20 (2.5 g), which was used without further purification.

[0387] Step 2: Preparation of ethyl (Z)-3-[(2-cyano-2-methyl-propanoyl)amino]-4,4-difluoro-but-2-enoate (E21)

[0388] To a solution of ethyl (Z)-3-amino-4,4-difluorobut-2-enoate (2 g, 12.1 mmol) in dioxane (20 mL) was added a solution of 2-cyano-2-methyl-propanoyl chloride (E20) (2.39 g, 18.2 mmol, 1.5 equiv.) in dioxane (20 mL) at room temperature. The reaction mixture was stirred at 110 °C for 12 h. The reaction progress was monitored using TLC (PE / ethyl acetate = 5 / 1). The reaction mixture was concentrated to dryness, and the residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, 0-7% EtOAc / PE gradient eluent @ 40 mL / min) to give E21 (2.4 g, 76% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.90(s,1H),6.95-7.27(m,1H),5.81(s,1H),4.12-4.29(m,2H),1.51-1.69(m,6H),1.20(t,3H);LCMS:m / z 259.1[M+H] + .

[0389] Step 3: Preparation of ethyl 2-(1-cyano-1-methyl-ethyl)-4-(difluoromethyl)oxazole-5-carboxylate (E22)

[0390] To a solution of ethyl (Z)-3-[(2-cyano-2-methyl-propanoyl)amino]-4,4-difluorobut-2-enoate (E21) (2.4 g, 9.22 mmol) in DCE (20 mL) was added BF3.Et2O (2.62 g, 18.4 mmol, 2.28 mL, 2 equiv.) and PIDA (4.16 g, 12.9 mmol, 1.4 equiv.) at room temperature. The mixture was stirred at 90 °C for 18 h. The reaction progress was monitored by TLC (PE / EtOAc). The reaction mixture was concentrated to dryness. DCM (100 mL) was added to the residue, and the organic layer was washed with saturated Na2CO3 solution (10 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® Silica Flash Column, eluent of 0-7% EtOAc / PE gradient @ 30 mL / min) to give E22 (0.25 g, 11% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.03-7.55 (m, 1H), 4.35 (q, 2H), 1.77 (s, 6H), 1.29 (t, 3H).

[0391] Step 4: Preparation of 2-(1-cyano-1-methyl-ethyl)-4-(difluoromethyl)oxazole-5-carboxylic acid (E23)

[0392] To a solution of ethyl 2-(1-cyano-1-methyl-ethyl)-4-(difluoromethyl)oxazole-5-carboxylate (E22) (0.25 g, 968 μmol) in THF (3 mL) and HO (1 mL) was added LiOH.HO (48.8 mg, 1.16 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 18 h. The completeness of the reaction was checked using TLC (PE: EtOAc = 5:1). The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous portion was adjusted to pH 7 with 2 M HCl and then lyophilized under vacuum to give E23 (0.22 g, 99% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.23-7.74(m, 1H), 1.73(s, 6H).

[0393] Intermediate 4-(difluoromethyl)-2-(pyrimidin-2-yl)oxazole-5-carboxylic acid via General Scheme 5, Method B [ka]

[0394] Step 1: Preparation of ethyl 4-(difluoromethyl)-2-pyrimidin-2-yl-oxazole-5-carboxylate (E24)

[0395] To a solution of ethyl 4-(difluoromethyl)oxazole-5-carboxylate (E4) (1 g, 5.23 mmol), Pd(dba) (240 mg, 262 μmol, 0.05 equiv.), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (151 mg, 262 μmol, 0.05 equiv.), and CsCO (3.41 g, 10.5 mmol, 2 equiv.) in 1,2-dimethoxyethane (3 mL) was added 2-chloropyrimidine (599 mg, 5.23 mmol) under a N atmosphere. The reaction mixture was stirred at 90 °C for 12 h. DCM (50 mL) was added to the reaction mixture, and the organic portion was washed with water (40 mL) and brine (40 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 1) to give E24 (400 mg, yield 25%). 1 H NMR (400MHz, CDCl3) δ 9.02(br d,2H),7.52(t,1H),7.38(s,1H),7.24(s,1H),7.11(s,1H),4.54(q,2H),1.48(t,3H).

[0396] Step 2: Preparation of 4-(difluoromethyl)-2-pyrimidin-2-yl-oxazole-5-carboxylic acid (E25)

[0397] To a solution of ethyl 4-(difluoromethyl)-2-pyrimidin-2-yl-oxazole-5-carboxylate (E24) (450 mg, 1.67 mmol) in THF (2 mL) and HO (2 mL) was added LiOH.HO (77.2 mg, 1.84 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to remove THF, and HO (10 mL) was added. The aqueous layer was extracted with TBME (30 mL). The aqueous layer was then adjusted to pH 6 with 0.5 M HCl and extracted three times with DCM / MeOH (30 / 3 mL). The combined DCM / MeOH organic layers were dried over NaSO, filtered, and concentrated to dryness to give E25 (350 mg), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 9.06 (d, 2H), 7.75 (t, 1H), 7.20-7.57 (m, 1H).

[0398] General Scheme 4 and General Scheme 6, Intermediate 2-(1-hydroxy-1-methyl-ethyl)-4-methyl-oxazole-5-carboxylic acid according to Method A [ka]

[0399] Step 1: Preparation of ethyl 2-amino-4-methyl-oxazole-5-carboxylate (E26)

[0400] A mixture of ethyl 2-chloro-3-oxo-butanoate (55 g, 334 mmol, 46.2 mL) and urea (100.34 g, 1.67 mol, 89.6 mL, 5 equiv) in DMF (100 mL) was stirred at 120 °C for 12 h. TLC (PE: EtOAc = 5:1) was used to check the reaction progress. The reaction mixture was cooled to room temperature, poured into HO (400 mL), and stirred at 0 °C for 30 min. The solid was collected by filtration, rinsed with water (30 mL), and then dried in vacuo to give E26 (22.2 g, 39% yield). 1 H NMR (400MHz, CD3OD) δ 4.29(q,2H),2.32(s,3H),1.35(t,3H).

[0401] Step 2: Preparation of ethyl 2-bromo-4-methyl-oxazole-5-carboxylate (E27)

[0402] To a solution of E26 (11.1 g, 65.2 mmol) in MeCN (120 mL) was added CuBr2 (21.85 g, 97.9 mmol, 4.58 mL, 1.5 equiv) at 0 °C. The mixture turned dark green and was further stirred at room temperature for 15 min. t-BuONO (10.09 g, 97.9 mmol, 11.6 mL, 1.5 equiv) was added. The reaction was stirred at room temperature for 2 h and then heated at 50 °C for 4 h. TLC (petroleum ether: EtOAc = 3:1) was used to check the reaction progress. The reaction mixture was concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® Silica Flash Column, elution with a 0-5% EtOAc / PE gradient at 100 mL / min) to give E27 (8.5 g, 56% yield). 1 H NMR (400MHz, CDCl3) δ 4.25-4.35(m,2H),2.45(s,3H),1.32(t,3H).

[0403] Step 3: Preparation of ethyl 2-acetyl-4-methyloxazole-5-carboxylate (E28)

[0404] A mixture of E27 (9.5 g, 40.6 mmol), tributyl(1-ethoxyvinyl)stannane (17.59 g, 48.7 mmol, 16.4 mL, 1.2 equiv.), and Pd(PPh3)2Cl2 (2.85 g, 4.06 mmol, 0.1 equiv.) in toluene (200 mL) was stirred at 90 °C for 12 h under a N2 atmosphere. The reaction progress was monitored using TLC (petroleum ether: EtOAc = 5:1). EtOAc (300 mL) was added, followed by saturated KF solution (500 mL). The resulting mixture was stirred at room temperature for 40 min, filtered, and the filtrate separated. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was dissolved in THF (300 mL), and 4 N HCl (300 mL) was added. The mixture was stirred at room temperature for 12 h. LCMS showed that the desired mass was detected. The reaction mixture was extracted with DCM (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 24 g SepaFlash® Silica Flash Column, eluent of 0-10% EtOAc / PE gradient @ 35 mL / min) to give E28 (6.8 g, 85% yield). 1 H NMR(400MHz,CDCl3)δ 4.35(q,2H),2.62(s,3H),2.48(s,3H),1.34(t,3H);LCMS:m / z 198.1(M+H) + .

[0405] Step 4: Preparation of ethyl 2-(2-hydroxypropan-2-yl)-4-methyloxazole-5-carboxylate (E29)

[0406] To a solution of E28 (2.5 g, 12.7 mmol) in THF (25 mL) was added MeMgBr (3 M, 12.7 mL, 3 equiv.) dropwise under N at −78 °C. The reaction was stirred at −78 °C for 1.5 h. TLC (petroleum ether: EtOAc = 5:1, by UV) was used to check the reaction progress. The reaction was quenched by slowly adding saturated NH4Cl solution (30 mL), and then the organic portion was extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give E29 (1.7 g, 63% yield). 1 H NMR (400MHz, CDCl3) δ 4.39(q,2H),2.47(s,3H),1.67(s,6H),1.40(t,3H).

[0407] Alternatively, E29 can be prepared by reacting ethyl 2-hydroxy-2-methylpropanamide with 2-chloro-3-oxo-butanoate in a neat reaction at 150° C. for 6 hours.

[0408] Step 5: Preparation of ethyl 2-(2-hydroxypropan-2-yl)-4-methyloxazole-5-carboxylate (E30)

[0409] To a solution of E29 (3.4 g, 16.0 mmol) in THF (30 mL) and HO (15 mL) was added LiOH.HO (803 mg, 19.1 mmol, 1.2 equiv). The reaction was stirred at room temperature for 1.5 h. LCMS was used to follow the reaction progress. The reaction mixture was adjusted to pH 7 with HCl (1 M) and concentrated to dryness to give E30 (4 g), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 5.67(s,1H),2.30(s,2H),1.44(s,6H);LCMS:m / z 186.1(M+H) + .

[0410] Intermediate 4-cyclopropyl-2-(2-hydroxypropan-2-yl)oxazole-5-carboxylic acid according to general scheme 4 [ka]

[0411] Step 1: Preparation of ethyl 2-bromo-3-cyclopropyl-3-oxo-propanoate (E31)

[0412] To a solution of ethyl 3-cyclopropyl-3-oxopropanoate (8 g, 51.2 mmol) in DCM (100 mL) was added NBS (9.12 g, 51.2 mmol) and TsOH.HO (1.95 g, 10.2 mmol, 0.2 equiv). The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored using TLC (PE: EtOAc = 10:1). The reaction mixture was concentrated to dryness. EtOAc (120 mL) was added to the residue, and the mixture was filtered. The filtrate was washed with saturated NaHCO3 solution (2 × 100 mL) and water (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1:0 to 10:1) to give E31 (12 g, 100% yield). 1 H NMR(400MHz,DMSO-d6)δ 5.71(s,1H),4.18(q,2H),2.14-2.28(m,1H),1.18(t,3H),1.01-1.08(m,2H),0.89-0.96(m,2H);LCMS:m / z 235.0[M+H] + .

[0413] Step 2: Preparation of ethyl 4-cyclopropyl-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylate (E32)

[0414] To a solution of ethyl 2-bromo-3-cyclopropyl-3-oxopropanoate (E31) (1 g, 4.25 mmol) in DMF (2 mL) was added 2-hydroxy-2-methyl-propanamide (2.19 g, 21.3 mmol, 5 equiv.). The mixture was stirred at 110 °C for 40 h. LC-MS was used to monitor the reaction progress. The reaction mixture was adjusted to pH 8 by the addition of saturated aqueous NaHCO at 0 °C. HO (50 mL) was added, and the aqueous portion was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1:0 to 2:1) to give E32 (0.15 g, 14% yield). 1 LCMS:m / z 240.0[M+H] + .

[0415] Step 3: Preparation of 4-cyclopropyl-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylic acid (E33)

[0416] To a solution of ethyl 4-cyclopropyl-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylate (E32) (590 mg, 2.47 mmol) in THF (4 mL) and HO (4 mL) was added LiOH.HO (114 mg, 2.71 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 16 h. LC-MS was used to follow the reaction progress. The reaction mixture was concentrated to remove THF. The aqueous portion was adjusted to pH 7 by the addition of HCl (1 M) and then lyophilized to give E33 (550 mg, 90% yield). 1 H NMR(400MHz,DMSO-d6)δ 2.70-2.84(m,1H),1.39(s,6H),0.62-0.81(m,4H);LCMS:m / z 212.0[M+H] + .

[0417] Intermediate 4-cyanooxazole-5-carboxylic acid [ka]

[0418] Step 1: Preparation of ethyl 4-cyanooxazole-5-carboxylate (E34)

[0419] To a solution of ethyl 4-bromooxazole-5-carboxylate (E14) (10 g, 45.5 mmol) in THF (30 mL) and HO (150 mL) was added Zn(CN) (3.74 g, 31.8 mmol, 2.02 mL, 0.7 equiv.) and t-BuXPhos-Pd-G (1.81 g, 2.27 mmol, 0.05 equiv.). The reaction mixture was degassed under vacuum and purged with N three times, and then the mixture was stirred under N at 40 °C for 16 h. TLC (PE: EtOAc = 5:1) was used to monitor the reaction progress. EtOAc (300 mL) was added to the reaction mixture, and the organic layer was washed with HO (50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 10 / 1) to give E34 (7.5 g, yield 99%). 1 H NMR (400MHz, DMSO-d6) δ 8.89 (s, 1H), 4.37 (q, 2H), 1.30 (t, 3H).

[0420] Step 2: Preparation of (4-cyanooxazole-5-carbonyl)oxylithium (E35)

[0421] To a solution of E34 (5 g, 30.1 mmol) in THF (40 mL) and HO (80 mL) was added LiOH.HO (1.33 g, 31.6 mmol, 1.05 equiv). The mixture was stirred at room temperature for 2 h. TLC (PE: EtOAc = 5:1) was used to follow the reaction progress. The reaction mixture was concentrated in vacuo to remove most of the THF and then lyophilized in vacuo to give E35 (4.5 g), which was used without further purification.1 H NMR (400MHz, DMSO-d6) δ 8.47 (s, 1H).

[0422] Intermediate [5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3,4-oxadiazole-2-carbonyl]oxylithium according to general scheme 9 [ka]

[0423] Step 1: Preparation of ethyl 5-methylsulfanyl-1,3,4-oxadiazole-2-carboxylate (E36)

[0424] A mixture of ethyl 2-hydrazino-2-oxoacetate (16 g, 121 mmol) and di(1H-imidazol-1-yl)methanethione (25.90 g, 145 mmol, 1.2 equiv.) in THF (300 mL) was stirred at room temperature for 12 h and then heated to 75 °C for 4 h. After cooling to room temperature, KCO (50.21 g, 363 mmol, 3 equiv.) and CHI (85.95 g, 606 mmol, 37.7 mL, 5 equiv.) were added. The resulting mixture was stirred at room temperature for 2 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. The reaction mixture was combined with another reaction carried out with 8.5 g of ethyl 2-hydrazino-2-oxoacetate and quenched by the addition of HO (100 mL). DCM (500 mL) was added, and the organic layer was separated, washed with brine (2×100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (eluent of 0-25% PE:EtOAc @ 40 mL / min) to give E36 (25 g). 1 H NMR (400MHz, CDCl3) δ 4.43(q,2H),2.72(s,3H),1.38(t,3H).

[0425] Step 2: Preparation of ethyl 5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3,4-oxadiazole-2-carboxylate (E37)

[0426] A mixture of E36 (233 mg, 1.24 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (410 mg, 1.49 mmol, 1.2 equiv), NaCO (394 mg, 3.71 mmol, 3 equiv), thiophene-2-carbonyloxycopper (472 mg, 2.48 mmol, 2 equiv), and Pd(dppf)Cl (181 mg, 248 μmol, 0.2 equiv) in dioxane (9 mL) was degassed and purged with N three times, and the reaction mixture was stirred under N at 75 °C for 16 h. The reaction progress was monitored using TLC (PE: EtOAc = 2:1). EtOAc (100 mL) was added to the reaction mixture, and the organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 2 / 1) to give E37 (140 mg, 39% yield). 1 H NMR(400MHz,CD3OD)δ 8.61(s,1H),8.22(s,1H),5.12(q,2H),4.51(q,2H),1.44(t,3H);LCMS:m / z 291.1(M+H) + .

[0427] Step 3: Preparation of [5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3,4-oxadiazole-2-carbonyl]oxylithium (E38)

[0428] To a solution of E37 (140 mg, 482 μmol) in THF (1.5 mL) was added LiOH.HO (22.3 mg, 531 μmol, 1.1 equiv) in HO (3 mL). The reaction mixture was stirred at room temperature for 2 h. TLC (DCM:MeOH) was used to follow the reaction progress. The reaction mixture was concentrated in vacuo to remove most of the THF and then lyophilized in vacuo to give E38 (115 mg), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 8.14 (s, 1H), 5.27 (q, 2H).

[0429] Alternatively, ethyl 5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3,4-oxadiazole-2-carboxylate (E37) can be prepared according to the following scheme: [ka]

[0430] Step A: Preparation of ethyl 1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate (E39)

[0431] To a solution of ethyl 1H-pyrazole-4-carboxylate (10 g, 71.4 mmol) and K2CO3 (19.72 g, 142 mmol, 2 equiv.) in DMF (45 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (21.53 g, 92.8 mmol, 1.3 equiv.) was added dropwise, and the resulting mixture was stirred at 50 °C for 6 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. EtOAc (300 mL) was added to the reaction mixture, and the organic layer was washed with HO (100 mL) and brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0–12% PE / EtOAc @ 60 mL / min) to give E39 (16 g). 1H NMR (400MHz, CDCl3) δ 8.01(d,2H),4.73(q,2H),4.32(q,2H),1.36(t,3H).

[0432] Step B: Preparation of 1-(2,2,2-trifluoroethyl)pyrazole-4-carbohydrazide (E40)

[0433] To a solution of E39 (16 g, 72.0 mmol) in THF (100 mL) was added NH2NH2.H2O (7.73 g, 151 mmol, 7.5 mL, 98% purity, 2.1 equivalents), and the reaction mixture was then stirred at 80 °C for 15 h. TLC (PE: EtOAc = 1:1) was used to follow the reaction progress. The reaction mixture was concentrated to dryness. The residue was triturated with TBME (50 mL) and stirred for 15 min. The precipitate was collected by filtration and then dried in vacuo to give E40 (13 g). 1 H NMR (400MHz, CD3OD) δ 8.19 (s, 1H), 7.93 (s, 1H), 4.98 (q, 2H).

[0434] Step C: Preparation of ethyl N-[[1-(2,2,2-trifluoroethyl)pyrazole-4-carbonyl]amino]carbamate (E41)

[0435] To a solution of E40 (3 g, 14.4 mmol) in THF (70 mL) was added 2-chloro-2-oxo-acetate (2.36 g, 17.3 mmol, 1.9 mL, 1.2 equiv) dropwise at 0° C., and the reaction mixture was then stirred at room temperature for 3 h. The precipitate was collected by filtration, rinsed with TBME (30 mL), and then dried in vacuo to give E41 (1.5 g, 37% yield). 1 H NMR (400MHz, CDCl3) δ 9.75 (br s, 1H), 9.06 (br s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 4.76 (q, 2H), 4.42 (q, 2H), 1.42 (t, 3H).

[0436] Step D: Preparation of ethyl 5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3,4-oxadiazole-2-carboxylate (E37)

[0437] To a solution of E41 (1.5 g, 5.35 mmol) and EtN (271 mg, 2.68 mmol, 373 μL, 0.5 equiv.) in DCM (30 mL) was added TsCl (491 mg, 6.96 mmol, 1.3 equiv.) portionwise at 0 °C, and the resulting mixture was stirred at room temperature for 18 h. TLC (PE: EtOAc = 1:1) was used to monitor the reaction progress. DCM (100 mL) was added to the reaction mixture, and the organic layer was washed with saturated NaCO solution (60 mL) and brine (60 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0–16% PE / EtOAc @ 40 mL / min) to give E37 (0.65 g, 42% yield). 1 H NMR (400MHz, CDCl3)δ 8.16-8.29(m,2H),4.80(q,2H),4.53(q,2H),1.47(t,3H).

[0438] Intermediate lithium 5-morpholino-1,3,4-oxadiazole-2-carboxylate according to general scheme 10 [ka]

[0439] Step 1: Preparation of ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (E42)

[0440] To a solution of ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (5 g, 31.8 mmol) in MeCN (60 mL) was added CuBr (10.66 g, 47.7 mmol, 2.2 mL, 1.5 equiv.) at 0 °C. The reaction mixture turned dark green and was stirred at room temperature for 15 min. t-BuONO (4.92 g, 47.7 mmol, 5.7 mL, 1.5 equiv.) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h and then heated at 50 °C for an additional 12 h. The reaction progress was monitored using TLC (PE / EtOAc = 1 / 1). The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0-50% EtOAc / PE gradient @ 40 mL / min) to give E42 (4.5 g, 64% yield). 1 H NMR (400MHz, CDCl3) δ 4.52(q,2H),1.45(t,3H).

[0441] Step 2: Preparation of ethyl 5-morpholino-1,3,4-oxadiazole-2-carboxylate (E43)

[0442] To a solution of ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (E42) (1 g, 4.52 mmol) and morpholine (473 mg, 5.43 mmol, 478 μL, 1.2 equiv.) in THF (40 mL) was added DIPEA (1.17 g, 9.05 mmol, 1.6 mL, 2 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction progress was checked using TLC (PE / EtOAc = 1 / 1). EtOAc (100 mL) was added to the reaction mixture, and the organic portion was washed with water (30 mL) and brine (30 mL × 2), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® Silica Flash Column, eluent of 0-30% EtOAc / PE gradient @ 35 mL / min) to give E43 (800 mg, 78% yield). 1H NMR (400MHz, DMSO-d6) δ 4.37(q,2H),3.68-3.74(m,4H),3.48-3.52(m,4H),1.31(t,3H).

[0443] Step 3: Preparation of (5-morpholino-1,3,4-oxadiazole-2-carbonyl)oxylithium (E44)

[0444] To a solution of ethyl 5-morpholino-1,3,4-oxadiazole-2-carboxylate (E43) (800 mg, 3.52 mmol) in THF (8 mL) and HO (12 mL) was added LiOH.HO (162 mg, 3.87 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction progress was checked using TLC (PE / EtOAc = 1 / 1). The reaction mixture was concentrated to dryness to give E44 (600 mg), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 3.62-3.74 (m, 4H), 3.36 (br d, 4H).

[0445] General Scheme 9, Method A to Intermediate [5-(5-fluoro-2-pyridyl)-1,3,4-oxadiazole-2-carbonyl]oxylithium [ka]

[0446] Step 1: Preparation of methyl 5-fluoropyridine-2-carboxylate (E45)

[0447] A solution of 5-fluoropyridine-2-carbonitrile (15 g, 123 mmol) in HCl / MeOH (4 M, 180 mL, 5.9 equiv.) was stirred at 60° C. for 12 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (150 mL) and washed with saturated NaHCO solution (50 mL) and brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® Silica Flash Column, 0-25% EtOAc / PE gradient eluent @ 60 mL / min) to give E45 (15.24 g, 80% yield). 1 H NMR (400MHz, CDCl3) δ 8.58 (d, 1H), 8.20 (dd, 1H), 7.53 (ddd, 1H), 4.00 (s, 3H).

[0448] Step 2: Preparation of 5-fluoropyridine-2-carbohydrazide (E46)

[0449] A mixture of methyl 5-fluoropyridine-2-carboxylate (E45) (16 g, 103 mmol), NHNH.HO (11.06 g, 217 mmol, 10.7 mL, 98% purity, 2.1 equiv.) in EtOH (70 mL) was degassed and purged with N three times, and the reaction mixture was then stirred at room temperature under N for 3 h. The reaction mixture was concentrated to dryness to give E46 (15 g, 94% yield). 1 H NMR (400MHz, DMSO-d6) δ 9.89 (br s, 1H), 8.61 (d, 1H), 8.07 (dd, 1H), 7.88 (td, 1H), 4.57 (br s, 2H).

[0450] Step 3: Preparation of ethyl 2-[2-(5-fluoropyridine-2-carbonyl)hydrazino]-2-oxo-acetate (E47)

[0451] To a mixture of 5-fluoropyridine-2-carbohydrazide (E46) (13.5 g, 87.0 mmol) and TEA (17.61 g, 174 mmol, 24.2 mL, 2 equiv.) in DCM (500 mL) was added ethyl 2-chloro-2-oxo-acetate (15.45 g, 113 mmol, 12.7 mL, 1.3 equiv.) over 10 min at 0 °C. The reaction mixture was stirred at room temperature for 2 h. HO (100 mL) was added to the reaction mixture, and the aqueous portion was extracted with DCM (300 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® Silica Flash Column, eluent of 0-2.5% EtOAc / PE gradient @ 60 mL / min) to give E47 (16 g, 53% yield). 1 H NMR(400MHz,CDCl3)δ 10.03-10.15(m,1H),9.65(br d,1H),8.35-8.42(m,1H),8.11-8.18(m,1H),7.51(td,2H),4.35(q,1H),1.34(t,3H);LCMS:m / z 256.2[M+H] + .

[0452] Step 4: Preparation of ethyl 5-(5-fluoro-2-pyridyl)-1,3,4-oxadiazole-2-carboxylate (E48)

[0453] To a solution of ethyl 2-[2-(5-fluoropyridine-2-carbonyl)hydrazino]-2-oxo-acetate (E47) (16 g, 62.7 mmol) in DCM (350 mL) was added TEA (8.25 g, 81.5 mmol, 11.3 mL, 1.3 equiv) and TosCl (5.98 g, 31.4 mmol, 0.5 equiv) in three portions at 0 °C. The mixture was stirred at room temperature for 3 h. Saturated NaHCO solution (200 mL) was added, and the aqueous portion was extracted with DCM (400 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® Silica Flash Column, eluent of 0-2.5% MeOH:DCM @ 85 mL / min) to give E48 (8.2 g, 49% yield). 1 H NMR(400MHz,CDCl3)δ 8.71(d,1H),8.39(dd,1H),7.66(ddd,1H),4.59(q,2H),1.51(t,3H);LCMS:m / z 238.2[M+H] + .

[0454] Step 5: Preparation of [5-(5-fluoro-2-pyridyl)-1,3,4-oxadiazole-2-carbonyl]oxylithium (E49)

[0455] To a solution of ethyl 5-(5-fluoro-2-pyridyl)-1,3,4-oxadiazole-2-carboxylate (E48) (12 g, 50.6 mmol) in THF (140 mL) and HO (180 mL) was added LiOH.HO (2.23 g, 53.1 mmol, 1.05 equiv). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to remove most of the THF, and the aqueous portion was lyophilized in vacuo to give E49 (11.5 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.79 (d, 1H), 8.24 (dd, 1H), 7.99 (td, 1H).

[0456] Intermediate 5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid [ka]

[0457] Step 1: Preparation of ethyl 5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate (E50)

[0458] To a solution of (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (1 g, 4.52 mmol) in THF (8 mL) was added 2,2,2-trifluoroethylhydrazine (670 mg, 5.88 mmol, 1.3 equiv) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 16 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated to dryness, and the residue was purified by flash silica gel chromatography (eluent: 0-5% EtOAc / PE gradient) to give E50 (850 mg, 69% yield). 1 H NMR(400MHz,CDCl3)δ 8.02(s,1H),7.38-7.75(m,1H),4.95(q,2H),4.37(q,2H),1.40(t,3H);LCMS:m / z 273.1[M+H] + .

[0459] Step 2: Preparation of 5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid (E51)

[0460] To a solution of ethyl 5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate (E50) (910 mg, 3.34 mmol) in THF (5 mL) and HO (5 mL) was added LiOH.HO (224 mg, 5.35 mmol, 1.6 equiv). The mixture was stirred at room temperature for 2 h. The reaction progress was checked using TLC (PE: EtOAc = 2:1). The reaction mixture was concentrated to remove THF. The aqueous portion was adjusted to pH ∼6 by the addition of HCl (1 M). The resulting precipitate was collected by filtration and then dried in vacuo to give E51 (816 mg, 100% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.08 (s, 1H), 7.45-7.78 (m, 1H), 5.30 (q, 2H).

[0461] Intermediate Ethyl 2-(2-pyridyl)pyrazole-3-carboxylate [ka]

[0462] Step 1: Preparation of ethyl (E)-4-(dimethylamino)-2-oxo-but-3-enoate (E52)

[0463] Ethyl 2-oxopropanoate (2 g, 17.2 mmol, 1.9 mL) and 1,1-dimethoxy-N,N-dimethyl-methanamine (2.09 g, 17.6 mmol, 2.3 mL, 1.02 equiv.) were stirred at room temperature for 12 hours. The reaction progress was monitored using TLC (PE: EtOAc = 10:1). The reaction mixture was concentrated to dryness to give E52 (2.4 g), which was used without further purification.

[0464] Step 2: Preparation of ethyl 2-(2-pyridyl)pyrazole-3-carboxylate (E53)

[0465] A mixture of ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate (E52) (2.4 g, 14.0 mmol) and 2-pyridylhydrazine (1.53 g, 14.0 mmol) in HOAc (100 mL) was stirred at 110 °C for 12 h. TLC (PE: EtOAc = 10:1) was used to check the reaction progress. The reaction mixture was adjusted to pH 9 by adding saturated Na2CO3 solution. The aqueous portion was extracted with EtOAc (300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 50 / 1) to give E53 (1.03 g, 34% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.48(dt,1H),8.05(td,1H),7.83-7.96(m,1H),7.76(d,1H),7.49(ddd,1H),6.96-7.05(m,1H),4.21(q,2H),1.05-1.23(m,3H);LCMS:m / z 218.1[M+H] + .

[0466] Ethyl 1-(2-pyridyl)pyrazole-3-carboxylate (E53a) was also obtained (190 mg, 6% yield). 1 H NMR (400 MHz, DMSO-d) δ 8.70-8.81 (m, 1H), 8.54 (dd, 1H), 7.92-8.13 (m, 2H), 7.47 (ddd, 1H), 7.02 (d, 1H), 4.35 (q, 2H), 1.34 (t, 3H). The regiochemistry of E53 and E53a was confirmed by HSQC and HMBC NMR analysis.

[0467] Step 3: Preparation of 2-(2-pyridyl)pyrazole-3-carboxylic acid (E54)

[0468] To a solution of ethyl 2-(2-pyridyl)pyrazole-3-carboxylate (E53) (1 g, 4.60 mmol) in THF (10 mL) and HO (10 mL) was added LiOH.HO (386 mg, 9.21 mmol, 2 equiv.), and the reaction mixture was stirred at room temperature for 12 h. TLC (PE / EtOAc = 1 / 1) was used to check the reaction progress. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous portion was adjusted to pH 7 by the addition of 2 M HCl and lyophilized in vacuo to give (E54) (1.2 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.36-8.44 (m, 1H), 7.88 (td, 1H), 7.44-7.53 (m, 2H), 7.35 (ddd, 1H), 6.44 (d, 1H).

[0469] Intermediate [5-(difluoromethyl)-2-methyl-1,2,4-triazole-3-carbonyl]oxylithium [ka]

[0470] Step 1: Preparation of tert-butyl (Z)-2-(1-amino-2-ethoxy-2-oxoethylidene)hydrazine-1-carboxylate (E55)

[0471] tert-Butyl (Z)-2-(1-amino-2-ethoxy-2-oxoethylidene)hydrazine-1-carboxylate was prepared from ethyl 2-amino-2-thioxoacetate according to the procedure in Bioorg. Med. Chem., 26 (2016) 3223-3225. The reaction was heated to reflux.

[0472] Step 2: Preparation of ethyl 3-(difluoromethyl)-1H-1,2,4-triazole-5-carboxylate (E56)

[0473] The reagent 2,2-difluoroacetyl chloride was prepared by adding oxalyl dichloride (18.90 g, 149 mmol, 13.0 mL, 1.1 equiv) dropwise to a solution of 2,2-difluoroacetic acid (13 g, 135 mmol, 8.5 mL) and DMF (989 mg, 13.5 mmol, 1.0 mL, 0.1 equiv) in DCM (80 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h, and the solution was used without further purification.

[0474] To a solution of tert-butyl (Z)-2-(1-amino-2-ethoxy-2-oxoethylidene)hydrazine-1-carboxylate (E55) (13 g, 56.2 mmol) in pyridine (90 mL) was added 2,2-difluoroacetyl chloride (15.47 g, 135 mmol, 2.4 equiv.). The reaction mixture was heated to 120 °C and stirred for 12 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated to dryness. DCM (200 mL) was added to the residue, and the organic portion was washed with 1 M HCl (30 mL) and brine (60 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 to 2:1) to give E56 (8.87 g, 83% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.01-7.32(m,1H),4.36(q,2H),1.30(t,3H);LCMS:m / z 192.0[M+H] + .

[0475] Step 3: Preparation of ethyl 5-(difluoromethyl)-2-methyl-1,2,4-triazole-3-carboxylate (E57)

[0476] To a solution of ethyl 3-(difluoromethyl)-1H-1,2,4-triazole-5-carboxylate (E56) (10 g, 52.3 mmol) in DMF (80 mL) was added MeI (22.28 g, 157 mmol, 9.8 mL, 3 equiv.) and K2CO3 (21.69 g, 157 mmol, 3 equiv.). The mixture was stirred at room temperature for 12 h. The reaction progress was checked using TLC (PE: EtOAc = 1:1). The reaction mixture was filtered, and the precipitate was rinsed with EtOAc (150 mL). The filtrate was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1 to 1:1) to give E57 (4.46 g, 42% yield). 1 H NMR (400MHz, DMSO-d6) δ 6.99-7.34 (m, 1H), 4.39 (q, 2H), 4.11-4.22 (m, 3H), 1.35 (t, 3H).

[0477] Step 4: Preparation of [5-(difluoromethyl)-2-methyl-1,2,4-triazole-3-carbonyl]oxylithium (E58)

[0478] To a solution of ethyl 5-(difluoromethyl)-2-methyl-1,2,4-triazole-3-carboxylate (E57) (2.35 g, 11.5 mmol) in THF (40 mL) and HO (10 mL) was added LiOH.HO (505 mg, 12.0 mmol, 1.05 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction progress was checked using TLC (PE: EtOAc = 2:1). The reaction mixture was concentrated in vacuo to remove THF. HO (20 mL) was added, and the aqueous portion was extracted with TBME (20 mL) and then lyophilized in vacuo to give E58 (2.15 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 6.75-7.21 (m, 1H), 4.09 (s, 3H).

[0479] Intermediate Ethyl 3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-carboxylate [ka]

[0480] Step 1: Preparation of N',2-dihydroxy-2-methyl-propanidine (E59)

[0481] To a solution of 2-hydroxy-2-methyl-propanenitrile (2.14 g, 25.2 mmol, 2.3 mL) in EtOH (20 mL) was added hydroxylamino hydrochloride (3.49 g, 50.3 mmol, 2 equiv.) and Na2CO3 (5.33 g, 50.3 mmol, 2 equiv.), and the reaction was then stirred at 70 °C for 16 h. The reaction mixture was concentrated to dryness. EtOAc (200 mL) was added to the residue, and the organic portion was washed twice with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness to give E59 (1 g), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 10.11 (s, 1H), 8.86 (s, 1H), 5.03 (br s, 1H), 1.70 (s, 3H), 1.66 (s, 3H).

[0482] Step 2: Preparation of ethyl 3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-carboxylate (E60)

[0483] To a solution of N',2-dihydroxy-2-methyl-propanimidine (E59) (520 mg, 4.40 mmol) and pyridine (696 mg, 8.80 mmol, 711 μL, 2 equiv.) in toluene (15 mL) was added ethyl 2-chloro-2-oxo-acetate (601 mg, 4.40 mmol, 493 μL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then at 100° C. for 15 h. The reaction progress was checked using LCMS. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 2 / 1) and further purified by preparative HPLC (column: Boston Uni C18 40*150*5um, mobile phase: [water (0.225% FA)-ACN], B%: 16% to 46%, 7.7 min) to give E60 (250 mg, yield 28%). 1 H NMR(400MHz,CDCl3)δ 4.52(q,2H),2.65(br s,1H),1.67(s,6H),1.45(t,3H);LCMS:m / z 201.1[M+H] + .

[0484] Step 3: Preparation of ethyl 3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-carboxylate (E61)

[0485] To a solution of 3-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazole-5-carboxylate (E60) (200 mg, 999 μmol) in THF (5 mL) and HO (5 mL) was added LiOH.HO (41.9 mg, 999 μmol), and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the aqueous portion was lyophilized in vacuo to give E61 (170 mg), which was used without further purification.

[0486] Intermediates E62, E63, E64, E65, E66, and E67 [ka]

[0487] Step A: Preparation of methyl 6-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (E62) and methyl 6-bromo-7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (E63)

[0488] To a solution of methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 g, 3.92 mmol) in THF (10 mL) was added i-PrMgCl-LiCl (1.3 M, 6.03 mL, 2 equiv.) at −78° C. The reaction mixture was stirred at −78° C. for 15 minutes, and then acetone (1.37 g, 23.5 mmol, 1.7 mL, 6 equiv.) was added dropwise to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hour. LCMS was used to check the reaction progress. The reaction mixture was added dropwise to 10 mL of aqueous NH4Cl solution. Water (30 mL) was added, and the aqueous portion was extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 20:1) to give E62 (320 mg, yield 34%) and E63 (300 mg, yield 23%).

[0489] E62: 1 H NMR(400MHz,CD3OD)δ 8.40-8.54(m,1H),8.14(dd,1H),7.57(dd,1H),7.27(dd,1H),3.88-4.03(m,3H),1.77-1.92(m,6H);LCMS:m / z 235.2[M+H] + .

[0490] E63: 1 H NMR(400MHz,CD3OD)δ 8.46(s,1H),8.02(d,1H),7.76(d,1H),3.93(s,3H),1.95(s,6H);LCMS:m / z 313.0[M+H] + .

[0491] Step B: Preparation of 6-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (E64)

[0492] To a solution of methyl 6-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (E62) (500 mg, 2.13 mmol) in MeOH (3 mL) and HO (1 mL) was added LiOH.HO (116 mg, 2.77 mmol, 1.3 equiv). The reaction mixture was stirred at 40 °C for 12 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated in vacuo to remove MeOH, and water (50 mL) was added. The aqueous portion was extracted with TBME (30 mL), and then the aqueous layer was adjusted to pH 6 by the addition of 0.5 M HCl. The resulting suspension was extracted three times with DCM / MeOH (100 / 10 mL). The combined DCM / MeOH organic layers were dried over NaSO, filtered, and concentrated to dryness to give E64 (420 mg, 89% yield). LCMS: m / z 221.1 [M+H] + .

[0493] Step C: Preparation of 6-bromo-7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (E65)

[0494] To a solution of methyl 6-bromo-7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (E63) (120 mg, 383 μmol) in MeOH (2 mL) and HO (1 mL) was added LiOH.HO (17.69 mg, 422 μmol, 1.1 equiv.), and the mixture was stirred at 40 °C for 12 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated in vacuo to remove MeOH, and water (10 mL) was added. The aqueous portion was extracted with TBME (30 mL), then adjusted to pH 6 by the addition of 0.5 M HCl. The resulting suspension was extracted three times with DCM / MeOH (30 / 3 mL). The combined DCM / MeOH organic layers were dried over NaSO, filtered, and concentrated to dryness to give E65 (100 mg, 87% yield). 1H NMR(400MHz,CD3OD)δ 8.44(s,1H),8.07(d,1H),7.74(d,1H),1.96(s,6H);LCMS:m / z 301.1[M+H] + .

[0495] Step D: Preparation of methyl 7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (E66)

[0496] To a solution of methyl 6-bromo-7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (E63) (450 mg, 1.44 mmol) in MeOH (10 mL) was added Pd / C (100 mg, 10% purity) under N. The resulting mixture was degassed under vacuum and purged with H three times, then the mixture was stirred under H (15 psi) at room temperature for 1 h. The reaction progress was checked using LCMS. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness in vacuo to give E66 (350 mg), which was used without further purification. LCMS: m / z 234.9 [M+H] + .

[0497] Step E: Preparation of 7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (E67)

[0498] To a solution of methyl 7-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (E66) (350 mg, 1.49 mmol) in MeOH (5 mL) and HO (1 mL) was added NaOH (89.64 mg, 2.24 mmol, 1.5 equiv.), and the mixture was stirred at 40 °C for 12 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated in vacuo to remove MeOH, and water (10 mL) was added. The aqueous portion was extracted with TBME (30 mL), then adjusted to pH 6 by the addition of 0.5 M HCl. The resulting suspension was extracted three times with DCM / MeOH (30 / 3 mL). The combined DCM / MeOH organic layers were dried over NaSO, filtered, and concentrated to dryness to give E67 (320 mg), which was used without further purification. LCMS: m / z 220.9 [M+H] + .

[0499] Intermediate E72 via General Scheme 7, Methods C and D [ka]

[0500] Step A: Preparation of methyl 6-vinylpyrazolo[1,5-a]pyridine-3-carboxylate (E68)

[0501] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (8.15 g, 52.9 mmol, 8.98 mL), methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (9 g, 35.3 mmol), KPO (22.47 g, 106 mmol), and Pd(dppf)Cl (1.29 g, 1.76 mmol) in dioxane (80 mL) and HO (40 mL) was stirred at 80 °C under N for 12 h. LCMS was used to check the reaction progress. The reaction mixture was combined with another 1 g batch reaction, and DCM (200 mL) was added. The organic layer was washed with brine (2 × 80 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 4 / 1) to give E68 (6.4 g, yield 80.2%). 1 LCMS:m / z 203.1[M+H] + .

[0502] Step B: Preparation of methyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate (E69)

[0503] To a solution of 6-vinylpyrazolo[1,5-a]pyridine-3-carboxylate (E68) (6.4 g, 31.7 mmol) in THF (80 mL) and HO (80 mL) was added KOsO.2HO (583 mg, 1.58 mmol) and NaIO (16.92 g, 79.1 mmol, 4.38 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. LCMS was used to check the reaction progress. DCM (200 mL) was added to the reaction mixture, and the organic layer was washed with brine (2 × 80 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, DCM / EtOAc = 1 / 0 to 6 / 1) to give E69 (5.9 g, 91.3% yield). 1H NMR(400MHz,CDCl3)δ 9.94(s,1H),8.90-8.98(m,1H),8.48(s,1H),8.18(d,1H),7.80(dd,1H),3.88(s,3H);LCMS:m / z 204.9[M+H] + .

[0504] Step C: Preparation of methyl 6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (E70)

[0505] To a solution of methyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate (E69) (2.4 g, 11.8 mmol) in THF (30 mL) and MeOH (30 mL) was added NaBH (1.78 g, 47.0 mmol) at 0 °C, and the reaction mixture was then stirred at room temperature for 1 h. LCMS was used to check the reaction progress. The reaction mixture was quenched by the addition of saturated aqueous NH Cl (50 mL), and the aqueous portion was extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (40 mL), dried over Na SO , filtered, and concentrated to dryness to give E70 (2.3 g, 94.9% yield). 1 H NMR(400MHz,CDCl3)δ 8.54(s,1H),8.38(s,1H),8.11(d,1H),7.41(dd,1H),4.78(s,2H),3.93(s,3H);LCMS:m / z 207.0[M+H] + .

[0506] Step D: Preparation of methyl 6-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (E71)

[0507] To a solution of methyl 6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (E70) (2.2 g, 10.7 mmol) in THF (50 mL) was added NaH (512 mg, 12.8 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and then MeI (1.82 g, 12.8 mmol, 797 μL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h, and the reaction progress was checked using LCMS. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (40 mL), and the aqueous portion was extracted with DCM (2 × 60 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 5 / 1) to give E71 (1.8 g, yield 76.6%). 1 H NMR(400MHz,CDCl3)δ 8.52(s,1H),8.41(s,1H),8.16(d,1H),7.42(dd,1H),4.53(s,2H),3.94(s,3H),3.46(s,3H);LCMS:m / z 221.1[M+H] + .

[0508] Step E: Preparation of 6-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (E72)

[0509] To a solution of methyl 6-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (E71) (1.8 g, 8.17 mmol) in MeOH (40 mL) and HO (40 mL) was added NaOH (719 mg, 18.0 mmol), and the reaction mixture was stirred at 40 °C for 12 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated to remove MeOH, and then HO (10 mL) was added. The pH of the aqueous mixture was adjusted to approximately 6 by the addition of 0.5 M HCl, and the aqueous mixture was filtered. The precipitate was dried in vacuo to give E72 (1.6 g, 94.9% yield). 1H NMR(400MHz,CDCl3)δ 8.57(s,1H),8.45-8.51(m,1H),8.21(d,1H),7.48(dd,1H),4.55(s,2H),3.48(s,3H);LCMS:m / z 206.7[M+H] + .

[0510] General Scheme 9, Intermediate E78 via Method A [ka]

[0511] Step A: Preparation of 2,6-difluorobenzohydrazide (E73)

[0512] To a solution of methyl 2,6-difluorobenzoate (25 g, 145 mmol) in MeOH (250 mL) was added NHNH.H0 (18.18 g, 363 mmol, 17.7 mL) and the reaction mixture was stirred at 60 °C for 12 h. TLC was used to check the reaction progress. Additional NHNH.H0 (7.27 g, 145 mmol, 7.05 mL) was added and the reaction mixture was stirred at 60 °C for an additional 3 h. The reaction mixture was concentrated in vacuo to give E73 (25 g), which was used without further purification. 1 H NMR (400MHz, CDCl3) δ 7.37 (s, 1H), 6.93 (t, 2H), 3.45-3.89 (m, 2H).

[0513] Step B: Preparation of methyl 2-[2-(2,6-difluorobenzoyl)hydrazino]-2-oxo-acetate (E74)

[0514] To a solution of 2,6-difluorobenzohydrazide (E73) (25 g, 145 mmol) in THF (250 mL) was added methyl 2-chloro-2-oxo-acetate (19.57 g, 160 mmol, 14.7 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 1 h. TLC was used to check the reaction progress. The reaction mixture was filtered. The precipitate was washed with MTBE (800 mL) and then dried in vacuo to give E74 (37 g).1 H NMR (400MHz, DMSO-d6) δ 7.59 (ddd, 2H), 7.21 (t, 1H), 3.83 (s, 2H).

[0515] Step C: Preparation of methyl 5-(2,6-difluorophenyl)-1,3,4-oxadiazole-2-carboxylate (E75)

[0516] To a solution of methyl 2-[2-(2,6-difluorobenzoyl)hydrazino]-2-oxo-acetate (E74) (15 g, 58.1 mmol) in DCM (250 mL) was added EtN (23.52 g, 232 mmol, 32.4 mL) and TosCl (14.40 g, 75.5 mmol) portionwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. The reaction progress was checked using TLC. DCM (100 mL) was added to the reaction mixture, and the organic layer was washed with saturated aqueous NaHCO (100 mL) and water (100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 to 1 / 1) to give E75 (4.3 g, 30.8% yield). 1 H NMR (400MHz, CDCl3) δ 7.61 (tt, 1H), 7.14 (t, 2H), 4.10 (s, 3H).

[0517] Step D: Preparation of 5-(2,6-difluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid (E76)

[0518] To a solution of methyl 5-(2,6-difluorophenyl)-1,3,4-oxadiazole-2-carboxylate (E75) (300 mg, 1.25 mmol) in HO (2 mL) and THF (4 mL) was added LiOH.HO (52.4 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 1 h. LCMS was used to check the reaction progress. The reaction mixture was concentrated in vacuo to give E76 (300 mg), which was used without further purification. LCMS: m / z 226.8 [M+H] +

[0519] Step E: Preparation of 2-(2,6-difluorophenyl)-1,3,4-oxadiazole (E77)

[0520] To a solution of 5-(2,6-difluorophenyl)-1,3,4-oxadiazole-2-carboxylic acid (E76) (4 g, 17.7 mmol) in HO (20 mL) was added HCl (1 M, 35.4 mL), and the reaction mixture was stirred at room temperature for 1 h. LCMS and TLC were used to check the reaction progress. DCM (60 mL) was added to the reaction mixture, and the organic layer was washed with water (20 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 to 1 / 1) to give E77 (1.5 g, 46.6% yield). 1 H NMR(400MHz,CDCl3)δ 8.63(s,1H),7.57(tt,1H),7.12(t,2H);LCMS:m / z 182.8[M+H] + .

[0521] Step F: Preparation of 2-bromo-5-(2,6-difluorophenyl)-1,3,4-oxadiazole (E78)

[0522] To a solution of 2-(2,6-difluorophenyl)-1,3,4-oxadiazole (E77) (1.5 g, 8.24 mmol) in THF (50 mL) was added LiHMDS (1 M, 16.5 mL) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then Br (2.63 g, 16.5 mmol, 849 μL) was added dropwise to the reaction mixture at −78° C. The reaction mixture was stirred at −78° C. for 2 hours. TLC was used to check the reaction progress. Saturated aqueous NH4Cl (100 mL) was added to the reaction mixture, and the aqueous portion was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to give E78 (1.6 g, yield 54.2%). 1H NMR(400MHz,DMSO-d6)δ 7.79(tt,1H),7.41(t,2H);LCMS:m / z 341.2[M+H] + .

[0523] Preparation of Examples 640 and 641 via General Scheme 1, Method C [ka]

[0524] Step 1: Preparation of 4-(pyrazolo[1,5-a]pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine

[0525] A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (C3) (9.2 g, 63.0 mmol), 2-(1H-imidazol-5-yl)ethanamine (15.06 g, 81.8 mmol, 1.3 equiv., 2HCl salt), and K2CO3 (17.40 g, 126 mmol, 2 equiv.) in EtOH (300 mL) was stirred at 80 °C under N2 for 16 h. LCMS was used to check the reaction progress. The reaction mixture was combined with another reaction mixture carried out using 5 g of C3, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM:MeOH=20:1 to 10:1) to give 4-pyrazolo[1,5-a]pyridin-2-yl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (11.4 g). 1 H NMR(400MHz,CD3OD)δ 8.48(d,1H),7.54-7.62(m,2H),7.09-7.29(m,1H),6.82-6.90(m,1H),6.44(s, 1H),5.28(s,1H),3.28(dt,1H),3.04-3.12(m,1H),2.73-2.80(m,2H);LCMS:m / z 240.2(M+H) + .

[0526] Step 2: Preparation of 5-(4-pyrazolo[1,5-a]pyridin-2-yl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carbonyl)oxazole-4-carbonitrile

[0527] To a solution of 4-pyrazolo[1,5-a]pyridin-2-yl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (4 g, 16.7 mmol) and (4-cyanooxazole-5-carbonyl)oxylithium (E35) (3.37 g, 23.4 mmol, 1.4 equiv.) in DMF (90 mL) was added HATU (7.63 g, 20.1 mmol, 1.2 equiv.) and pyridine (3.97 g, 50.2 mmol, 4.1 mL, 3 equiv.). The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using LCMS, and the reaction mixture was stirred at room temperature for an additional 12 hours. The reaction progress was monitored using TLC (DCM:MeOH = 10:1). DCM (300 mL) was added, and the organic portion was washed with saturated NaHCO solution (100 mL) and brine (100 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, eluent of 0–8.5% MeOH / DCM @ 35 mL / min) to give 5-(4-pyrazolo[1,5-a]pyridin-2-yl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carbonyl)oxazole-4-carbonitrile (2.6 g). 1 H NMR(400MHz,CD3OD)δ 8.51(s,1H),8.46(d,1H),7.69(s,1H),7.57-7.65(m,1H),7.17-7.23(m,1H),6.83-6.91(m,2H),6.59-6.72(m,1H),4.40(br d,1H),3.77(br d,1H),3.19(s,1H),2.85(br s,1H);LCMS:m / z 360.2(M+H) + .

[0528] Step 3: SFC separation

[0529] 5-(4-Pyrazolo[1,5-a]pyridin-2-yl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carbonyl)oxazole-4-carbonitrile (2.6 g) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm), mobile phase: [Neu-ETOH], B%: 45% to 45%, min) to give Enantiomer 1 (650 mg, Rt = 1.884 min) and Enantiomer 2 (450 mg, Rt = 2.124 min).

[0530] Enantiomer 1 (Example 640): (S)-5-(4-(pyrazolo[1,5-a]pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)oxazole-4-carbonitrile. 1 H NMR(400MHz,CD3OD)δ 8.52(s,1H),8.46(dd,1H),7.71(s,1H),7.62(br d,1H),7.17-7.26(m,1H),6.85-6.92(m,1.7H),6.48-6.69(m,1.3H),4.77-4.87(m,0.4H),4.40(br d,0.6H),3.79(br s,1H),3.10-3.19(m,1H),2.79-2.91(m,1H);LCMS:m / z 360.1(M+H) + ;SFC:94.1% ee.

[0531] Enantiomer 2 (Example 641): (R)-5-(4-(pyrazolo[1,5-a]pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)oxazole-4-carbonitrile. 1H NMR(400MHz,CD3OD)δ 8.51(s,1H),8.46(dd,1H),7.71(s,1H),7.62(br d,1H),7.13-7.26(m,1H),6.84-6.94(m,1.7H),6.49-6.70(m,1.3H),4.77-4.87(m,0.4H),4.40(br d,0.6H),3.71-3.91(m,1H),3.08-3.19(m,1H),2.79-2.89(m,1H);LCMS:m / z 360.2(M+H) + ;SFC:96.7% ee.

[0532] Preparation of Examples 836 and 837 via General Scheme 1, Method C [ka]

[0533] Step 1: Preparation of (5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)(4-(4-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

[0534] To a solution of 4-[4-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (150 mg, 488 μmol) and 5-(1-methylpyrazol-3-yl)-1,3,4-oxadiazole-2-carboxylic acid (prepared according to General Scheme 9, Method A, starting from 1-methyl-1H-pyrazole-3-carboxylate methyl) (142 mg, 732 μmol) in DMSO (3 mL), pyridine (116 mg, 1.46 mmol, 118 μL) and HATU (241 mg, 635 μmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. LCMS was used to check the reaction progress. The reaction mixture was subjected to preparative HPLC (column: Welch Xtimate C18 150*30mm*5um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN], B%: 27%-57%, 9 min) to give (5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)(4-(4-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, yield 42.4%). LCMS: m / z 484.1 [M+H] + .

[0535] Step 2: SFC separation

[0536] The compound (5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)(4-(4-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 207 μmol) was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm * 50 mm, 10 μm), mobile phase: [0.1% NH3HO EtOH], B%: 50% to 50%, 1 min) to give enantiomer 1 (46.1 mg, 46.1% yield, Rt = 5.268 min) and enantiomer 2 (46.2 mg, 45.6% yield, Rt = 10.218 min).

[0537] Enantiomer 1 (Example 836): (S)-(5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)(4-(4-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone. 1 H NMR(400MHz,CD3OD)δ 8.59-8.76(m,1H),7.81(d,1H),7.74(s,1H),7.53-7.66(m,1H),6.86-7.12(m,3H),6.76-6.84(m,1H),5.08(br dd,1H),4.03(s,3H),3.72-3.84(m,0.6H),3.41(td,0.4H),3.13-3.27(m,0.6H),2.95-3.09(m,0.4H),2.77-2.94(m,1H);L...

Claims

1. Compounds of Formula I: 【Chemical 282】 or a pharma- ceutically acceptable salt thereof, wherein: m is 1 or 2; R １ but, 【Chemistry 283】 and x is 0 to 5; Each R ａ But independently, Halo, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Alkoxy or C １－６ is haloalkoxy; R ２ But, C １－４ Alkyl, optionally substituted C ３－８ cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R ３ But H or C １－６ is alkyl, R ４ But H or C １－６ Is it an alkyl group? Or R ３ and R ４ together with the atoms to which they are attached, C ３－６ Forming a cycloalkyl, R ５ is H or D, R ５Ａ is H or D, L is a bond, carbonyl, optionally substituted C １－６ Alkylene, optionally substituted C １－６ Alkylenecarbonyl, optionally substituted C ２－６ Alkenylenecarbonyl, optionally substituted C １－６ haloalkylenecarbonyl, or an optionally substituted —C(O)NR ｂ (C １－６ alkylene)-, the carbon atom of the carbonyl group being bonded to the N in formula I, R ｂ is H or C １－６ or a pharma- ceutically acceptable salt thereof, wherein:

2. R ５Ａ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

3. R ５Ａ is H; or a pharma- ceutically acceptable salt thereof.

4. The compound is a compound of formula IA: 【Chemical 284】 for example, 【Chemistry 285】 2. The compound of claim 1, wherein:

5. The compound is a compound of formula I-B: 【Chemistry 286】 for example, 【Chemistry 287】 2. The compound of claim 1, wherein:

6. The compound is a compound of formula IC: 【Chemistry 288】 for example, 【Chemical 289】 2. The compound of claim 1, wherein:

7. The compound is a compound of formula ID: 【Chemistry 290】 for example, 【Chemical 291】 2. The compound of claim 1, wherein:

8. The compound is a compound of formula I-E: 【Chemical 292】 for example, 【Chemical 293】 2. The compound of claim 1, wherein:

9. L is a bond, -C(O)-, -C(O)CH ２ -, -C(O)CH ２ CH ２ -, -C(O)CH ２ CH ２ CH ２ -, -C(O)CF ２ -、-C(O)CHF-、-C(O)C(CH ３ ) ２ -、-C(O)CH=CH-、 【Chemical 294】 -C(O)NHCH ２ --, --CH ２ - or -CH ２ CH ２ The compound according to any one of claims 1 to 4, wherein R is -, or a pharma- ceutically acceptable salt thereof.

10. L is a bond, -C(O)-, or C(O)CH ２ - or -C(O)CF ２ The compound according to claim 9, wherein:

11. R ３ and R ４ The compound according to any one of claims 1 to 3, 9, and 10, or a pharma- ceutically acceptable salt thereof, wherein each of is hydrogen.

12. The compound according to any one of claims 1 to 11, wherein m is 1, or a pharma- ceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein m is 2.

14. The compound according to any one of claims 1 to 13, wherein x is 0 or 1, or a pharma- ceutically acceptable salt thereof.

15. R １ but, 【Chemistry 295】 15. The compound according to any one of claims 1 to 14, wherein:

16. R ａ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 15, wherein is halo, such as F, Br, or Cl.

17. R ａ is methyl, ethyl, or isopropyl, １－６ 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

18. R ａ is methoxy or ethoxy, １－６ 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

19. R ａ But, CF ３ or CHF ２ C １－６ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

20. R ａ However, O.C.F. ３ Or OCHF ２ C １－６ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, which is haloalkoxy.

21. R ａ However, C such as cyclopropyl ３－６ 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

22. R ５ The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein

23. R ５ or a pharma- ceutically acceptable salt thereof.

24. R ２ is optionally substituted C ３－８ 24. The compound of any one of claims 1 to 23, which is cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or a pharma- ceutically acceptable salt thereof.

25. R ２ or a pharma- ceutically acceptable salt thereof, each of which is optionally substituted.

25. The compound of claim 24, wherein R is cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, azetidinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiadiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, thiophenyl, isoxazolyl, isothiazolyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]isothiazolyl, furanyl, pyrazinyl, or quinolinyl, each of which is optionally substituted.

26. R ２ or a pharma- ceutically acceptable salt thereof, each of which is unsubstituted.

25. The compound of claim 24, wherein R is cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, azetidinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiadiazolyl, imidazole[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, thiophenyl, isoxazolyl, isothiazolyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]isothiazolyl, furanyl, pyrazinyl, or quinolinyl, each of which is unsubstituted.

27. R ２ azetidin-1-yl, azetidin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2, 4-oxadiazol-5-yl, pyrazolo[1,5-a]pyridin-3-yl, indazol-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,3,4-thiadiazol-2-yl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidine- 2-yl, imidazol[1,5-a]pyridin-1-yl, pyrrolo[1,2-b]pyridazin-5-yl, pyrrolo[1,2-b]pyridazin-6-yl, thiophen-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-3-yl, benzo[d]imidazol-2-yl, benzo[d]oxazo 25. The compound of claim 24, or a pharma- ceutically acceptable salt thereof, wherein the aryl group is benzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, furan-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazin-2-yl, benzo[c]isoxazol-3-yl, or quinolin-3-yl, each of which is optionally substituted.

28. R ２ but, C such as methyl, ethyl, propyl, isopropyl, or tert-butyl; １－６ Alkyl, CH=CH ２ 、CH=CHC(CH ３ ) ２ OH、 or Optionally substituted C such as CH=CH-cyclopropyl ２－６ Alkenyl, halo, such as Br, Cl, or F; C.N., C (CH ３ ) ２ C such as CN １－６ Cyanoalkyl, CF ３ , C.H.F. ２ , C.H. ２ F, CH (CH ３ ) F, C.H. ２ CF ３ , C(CH ３ ) ２ F, C (CH ３ ) F ２ , or C.H. ２ CHF ２ Such as C １－６ Haloalkyl, O.H. Optionally substituted C, such as optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. ３－８ Cycloalkyl, Optionally substituted C alkylenes, such as optionally substituted cyclopropyl(alkylene) or optionally substituted cyclobutyl(alkylene). ３－８ Cycloalkyl(alkylene), Optionally substituted C such as optionally substituted cyclohexenyl ３－８ Cycloalkenyl, optionally substituted aryl, such as optionally substituted phenyl; optionally substituted aryl(alkylene), such as optionally substituted benzyl; optionally substituted heteroaryl, such as optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl; optionally substituted heterocyclyl, such as optionally substituted azetidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted morpholinyl, or optionally substituted 6-azaspiro[2.5]octan-6-yl; optionally substituted heterocyclyl(alkylene), such as optionally substituted morpholinyl(alkylene), piperidinyl(alkylene), optionally substituted piperazinyl(alkylene), or optionally substituted azetidinyl(alkylene); C (CH ３ ) ２ OH, CH(CH ３ )OH, C(CH ３ ) ２ CH ２ O.H., C.H. ２ C (CH ３ ) ２ OH, or CH(CH ２ CH ３ )OH, etc. １－６ Hydroxyalkyl, O.C.F. ３ , O.C.H. ２ CF ３ , or OCH ２ CH ２ CF ３ C １－６ Haloalkoxy, CH ２ O.C.F. ３ C etc. １－６ haloalkoxy(alkylene), C, such as methoxy or ethoxy １－６ Alkoxy, C (CH ３ ) ２ OCH ３ , C.H. ２ OCH ３ , or (CH ２ ) ２ OCH ３ Such as C １－６ Alkoxy (alkylene), CH ２ OCD ３ C etc. １－６ deuterated alkoxy(alkylene); C(=O)CH ３ or CH ２ C(=O)CH ３ Such as C １－６ Alkyl carbonyl, C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl ３－８ cycloalkylsulfonyl, C such as methylsulfonyl, ethylsulfonyl, or propylsulfonyl １－６ Alkylsulfonyl, C (CH ３ ) ２ SO ２ CH ３ C etc. １－６ Alkylsulfonyl(alkylene), (CR ｖ R ｘ ) ｐ N.R. ｙ R ｚ Wherein R ｖ and R ｘ are independently H or C １－６ alkyl, R ｙ and R ｚ However, independently, H, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Alkoxy (alkylene), or C(O)OC １ - ６ alkyl, and p is 0, 1, 2, or 3; ｖ R ｘ ) ｐ N.R. ｙ R ｚ , for example, NH ２ , NHcyclopropyl, NHCH ３ , N(CH ３ ) ２ , C.H. ２ N (CH ３ ) ２ , (CH ２ ) ２ N (CH ３ ) ２ , C.H. ２ N (CH ３ ) (CH ２ CH ３ ), C(CH ３ ) ２ NH (CH ３ ), C(CH ３ ) ２ N (CH ３ ) ２ , C.H. ２ N (CH ３ ) cyclobutyl, or CH ２ N (CH ３ ) (C(O)O tert-butyl), and C(O)NR ｙ２ R ｚ２ Wherein R ｙ２ and R ｚ２ However, independently, H, C １－６ Alkyl, or C ３－６ cycloalkyl, C(O)NR ｙ２ R ｚ２ , for example, C(O)N(CH ３ ) ２ or C(O)NHcyclopropyl; or a pharma- ceutically acceptable salt thereof.

29. R ２ But, Halo, C １－６ 25. The compound of claim 24, or a pharma- ceutically acceptable salt thereof, which is heterocyclyl optionally substituted with one or more of haloalkyl, or optionally substituted heteroaryl.

30. R ２ But, Halo, C １－６ Alkyl, C １－６ C optionally substituted with one or more of haloalkyl, or OH ３－８ 25. The compound of claim 24, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

31. R ２ unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, 【Chemical 296】 31. The compound of claim 30, which is: or a pharma- ceutically acceptable salt thereof.

32. R ２ But halo or C １－６ 25. The compound of claim 24, or a pharma- ceutically acceptable salt thereof, which is aryl optionally substituted with one or more of alkoxy.

33. R ２ 26. The compound of claim 25, wherein is optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl, or a pharma- ceutically acceptable salt thereof.

34. The pyridinyl, pyrimidinyl, or pyrazinyl is halo, C １－６ Haloalkyl, cyano, or NR ｙ R ｚ and R ｙ and R ｚ are independently H or C １－６ 34. The compound of claim 33, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

35. R ２ But, C １－６ Alkyl, C １－６ Cyanoalkyl, C １－６ Haloalkyl, or C １－６ 28. The compound of any one of claims 24, 25, and 27, or a pharma- ceutically acceptable salt thereof, which is heteroaryl substituted with one or more of hydroxyalkyl.

36. R ２ is methyl, ethyl, isopropyl, tert-butyl, C(CH ３ ) ２ CN, CH (CH ３ )OH, C(CH ３ ) ２ OH, C(CH ３ ) ２ CH ２ OH, CH(CH ２ CH ３ ) OH, CH ２ C (CH ３ ) ２ O.H., C.H. ２ F, C.H.F. ２ , C.F. ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , CH(CH ３ ) F, C(CH ３ ) F ２ , or C(CH ３ ) ２ 36. The compound of claim 35, or a pharma- ceutically acceptable salt thereof, substituted with F.

37. R ２ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc. ３－８ Heteroaryl substituted with cycloalkyl, ３－８ Cycloalkyl is halo, such as F, Cl, or Br; OH; CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, or propyl １－６ alkyl; or C such as methoxy, ethoxy, or propoxy. １－６ 30. The compound of any one of claims 24, 25, and 27, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more of alkoxy.

38. R ２ but, 【Chemical 297】 38. The compound of claim 37, or a pharma- ceutically acceptable salt thereof, substituted with:

39. R ２ is heteroaryl substituted with aryl, such as phenyl, wherein the aryl is halo, such as F, Cl, or Br; CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, or propyl １－６ alkyl; or C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－８ 28. The compound of any one of claims 24, 25, and 27, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more of cycloalkyl.

40. R ２ but, 【Chemical 298】 40. The compound of claim 39, or a pharma- ceutically acceptable salt thereof, substituted with:

41. R ２ is heteroaryl substituted with an optionally substituted heteroaryl, said optional substitution being halo, such as F, Cl, or Br; CF ３ , C.H. ２ CHF ２ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl, C such as methyl, ethyl, propyl, or isopropyl １－６ Alkyl, C such as methoxy, ethoxy, or propoxy １－６ Alkoxy, O.C.F. ３ C etc. １－６ Haloalkoxy, C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－８ cycloalkyl, or cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl ３－８ 29. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, which is one or more of: cycloalkylsulfonyl.

42. R ２ is substituted with pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, pyrazin-5-yl, imidazol-4-yl, imidazol-5-yl, pyridazin-3-yl, or pyridazin-4-yl, each of which is optionally substituted, or a pharma- ceutically acceptable salt thereof.

43. R ２ but, 【Chemical 299】 43. The compound of claim 42, or a pharma- ceutically acceptable salt thereof, substituted with:

44. R ２ but, 【Chemistry 300】 43. The compound of claim 42, or a pharma- ceutically acceptable salt thereof, substituted with:

45. R ２ is an optionally substituted heterocyclyl, such as an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted morpholinyl, or an optionally substituted 6-azaspiro[2.5]octan-6-yl, or an optionally substituted heterocyclyl(alkylene), wherein the optional substitutions are halo, such as F, Cl, or Br; O.H. CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl, C such as methyl, ethyl, or propyl １－６ Alkyl, C (CH ３ ) ２ OH or CH(CH ３ )OH and other C １－６ Hydroxyalkyl, C such as methoxy, ethoxy, or propoxy １－６ Alkoxy, C(O)O(C) such as C(O)Omethyl, C(O)Oethyl, C(O)Opropyl, or C(O)Otert-butyl. １－６ alkyl), or C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－８ 28. The compound of any one of claims 24, 25, and 27, or a pharma- ceutically acceptable salt thereof, wherein: R is 0 or 1; and R is 1 or 2.

46. R ２ but, 【Chemistry 301】 46. ​​The compound of claim 45, or a pharma- ceutically acceptable salt thereof, substituted with:

47. R ２ but, 【Chemistry 302】 and During the ceremony, R ６ and R ７ However, independently, H, CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C １－６ Alkoxy (alkylene), C １－６ Haloalkoxy, C １－６ Haloalkoxy(alkylene), C １－６ Deuterated alkoxy (alkylene), halo, (CR ｖ R ｘ ) ｐ N.R. ｙ R ｚ , C(O)NR ｙ２ R ｚ２ , C １－６ Alkylcarbonyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ２－６ Alkenyl, optionally substituted C ３－８ Cycloalkenyl, optionally substituted C ３－８ Cycloalkyl(alkylene), optionally substituted aryl(alkylene), optionally substituted heterocyclyl(alkylene), or C １－６ is alkylsulfonyl, R ８ But, H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkylcarbonyl, C １－６ Hydroxyalkyl, (CR ｖ R ｘ ) ｐ N.R. ｙ R ｚ 、 Optionally substituted C ３－８ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted C ３－８ cycloalkyl(alkylene), R ｖ and R ｘ are independently H or C １－６ is alkyl, R ｙ and R ｚ However, independently, H, C １－６ Alkyl, C １－６ Alkoxy (alkylene), or C ３－６ is cycloalkyl, R ｙ２ and R ｚ２ However, independently, H, C １－６ Alkyl, or C ３－６ is cycloalkyl, The compound according to any one of claims 1 to 23, wherein p is 0, 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

48. R ６ , R ７ , and R ８ or a pharma- ceutically acceptable salt thereof.

49. R ６ is methyl, ethyl, isopropyl, or tert-butyl, etc. １－６ Alkyl, CF ３ , C.H.F. ２ , C.H. ２ F, C.H. ２ CF ３ , CH(CH ３ ) F, C(CH ３ ) F ２ , or C(CH ３ ) ２ C such as F １－６ Haloalkyl, C(CH ３ ) ２ C such as CN １－６ Cyanoalkyl, or C(CH ３ ) ２ OH, CH(CH ３ )OH, CH(CH ２ CH ３ ) OH, CH ２ C (CH ３ ) ２ OH or C(CH ３ ) ２ CH ２ C such as OH １－６ 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, which is hydroxyalkyl.

50. R ６ is halo, such as F, Cl, or Br; OH; CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, or propyl １－６ alkyl; or C such as methoxy, ethoxy, or propoxy. １－６ C, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with one or more of alkoxy; ３－６ 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

51. R ６ but, 【Chemistry 303】 or a pharma- ceutically acceptable salt thereof.

52. R ６ is halo, such as F, Cl, or Br; CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, or propyl １－６ alkyl; or C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－６ 48. The compound of claim 47, which is aryl, such as phenyl, optionally substituted with one or more of cycloalkyl; or a pharma- ceutically acceptable salt thereof.

53. R ６ but, 【Chemistry 304】 or a pharma- ceutically acceptable salt thereof.

54. R ６ is halo, such as F, Cl, or Br; CF ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, propyl, or isopropyl １－６ Alkyl; C such as methoxy, ethoxy, or propoxy １－６ Alkoxy; OCF ３ C etc. １－６ Haloalkoxy; C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－６ cycloalkyl; or C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl ３－６ 48. The compound of claim 47, which is heteroaryl, such as pyridinyl, pyrazolyl, pyrazinyl, pyridazinyl, imidazolyl, or pyrimidinyl, substituted with one or more of cycloalkylsulfonyl; or a pharma- ceutically acceptable salt thereof.

55. 55. The compound of claim 54, or a pharma- ceutically acceptable salt thereof, wherein said heteroaryl is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, imidazol-4-yl, imidazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, pyrazin-5-yl, pyridazin-3-yl, or pyridazin-4-yl, each of which is optionally substituted.

56. R ６ but, 【Chemistry 305】 56. The compound of claim 55, which is: or a pharma- ceutically acceptable salt thereof.

57. R ６ but, 【Chemistry 306】 56. The compound of claim 55, which is: or a pharma- ceutically acceptable salt thereof.

58. R ６ heterocyclyl, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, or heterocyclyl(alkylene), heterocyclyl and heterocyclyl(alkylene) groups each being halo, such as F, Cl, or Br; CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, or propyl １－６ Alkyl; C(CH ３ ) ２ C such as OH １－６ Hydroxyalkyl; C such as methoxy, ethoxy, or propoxy １－６ Alkoxy; C(O)O(C) such as C(O)Omethyl, C(O)Oethyl, C(O)Opropyl, or C(O)Otert-butyl １－６ alkyl); or C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－６ 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more cycloalkyl.

59. R ６ but, 【Chemistry 307】 or a pharma- ceutically acceptable salt thereof.

60. R ７ However, C such as H, CN, and methyl １－６ Alkyl, CF ３ , C.H. ２ F, C.H.F. ２ , C.F. ２ (CH ３ ), or C.H. ２ CHF ２ C etc. １－６ haloalkyl, halo such as Br or Cl, C such as cyclopropyl, phenyl, or pyridinyl ３－８ 60. The compound of any one of claims 47 to 59, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

61. R ２ but, 【Chemistry 308】 where: R ６ is H, methyl or tert-butyl, etc. １－６ Alkyl, C(CH ３ ) ２ C such as F １－６ Haloalkyl, C(CH ３ ) ２ C such as CN １－６ Cyanoalkyl, C(CH ３ ) ２ OH or CH(CH ３ )OH and other C １－６ Hydroxyalkyl, 【Chemistry 309】 Optionally substituted C such as ３－６ Cycloalkyl, 【Chemistry 310】 and optionally substituted heteroaryl such as R ７ However, C such as H, CN, and methyl １－６ Alkyl, CHF ２ Or CF ３ C etc. １－６ haloalkyl, halo such as Br or Cl, or C such as cyclopropyl ３－６ 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

62. The optionally substituted heteroaryl may include one or more C alkyl groups, such as methyl, ethyl, or isopropyl. １－６ 62. The compound of claim 61, or a pharma- ceutically acceptable salt thereof, which is substituted with alkyl.

63. The optionally substituted C ３－６ 62. The compound of claim 61, or a pharma- ceutically acceptable salt thereof, wherein cycloalkyl is substituted with one or more OH.

64. R ２ but, 【Chemistry 311】 where: R ６ H, tert-butyl, etc. １－６ Alkyl, C(CH ３ ) ２ F or C(CH ３ ) F ２ C etc. １－６ Haloalkyl, C(CH ３ ) ２ OH or CH(CH ３ )OH and other C １－６ is hydroxyalkyl, R ７ is H; or a pharma- ceutically acceptable salt thereof.

65. R ２ but, 【Chemistry 312】 where: R ６ is H, methyl, isopropyl, or tert-butyl, etc. １－６ Alkyl, CF ３ , C.H.F. ２ , C(CH ３ ) F ２ , or C(CH ３ ) ２ C such as F １－６ Haloalkyl, C(CH ３ ) ２ OH or CH(CH ３ )OH and other C １－６ Hydroxyalkyl, 【Chemistry 313】 Optionally substituted C such as ３－６ Cycloalkyl, 【Chemical 314】 Optionally substituted aryl such as 【Chemistry 315】 or 【Chemistry 316】 or a pharma- ceutically acceptable salt thereof.

66. The optionally substituted heteroaryl is a C aryl such as methyl, ethyl, or isopropyl. １－６ Alkyl, CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ haloalkyl, halo such as F, methoxy, ethoxy, or propoxy, etc. １－６ C such as alkoxy, cyclopropyl or cyclobutyl ３－６ Cycloalkyl, or C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl ３－６ 66. The compound of claim 65, or a pharma- ceutically acceptable salt thereof, substituted with one or more of: cycloalkylsulfonyl.

67. The optionally substituted C ３－６ Cycloalkyl and optionally substituted heterocyclyl are each selected from halo, such as F, or C, such as methyl. １－６ 66. The compound of claim 65, or a pharma- ceutically acceptable salt thereof, substituted with one or more of alkyl.

68. The optionally substituted aryl is halo such as F, C such as methyl, １－６ Alkyl, or CF ３ C etc. １－６ 66. The compound of claim 65, or a pharma- ceutically acceptable salt thereof, substituted with one or more of haloalkyl.

69. R ２ but, 【Chemistry 317】 and During the ceremony, R ６ and R ７ are independently H, halo such as Cl, C such as methyl １－６ Alkyl, CHF ２ Or CF ３ C etc. １－６ Haloalkyl, or NH ２ NR etc. ｙ R ｚ and R ８ is H, methyl or isopropyl, etc. １－６ Alkyl, CHF ２ , C.H. ２ CF ３ , or C.F. ３ C etc. １－６ Haloalkyl, cyclopropyl, etc. ３－６ 48. The compound of claim 47, which is cycloalkyl, or heteroaryl, such as pyridinyl, or a pharma- ceutically acceptable salt thereof.

70. R ２ but, 【Chemistry 318】 where: R ６ However, H, methyl, etc. １－６ Alkyl, halo such as Cl, CHF ２ Or CF ３ C etc. １－６ haloalkyl, or cyclopropyl, etc. ３－６ is cycloalkyl, R ８ is H or C such as methyl １－６ 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

71. R ６ and R ７ or a pharma- ceutically acceptable salt thereof.

72. R ２ but, 【Chemical 319】 and During the ceremony, W is S or NR １５ and W １ is S, O, or NR １５ and R １０ , R １１ , R １２ , R １３ , and R １４ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkoxy (alkylene), C １－６ Hydroxyalkyl, C １－６ Haloalkoxy, C １－６ Haloalkoxy(alkylene), C ２－６ Alkenyl, CN, halo, (CR ｖ R ｘ ) ｐ N.R. ｙ R ｚ , C(O)NR ｙ２ R ｚ２ , optionally substituted C ３－８ cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl(alkylene), optionally substituted aryl, or optionally substituted heteroaryl; R ｖ and R ｘ are independently H or C １－６ is alkyl, R ｙ and R ｚ However, independently, H, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Alkoxy (alkylene), or C(O)OC １ - ６ is alkyl, R ｙ２ and R ｚ２ However, independently, H, C １－６ Alkyl, or C ３－６ is cycloalkyl, p is 0, 1, 2, or 3; R １５ is H or C １－６ 24. The compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, which is alkyl.

73. R １０ , R １１ , R １２ , R １３ , and R １４ or a pharma- ceutically acceptable salt thereof.

74. R １０ , R １１ , R １２ , and R １３ or a pharma- ceutically acceptable salt thereof.

75. R ２ but, 【Chemistry 320】 where: R １０ , R １１ , R １２ , R １３ , and R １４ are independently H, methyl, etc. １－６ C such as alkyl, cyclopropyl, etc. ３－６ Cycloalkyl, methoxy, etc. １－６ Alkoxy, CH ２ OCH ３ Or (CH ２ ) ２ OCH ３ C etc. １－６ Alkoxy (alkylene), 【Chemistry 321】 Optionally substituted heterocyclyl such as 【Chemistry 322】 Optionally substituted heterocyclyl(alkylene), such as 【Chemistry 323】 or N(CH ３ ) ２ , C.H. ２ N (CH ３ ) ２ , or C.H. ２ CH ２ N (CH ３ ) ２ (CR ｖ R ｘ ) ｐ N.R. ｙ R ｚ and R ｖ and R ｘ are independently H or C １－６ is alkyl, R ｙ and R ｚ are independently H, methyl or ethyl, １－６ C such as alkyl, cyclobutyl, etc. ３－６ Cycloalkyl or C(O)OC such as C(O)O-t-butyl １ - ６ is alkyl, 73. The compound of claim 72, wherein p is 0, 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

76. The optionally substituted heterocyclyl and the optionally substituted heterocyclyl(alkylene) are each selected from halo, such as F, Cl, or Br; ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ Haloalkyl; C such as methyl, ethyl, or propyl １－６ Alkyl; OH; C(CH ３ ) ２ C such as OH １－６ C such as hydroxyalkyl, methoxy, ethoxy, or propoxy １－６ alkoxy; or C such as cyclopropyl, cyclobutyl, or cyclopentyl ３－６ 76. The compound of claim 75, or a pharma- ceutically acceptable salt thereof, substituted with one or more of cycloalkyl.

77. The optionally substituted heterocyclyl is 【Chemical 324】 76. The compound of claim 75, which is: or a pharma- ceutically acceptable salt thereof.

78. The optionally substituted heteroaryl is halo, such as F, Cl, or Br; CF ３ , C.H. ２ CF ３ , or CHF ２ C etc. １－６ haloalkyl; or C such as methyl, ethyl, propyl, or isopropyl. １－６ 76. The compound of claim 75, or a pharma- ceutically acceptable salt thereof, substituted with one or more of alkyl.

79. 79. The compound of claim 78, or a pharma- ceutically acceptable salt thereof, wherein said optionally substituted heteroaryl is pyrazolyl substituted with one methyl.

80. R １０ , R １３ , and R １４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 75 to 79, wherein each is hydrogen.

81. R １０ , R １１ , R １３ , and R １４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 75 to 79, wherein each is hydrogen.

82. 82. The compound of any one of claims 1 to 81, or a pharma- ceutically acceptable salt thereof, which is an S-enantiomer.

83. 2. The compound of claim 1, which is a compound of Table 1, or a pharma- ceutically acceptable salt thereof.

84. 84. The compound of claim 83, or a pharma- ceutically acceptable salt thereof, which is an S-enantiomer.

85. 85. A pharmaceutical composition comprising a compound according to any one of claims 1 to 84, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

86. 86. The pharmaceutical composition of claim 85, further comprising an additional therapeutic agent.

87. 85. A method for stabilizing a mutant PAH protein comprising contacting the protein with a compound of any one of claims 1 to 84, or a pharma- ceutically acceptable salt thereof.

88. 88. The method of claim 87, wherein the mutant PAH protein comprises at least one of R408W, R261Q, R243Q, Y414C, L48S, A403V, ​​I65T, R241C, L348V, R408Q, or V388M mutations.

89. 88. The method of claim 87, wherein the mutant PAH protein comprises at least one of R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutations.

90. 88. The method of claim 87, wherein the mutant PAH protein comprises at least one R408W mutation.

91. 88. The method of claim 87, wherein the mutant PAH protein comprises two R408W mutations.

92. 85. A method for reducing blood phenylalanine levels in a subject suffering from phenylketonuria, comprising administering a compound according to any one of claims 1 to 84 or a pharma- ceutically acceptable salt thereof.

93. 93. The method of claim 92, wherein the blood phenylalanine concentration is reduced to a concentration of about 600 μM or less.

94. 94. The method of claim 93, wherein the blood phenylalanine concentration is reduced to a concentration of about 360 μM or less.

95. 95. The method of any one of claims 92-94, wherein the subject has a blood phenylalanine concentration of greater than about 600 μM prior to administration of the compound.

96. 95. The method of any one of claims 92-94, wherein the subject has a blood phenylalanine concentration of greater than about 1200 μM prior to administration of the compound.

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